Headache in Children and Adolescents.

OBJECTIVE: This article reviews the assessment of children and adolescents presenting with headache, provides an overview of primary headache disorders, and reviews evidence-based management of headache in this age group. LATEST DEVELOPMENTS: In the last few years, new epidemiological data have shed light on less common pediatric headache disorders (eg, pediatric trigeminal autonomic cephalalgias) and psychosocial risk factors associated with primary headache disorders in children and adolescents. There has also recently been a substantial increase in interventions that target the calcitonin gene-related peptide pathway and that treat primary headache disorders using noninvasive neuromodulation. Although these interventions have primarily been studied in adults, there is emerging evidence of their use in the pediatric population. ESSENTIAL POINTS: Primary headache disorders are very common in youth, and the most commonly encountered headache diagnosis in neurology practice is migraine, which affects approximately 10% of children and adolescents. Diagnosing and effectively treating primary headache disorders before adulthood may have a sustained impact on the patient by improving long-term headache and mental health outcomes, thereby significantly reducing the burden of disability over time. There are several available and emerging acute and preventive interventions for youth with primary headache disorders, and treatment decisions should be made in the context of available evidence using a shared decision-making approach.

Parent Anxiety, Depression, Protective Responses, and Parenting Stress in the Context of Parent and Child Chronic Pain: A Daily Diary Study of Parent Variability.

Parents with (vs without) chronic pain report poorer psychosocial functioning (eg, worse mental health, parenting difficulties), which has been linked to poorer child outcomes (eg, child pain). However, emerging research suggests that individuals vary in their functioning from day-to-day, particularly those with chronic pain. This study used daily diaries to compare parents with (versus without) chronic pain on variability in their anxiety, mood, protective responses, and parenting stress. We also examined parent chronic pain status as a moderator of the associations between parent variability and youth daily pain and interference. Participants were 76 youth with chronic pain (Mage = 14.26; 71.1% female) and one of their parents (89.5% mothers; n = 38 or 50.0% endorsing chronic pain). Parents and youth completed self-report questionnaires and 7 days of diaries. Parent variability was calculated to reflect the frequency and size of day-to-day changes. Multilevel models revealed that parents with (vs without) chronic pain were significantly more variable in their parenting stress, but not in their anxiety, mood, or protective responses. Contrary to hypotheses, parent variability was not significantly related to youth daily pain intensity or interference and parent chronic pain did not moderate any associations. Instead, mean levels of parent anxiety, protective responses, and parenting stress across the week significantly predicted youth daily pain interference. Findings suggest that while variability was observed among parents (with and without chronic pain) of youth with chronic pain, it did not significantly predict youth's daily pain-related functioning. Further research is needed to confirm these initial findings. PERSPECTIVE: Parents with chronic pain have expressed concerns that the variable nature of their pain negatively impacts their children. Our results found that parents (with and without chronic pain) were variable in their anxiety, mood, protective responses, and parenting stress, but this variability did not significantly predict youth's chronic pain-related functioning.

Lifestyle Factors Associated With Frequent Recurrent Headaches in Children and Adolescents: A Canadian Population-Based Study.

BACKGROUND AND OBJECTIVES: Lifestyle behaviors have been postulated to affect headache frequency in youth and are often the primary target of self-management recommendations. Our study aimed to assess the association between various lifestyle factors and frequent recurrent headaches in children and youth. METHODS: Children and adolescents aged 5-17 years were enrolled in a large cross-sectional Canadian population-based health survey, completed on January 31, 2019. Headache frequency was dichotomized into "approximately once/week or less" or ">once/week" (defined as frequent recurrent headaches). The association between frequent headaches and meal schedules, screen exposure, physical activity, chronotype, and frequent substance use/exposure (alcohol, cigarettes, electronic cigarettes, and cannabis) was assessed using both unadjusted logistic regression models and models adjusted for age/sex. Fully adjusted models examined the odds of frequent headaches according to all exposures. Survey design effects were accounted for using bootstrap replicate weighting. RESULTS: There were an estimated nweighted = 4,978,370 eligible participants in the population. The mean age was 10.9 years (95% CI 10.9-11.0); 48.8% were female; 6.1% had frequent headaches. Frequent headaches were associated with older age (odds ratio [OR] = 1.31, 95% CI 1.28-1.34, p < 0.001) and female sex (OR = 2.39, 95% CI 2.08-2.75, p < 0.001). In models adjusted for age/sex, the odds of frequent headaches decreased with meal regularity (adjusted OR [aOR] = 0.90, 95% CI 0.89-0.92, p < 0.001) and increased with later chronotype (aOR = 1.10, 95% CI 1.05-1.15, p < 0.001) and excess screen exposure (≥21 hours vs none in past week: aOR = 2.97, 95% CI 1.53-5.77, p = 0.001); there was no significant association with reported physical activity (aOR = 0.95, 95% CI 0.67-1.34, p = 0.77). In 12- to 17-year-olds, frequent headaches were associated with frequent alcohol use (≥1/wk vs never: aOR = 3.50, 95% CI 2.18-5.62, p < 0.001), binge drinking (≥5 times in past month vs never: aOR = 5.52, 95% CI 2.95-10.32, p < 0.001), smoking cigarettes (daily vs never: aOR = 3.81, 95% CI 1.91-7.62, p < 0.001), using e-cigarettes (daily vs never: aOR = 3.10, 95% CI 2.29-4.20, p < 0.001), and cannabis use (daily vs never: aOR = 3.59, 95% CI 2.0-6.45, p < 0.001). In the entire sample, daily exposure to smoking inside the house was associated with frequent headaches (aOR = 2.00, 95% CI 1.23-3.27, p = 0.005). DISCUSSION: Several lifestyle behaviors were associated with frequent headaches in children and youth, such as meal irregularity, late chronotype, prolonged screen exposure, and frequent substance use/exposure, suggesting that these are potential modifiable risk factors to target in this population.

The association between parent mental health and pediatric chronic pain: a systematic review and meta-analysis.

ABSTRACT: Mental health problems are common among parents of children with chronic pain and associated with worse outcomes for the child with chronic pain. However, the effect sizes of these associations between parent mental health and pediatric chronic pain vary widely across studies. The aim of this systematic review and meta-analysis was to generate pooled estimates of the (1) prevalence of mental health problems among parents of children with chronic pain and (2) associations between parent mental health and the (2a) presence of child chronic pain and (2b) functioning of children with chronic pain. Embase, MEDLINE, PsycINFO, Web of Science, and CINAHL were searched up to November 2022. Observational studies that examined symptoms or diagnoses of parent anxiety, depression, or general distress and the presence of child chronic pain and/or related functioning were included. From 32,848 records, 2 coders identified 49 studies to include in random-effects meta-analyses. The results revealed that mental health problems among parents of children with chronic pain were common (anxiety: 28.8% [95% CI 20.3-39.1]; depression: 20.0% [15.7-25.2]; general distress: 32.4% [22.7-44.0]). Poorer parent mental health was significantly associated with the presence of chronic pain (anxiety: OR = 1.91 [1.51-2.41]; depression: OR = 1.90 [1.51-2.38]; general distress: OR = 1.74 [1.47-2.05]) and worse related functioning (ie, pain intensity, physical functioning, anxiety and depression symptoms; r s = 0.10-0.25, all P s < 0.05) in children. Moderator analyses were generally nonsignificant or could not be conducted because of insufficient data. Findings support the importance of addressing parent mental health in the prevention and treatment of pediatric chronic pain.

Co-designing clinical trials alongside youth with chronic pain.

Youth have a right to participate in research that will inform the care that they receive. Engagement with children and young people has been shown to improve rates of enrollment and retention in clinical trials as well as reduce research waste. The aim of the study is to gain practical insight on the design of trials specifically on (1) recruitment and retention preferences, (2) potential barriers to research, and (3) study design optimization. Based on this youth engagement, we will co-design two clinical trials in headaches with youth. Two recruitment strategies were used to recruit 16 youth from across Canada (aged 15-18 years) from an existing youth group, the KidsCan Young Persons' Research Advisory Group (YPRAG) and a new youth group in collaboration with Solutions for Kids in Pain (SKIP). Four virtual, semi-structured discussion groups were held between April and December 2020, which included pre-circulated materials and utilized two distinct upcoming planned trials as examples for specific methods feedback. Individual engagement evaluations were completed following the final group session using the Public and Patient Engagement Evaluation Tool. Descriptive results were shared with participants prior to publication to ensure appropriate interpretation. The discussion was centred around three themes: recruitment and retention preferences, potential barriers to participation, and study design optimization. Youth indicated that they would prefer to be contacted for a potential study directly by their physician (not over social media), that they would like to develop rapport with study staff, and that one of the barriers to participation is the time commitment. The youth also provided feedback on the design of the clinical trial including outcome measurement tools, data collection, and engagement methods. Feedback on the virtual format of the engagement events indicated that participants appreciated the ease of the online discussion and that the open-ended discussion allowed for easy exchange of ideas. They felt that despite a gender imbalance (towards females) it was an overall inclusive environment. All participants reported believing that their engagement will make a difference to the work of the research team in designing the clinical trials. Perspectives from a diverse group of youth meaningfully improved the design and conduct of two clinical trials for headaches in children. This study provides a framework for future researchers to engage youth in the co-design of clinical trials using online engagement sessions.

Impact of monthly headache days on migraine-related quality of life: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study.

OBJECTIVE: To characterize the direct impact of monthly headache days (MHDs) on health-related quality of life (HRQoL) in people with migraine and the potential mediating effects of anxiety, depression, and allodynia. BACKGROUND: Although the general relationship between increased migraine frequency (i.e., MHDs) and reduced HRQoL is well established, the degree to which reduced HRQoL is due to a direct effect of increased MHDs or attributable to mediating factors remains uncertain. METHODS: Cross-sectional baseline data from participants with migraine who completed the Core and Comorbidities/Endophenotypes modules in the 2012-2013 US Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a longitudinal web-based survey study, were analyzed. The potential contribution of depression, anxiety, and/or allodynia to the observed effects of MHDs on HRQoL as measured by the Migraine-Specific Quality-of-Life Questionnaire version 2.1 (MSQ) was evaluated. RESULTS: A total of 12,715 respondents were included in the analyses. The MSQ domain scores demonstrated progressive declines with increasing MHD categories (B = -1.23 to -0.60; p < 0.001). The observed HRQoL decrements associated with increasing MHDs were partially mediated by the presence of depression, anxiety, and allodynia. The MHD values predicted 24.0%-32.4% of the observed variation in the MSQ domains. Depression mediated 15.2%-24.3%, allodynia mediated 9.6%-16.1%, and anxiety mediated 2.3%-6.0% of the observed MHD effects on the MSQ. CONCLUSIONS: Increased MHD values were associated with lower MSQ scores; the impact of MHDs on the MSQ domain scores was partially mediated by the presence of depression, anxiety, and allodynia. MHDs remain the predominant driver of the MSQ variation; moreover, most of the variation in the MSQ remains unexplained by the variables we analyzed. Future longitudinal analyses and studies may help clarify the contribution of MHDs, comorbidities, and other factors to changes in HRQoL.

Beyond the Guidelines: A Narrative Review of Treatments on the Horizon for Migraine in Children and Adolescents.

Migraine is common in children and adolescents and can cause significant disability. There are relatively limited evidence-based treatment options available, especially when compared with treatment of migraine in adults. The Pediatric Research Equity Act requires the study of a new drug or biologic in pediatric populations. As such it is mandatory that the newest migraine treatment options available for adults be evaluated in children and adolescents. It will take years before results from clinical trials in pediatric patients become available. In the meantime, there is eagerness among clinicians to seek out the existing evidence that may help provide clarity on utilization of the newer migraine therapies in children and adolescents because many of the currently available, guideline-recommended treatments do not provide benefit for all patients. In this narrative review, the literature regarding onabotulinumtoxinA, neuromodulatory devices, calcitonin gene-related peptide (CGRP) monoclonal antibodies, 5-hydroxytryptamine (1F) agonists (i.e., ditans), and CGRP small-molecule receptor antagonists (i.e., gepants) for the treatment of migraine in children and adolescents will be summarized.

Association Between Peer Victimization, Gender Diversity, Mental Health, and Recurrent Headaches in Adolescents: A Canadian Population-Based Study.

BACKGROUND AND OBJECTIVES: It is unknown whether bullying and gender diversity are associated with increased headache frequency in adolescents. Our study aimed to assess the association between peer victimization, gender diversity, and frequent recurrent headaches in adolescents, while controlling for age, sex, socioeconomic status, and potential confounders (mood and anxiety disorders, suicidality). METHODS: This was a cross-sectional observational study of adolescents aged 12-17 years using data from a Canadian population-based health survey. Headache frequency was dichotomized into "≤once/wk" or ">once/wk" (i.e., frequent recurrent headaches). Logistic regression was used to quantify the association between frequent peer victimization (overt or relational), gender diversity (female sex at birth + male gender, male sex at birth + female gender, or gender diverse), mood/anxiety disorder, suicidality, and the odds of frequent recurrent headaches. The fully adjusted multivariable logistic regression model included all exposures and was controlled for age, sex, and socioeconomic status. Bootstrap replicate weighting was used to account for survey design effects. RESULTS: There were an estimated 2,268,840 eligible participants (weighted sample size) (mean age = 14.4 years, 48.8% female, 0.5% gender diverse), and 11.2% reported frequent recurrent headaches. Frequent recurrent headaches were associated with older age (odds ratio [OR] = 1.26 per year of age, 95% CI 1.20-1.31), female sex (OR = 2.89, 95% CI 2.47-3.37), and being gender diverse (OR = 3.30, 95% CI 1.64-6.63, adjusted for age/sex). Youth with frequent headaches had higher odds of experiencing both overt and relational bullying compared with peers (OR = 2.69, 95% CI 2.31-3.14, and OR = 3.03, 95% CI 2.58-3.54, adjusted for age/sex). In the fully adjusted model, frequent headaches were no longer associated with gender diversity (OR = 1.53, 95% CI 0.63-3.69) but were still associated with frequent overt and relational peer victimization (OR = 1.82, 95% CI 1.41-2.34, and OR = 1.54, 95% CI 1.17-2.03, respectively), suicidality (OR = 1.83, 95% CI 1.44-2.32), and having a mood or anxiety disorder (OR = 1.50, 95% CI 1.01-2.21, and OR = 1.74, 95% CI 1.24-2.45, respectively). In a model adjusted for age, sex, and mood/anxiety disorders, the risk of suicidality increased incrementally with headache frequency. DISCUSSION: Peer victimization and suicidality may be associated with higher headache frequency in adolescents with headaches, independently of mood and anxiety symptoms. Gender-diverse adolescents may have a higher risk of experiencing frequent headaches when compared with cisgender peers, and this may be explained by associated psychosocial factors (anxiety, depression, suicidality, and peer victimization).

Variation in Endpoints in FDA Medication Approvals: A Review of Acute and Preventive Migraine Medications.

BACKGROUND AND OBJECTIVE: To assess the characteristics and extent of variation of the endpoints used in trials supporting the US Food and Drug Administration (FDA) approval of medications treating migraine. METHODS: Using the Drugs@FDA online database, we identified novel prescription medications approved by the FDA between January 2001 and September 2022, for migraine with or without aura, for both acute and preventive treatment, and for episodic and chronic presentations. For each medication, we used the most recent FDA-approved labeling to identify indication, mechanism of action, mode of administration, manufacturer, approval year, number of pivotal trials, trial design, and primary endpoints. RESULTS: Sixteen FDA-approved medications for the acute or preventive treatment of migraine were supported by 45 pivotal trials. There were 5 primary endpoint types: (1) change in mean monthly migraine days from baseline; (2) change in mean monthly migraine attacks from baseline; (3) change in mean monthly headache days from baseline; (4) mild to no pain After 2 hours; (5) pain free at 2 hours. There were 3 combinations of coprimary endpoints: (1) Headache Pain Free at 2 Hours and Most Bothersome Symptom Free at 2 Hours; (2) Pain Free at 2 Hours and Sustained Pain Free from 2-24 Hours Postdose; (3) Pain Free at 2 Hours and 2-24 Hours Sustained Pain Free and 2-Hour Pain Relief. Of the 8 preventive migraine medications, the timing of endpoint measurement included the full double-blind period, segments of the double-blind period, and the final month of the double-blind period. DISCUSSION: Migraine medication trial endpoints were inconsistent within the same indication (episodic or chronic), mechanistic class, and route of administration, frustrating direct comparison among these medications. Furthermore, inconsistent definitions for the indications "episodic" and "chronic" migraine were also observed. Consistent endpoint selection for medications approved for preventive and acute migraine treatment would enhance the ability of patients, physicians, and payers to make informed choices among these medications.

Managing and Preventing Migraine in the Emergency Department: A Review.

Migraine is a leading cause of disability worldwide, and acute migraine attacks are a common reason for patients to seek care in the emergency department (ED). There have been recent advancements in the care of patients with migraine, specifically emerging evidence for nerve blocks and new pharmacological classes of medications like gepants and ditans. This article serves as a comprehensive review of migraine in the ED, including diagnosis and management of acute complications of migraine (eg, status migrainosus, migrainous infarct, persistent aura without infarction, and aura-triggered seizure) and use of evidence-based migraine-specific treatments in the ED. It highlights the role of migraine preventive medications and provides a framework for emergency physicians to prescribe them to eligible patients. Finally, it evaluates the evidence for nerve blocks in the treatment of migraine and introduces the possible role of gepants and ditans in the care of patients with migraine in the ED.

Engaging youth and parents in clinical pediatric research: A case-based example.

Background: Youth and parent engagement is a key component of clinical research. There are many ways to actively and meaningfully engage youth and parents as integral members of research teams, for example, through ad-hoc committees, advisory councils, or as co-leads on projects. When youth and parents are actively and meaningfully engaged in research projects, they share knowledge from their lived experiences to improve the quality and relevance of research. Methods: We describe a case-based example of engaging youth and parent research partners when co-designing a questionnaire to assess preferences for pediatric headache treatments, from both a researcher and youth/parent perspective. We also summarize best practices in patient and family engagement from the literature and pertinent guidelines to assist researchers with integrating patient and family engagement into their studies. Results: As researchers, we felt that the integration of a youth and parent engagement plan into our study significantly altered and strengthened questionnaire content validity. We encountered challenges throughout the process and detailed these experiences to help educate others about challenge mitigation and best practices in youth and parent engagement. As youth and parent partners, we felt that engaging in the process of questionnaire development was an exciting and empowering opportunity, and that our feedback was valued and integrated. Conclusions: By sharing our experience, we hope to catalyze thought and discussion around the importance of youth and parent engagement in pediatric research, with the goal of stimulating more appropriate, relevant, and high-quality pediatric research and clinical care in the future.

Longitudinal trajectories of posttraumatic headache after pediatric mild traumatic brain injury.

OBJECTIVE: This prospective, longitudinal cohort study examined the trajectory, classification, and features of posttraumatic headache after pediatric mild traumatic brain injury. METHODS: Children (N = 213; ages 8.00 to 16.99 years) were recruited from two pediatric emergency departments <24 hours of sustaining a mild traumatic brain injury or mild orthopedic injury. At 10 days, three months, and six months postinjury, parents completed a standardized questionnaire that was used to classify premorbid and posttraumatic headache as migraine, tension-type headache, or not otherwise classified. Multilevel mixed effects models were used to examine posttraumatic headache rate, severity, frequency, and duration in relation to group, time postinjury, and premorbid headache, controlling for age, sex, and site. RESULTS: PTH risk was greater after mild traumatic brain injury than mild orthopedic injury at 10 days (odds ratio = 197.41, p < .001) and three months postinjury (odds ratio = 3.50, p = .030), especially in children without premorbid headache. Posttraumatic headache was more frequent after mild traumatic brain injury than mild orthopedic injury, ß (95% confidence interval) = 0.80 (0.05, 1.55). Groups did not differ in other examined headache features and classification any time postinjury. CONCLUSIONS: Posttraumatic headache risk increases after mild traumatic brain injury relative to mild orthopedic injury for approximately three months postinjury, but is not clearly associated with a distinct phenotype.

Anxiety and Depressive Symptoms and Disorders in Children and Adolescents With Migraine: A Systematic Review and Meta-analysis.

Importance: Though it is presumed that children and adolescents with migraine are at risk of internalizing symptoms and disorders, high-level summative evidence to support this clinical belief is lacking. Objective: To determine if there is an association between internalizing symptoms and disorders and migraine in children and adolescents. Data Sources: A librarian-led, peer-reviewed search was performed using MEDLINE, Embase, PsycINFO, and CINAHL databases (inception to March 28, 2022). Study Selection: Case-control, cohort, and cross-sectional studies on the association between internalizing symptoms and disorders and migraine in children and adolescents 18 years or younger were eligible. Data Extraction and Synthesis: Two investigators independently completed abstract and full-text screening, data extraction, and quality appraisal using the Newcastle-Ottawa scales. Studies were pooled with random-effects meta-analyses using standardized mean differences (SMD) or odds ratios (OR) with 95% CIs. Where sufficient data for pooling were unavailable, studies were described qualitatively. Main Outcomes and Measures: The primary outcome was migraine diagnosis; additional outcomes included migraine outcomes and incidence. Associations between these outcomes and internalizing symptoms and disorders were evaluated. Results: The study team screened 4946 studies and included 80 studies in the systematic review. Seventy-four studies reported on the association between internalizing symptoms and disorders and migraine, and 51 studies were amenable to pooling. Meta-analyses comparing children and adolescents with migraine with healthy controls showed: (1) an association between migraine and anxiety symptoms (SMD, 1.13; 95% CI, 0.64-1.63); (2) an association between migraine and depressive symptoms (SMD, 0.67; 95% CI, 0.46-0.87); and (3) significantly higher odds of anxiety disorders (OR, 1.93, 95% CI, 1.49-2.50) and depressive disorders (OR, 2.01, 95% CI, 1.46-2.78) in those with, vs without, migraine. Stratification of results did not reveal differences between clinical vs community/population-based samples and there was no evidence of publication bias. Twenty studies assessing the association between internalizing symptoms or disorders and migraine outcomes (n = 18) or incident migraine (n = 2) were summarized descriptively given significant heterogeneity, with minimal conclusions drawn. Conclusions and Relevance: In this study, children and adolescents with migraine were at higher risk of anxiety and depression symptoms and disorders compared with healthy controls. It may be beneficial to routinely screen children and adolescents with migraine for anxiety and depression in clinical practice. It is unclear whether having anxiety and depressive symptoms or disorders has an affect on migraine outcomes or incidence.

Outpatient Approach to Resistant and Refractory Migraine in Children and Adolescents: a Narrative Review.

PURPOSE OF REVIEW: Migraine is one of the top reasons for consulting a pediatric neurologist. Although the majority of children and adolescents who receive evidence-based first-line interventions for migraine will improve substantially, a subset of patients develop resistant or refractory migraine. RECENT FINDINGS: In this review, we summarize the level of evidence for a variety of acute and preventive treatment options to consider in children and adolescents with resistant or refractory migraine. We describe the level of evidence for interventional procedures (onabotulinumtoxinA injections, greater occipital and other nerve blocks), neuromodulation (single-pulse transcranial magnetic stimulation, external trigeminal nerve stimulation, remote electrical neuromodulation, and non-invasive vagal nerve stimulation), calcitonin gene-related peptide (CGRP) pathway antagonists (anti-CGRP monoclonal antibodies and gepants), psychological therapies, and manual therapies (acupuncture, craniosacral therapy, massage and physical therapy, and spinal manipulation).

The spectrum of indomethacin-responsive headaches in children and adolescents.

BACKGROUND: Headaches with marked, specific response to indomethacin occur in children, but the phenotypic spectrum of this phenomenon has not been well-studied. METHODS: We reviewed pediatric patients with headache showing ≥80% improvement with indomethacin, from seven academic medical centers. RESULTS: We included 32 pediatric patients (16 females). Mean headache onset age was 10.9 y (range 2-16 y). Headache syndromes included hemicrania continua (n = 13), paroxysmal hemicrania (n = 10), primary stabbing headache (n = 2), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (n = 1), primary exercise headache (n = 1) and primary cough headache (n = 1). Adverse events were reported in 13, most commonly gastrointestinal symptoms, which often improved with co-administration of gastro-protective agents. CONCLUSION: Indomethacin-responsive headaches occur in children and adolescents, and include headache syndromes, such as primary cough headache, previously thought to present only in adulthood. The incidence of adverse events is high, and patients must be co-treated with a gastroprotective agent.

Adverse childhood experiences and onset of migraine in Canadian adolescents: A cohort study.

BACKGROUND: Adverse childhood experiences (ACEs) are cross-sectionally associated with headache, including migraine, in pediatric populations. OBJECTIVE: The objective of this study was to determine whether ACEs are prospectively associated with incident health-professional diagnosed migraine and prevalence of non-migraine frequent headache in adolescence, either directly or indirectly through symptoms of depression and anxiety. METHODS: We used data from the National Longitudinal Survey of Children and Youth, a Canadian cohort study that followed children aged 0/1 at baseline, and the person most knowledgeable about them (PMK) until the child reached adolescence. The PMK reported on 14 ACEs (e.g., parental death) when the child was 4/5 and 6/7 years, and symptoms of depression and anxiety in late childhood (age 8/9 years), using a validated tool. Migraine (primary outcome) was ascertained via PMK report of a health-professional diagnosis, and non-migraine frequent headache (>1 time per week) was adolescent self-report, both measured at age 14/15. We estimated direct and indirect effects (IEs) on the log-odds scale through symptoms of depression and anxiety (mediator). We adjusted for sex, parental migraine, and economic deprivation. The analytic sample sizes were: n = 2058 (migraine) and n = 1730 (frequent headache). RESULTS: There were nunweighted  = 71 respondents with migraine (3.4%, 71/2058) and nunweighted  = 204 with non-migraine frequent headache (11.8%, 204/1730). Most respondents experienced no ACEs (weighted percentage = 55.7), followed by 1 ACE (weighted percentage = 34.7) and greater than or equal to two ACEs (weighted percentage = 9.6), respectively. There were direct associations between experiencing one (odds ratio [OR] = 1.71, 95% confidence interval [CI]: 1.01-2.87) and equal to or greater than two (OR = 2.33, 95% CI: 1.13-4.80) ACEs and migraine, but not for non-migraine frequent headache. There were no indirect relationships through symptoms of depression and anxiety for migraine (1 ACE: OR = 1.06, 95% CI: 0.99-1.13 and ≥2 ACEs: OR = 1.11, 95% CI: 0.98-1.28) or non-migraine frequent headache (1 ACE: OR = 0.99, 95% CI: 0.95-1.03 and ≥2 ACEs: OR = 0.98, 95% CI: 0.90-1.07). CONCLUSIONS: ACEs may confer an increased risk of migraine onset in adolescence. The association was not explained by symptoms of depression and anxiety in late childhood.

A Pilot Study Investigating the Role of Gender in the Intergenerational Relationships between Gene Expression, Chronic Pain, and Adverse Childhood Experiences in a Clinical Sample of Youth with Chronic Pain.

Chronic pain is a highly prevalent and costly issue that often emerges during childhood or adolescence and persists into adulthood. Adverse childhood experiences (ACEs) increase risk for several adverse health conditions, including chronic pain. Recent evidence suggests that parental trauma (ACEs, post-traumatic stress disorder (PTSD) symptoms) confers risk of poor health outcomes in their children. Intergenerational relationships between parental trauma and child chronic pain may be mediated by epigenetic mechanisms. A clinical sample of youth with chronic pain and their parents completed psychometrically sound questionnaires assessing ACEs, PTSD symptoms, and chronic pain, and provided a saliva sample. These were used to investigate the intergenerational relationships between four epigenetic biomarkers (COMT, DRD2, GR, and SERT), trauma, and chronic pain. The results indicated that the significant biomarkers were dependent upon the gender of the child, wherein parental ACEs significantly correlated with changes in DRD2 expression in female children and altered COMT expression in the parents of male children. Additionally, the nature of the ACE (maltreatment vs. household dysfunction) was associated with the specific epigenetic changes. There may be different pathways through which parental ACEs confer risk for poor outcomes for males and females, highlighting the importance of child gender in future investigations.