Bridging the gap between preclinical scientists, clinical researchers, and clinicians: From animal research to clinical practice.

BACKGROUND: Collaborations amongst researchers and clinicians with complementary areas of expertise enhance knowledge for everyone and can lead to new discoveries. To facilitate these interactions, shared language and a general understanding of how colleagues in different subfields of headache and headache research approach their work are needed. METHODS: This narrative review focuses on research methods applied in animal studies, human studies including clinical trials, and provides an overview of clinical practice. RESULTS: For animal studies, we describe concepts needed to evaluate the quality and relevance of preclinical studies. For human research, fundamental concepts of neuroimaging, quantitative sensory testing, genetic and epidemiological research methods, and clinical research methodology that are commonly used in headache research are summarized. In addition, we provide an understanding of what guides headache clinicians, and summarize the practical approach to migraine management in adults and children. CONCLUSIONS: It is hoped that this review facilitates further dialogue between clinicians and researchers that will help guide future research efforts and implementation of research findings into clinical practice.

Melatonin for migraine prevention in children and adolescents: A randomized, double-blind, placebo-controlled trial after single-blind placebo lead-in.

BACKGROUND: Melatonin is effective for migraine prevention in adults. We hypothesized that melatonin would also be effective for migraine prevention in children and adolescents. METHODS: This was a randomized, double-blind trial of melatonin (3 mg or 6 mg) versus placebo for migraine prevention in 10-17 year-olds with 4-28/28 headache days at baseline. Participants were recruited from the UCSF Child & Adolescent Headache Program, UCSF child neurology clinic, and social media advertisements. Migraine diagnosis was confirmed by a headache specialist. Participants completed an 8-week single-blind placebo run-in. Those meeting randomization criteria (≥4 headache days and ≥23/28 electronic diary entries during weeks 5-8) were randomized 1:1:1 to placebo:melatonin 3 mg:melatonin 6 mg nightly for 8 weeks. The primary outcome measure was migraine days in weeks 5-8 of randomized treatment between melatonin (combined 6 mg + 3 mg) versus placebo. We aimed to enroll n = 210. RESULTS: The study closed early due to slow enrollment (n = 72). Two participants were in the single-blind phase when the study closed, therefore the meaningful n = 70. Sixteen percent (11/70) were lost to follow-up during the single-blind phase. An additional 21% (15/70) did not meet randomization criteria (<4 headache days: n = 5, <23/28 diary days: n = 7, both: n = 3). Sixty-three percent (44/70) were eligible to randomize, of whom 42 randomized (n = 14 per arm). Taking another preventive at enrollment (OR 8.3, 95% CI 1.01 to 68.9) was the only variable associated with meeting randomization criteria. Of those randomized, 91% (38/42) provided diary data in the final 4-weeks. However, given the amount of missing data, only those with ≥21/28 diary days were analyzed-7/14 (50%) in the placebo group, and 20/28 (71%) in the melatonin groups combined. Median (IQR) migraine/migrainous days in weeks 5-8 of double-blind treatment was 2 (1-7) in the placebo group versus 2 (1-12) in the melatonin groups combined; the difference in medians (95% CI for the difference) was 0 days (-9 to 3). There were no differences in adverse events between groups. CONCLUSIONS: When compared to recall at enrollment, headache days decreased across the single-blind placebo phase and the double-blind phase. There was no suggestion of superiority of melatonin; however, given the substantial portion of missing data, numerically higher in the placebo arm, and underpowering, this should not be interpreted as proof of inefficacy. Melatonin was generally well tolerated with no serious adverse events. Future migraine preventive trials in this age group may find this trial helpful for anticipating enrollment needs if using a single-blind placebo run-in. Enriching for those already on a migraine preventive may improve randomization rates in future trials, though would change the generalizability of results.

Biopsychosocial treatment response among youth with continuous headache: A retrospective, clinic-based study.

BACKGROUND: Youth with continuous (always present) headache are vastly understudied; much remains to be understood regarding treatment response in this population. OBJECTIVE: To describe and explore biopsychosocial factors related to initial clinical outcomes among treatment-seeking youth with continuous headache. METHODS: This retrospective cohort study extracted data of 782 pediatric patients (i.e., aged <18 years) with continuous headache from a large clinical repository. Youth in this study had experienced continuous headache for ≥1 month before presenting to a multidisciplinary headache specialty clinic appointment. Extracted data from this appointment included patients' headache history, clinical diagnoses, and headache-related disability, as well as information about biopsychosocial factors implicated in headache management and/or maintenance (e.g., healthy lifestyle habits, history of feeling anxious or depressed). Additional data regarding patient headache characteristics, disability, and lifestyle habits were extracted from a subset of 529 youth who returned to clinic 4-16 weeks after their initial follow-up visit. After characterizing initial treatment response, exploratory analyses compared youth with the best and worst treatment outcomes on several potentially influential factors. RESULTS: Approximately half of youth (280/526; 53.2%) continued to have continuous headache at follow-up, ~20% of youth (51/526) reported a significant (≥50%) reduction in headache frequency. Improvements in average headache severity (e.g., percentage with severe headaches at initial visit: 45.3% [354/771]; percentage with severe headaches at follow-up visit: 29.8% [156/524]) and headache-related disability were also observed (e.g., percentage severe disability at initial visit: 62.9% [490/779]; percentage severe disability at initial follow-up visit: 34.2% [181/529]). Individuals with the worst headache frequency and disability had a longer history of continuous headache (mean difference estimate = 5.76, p = 0.013) and worse initial disability than the best responders (χ2 [3, 264] = 23.49, p < 0.001). They were also more likely to have new daily persistent headache (χ2 [2, 264] = 12.61, p = 0.002), and were more likely to endorse feeling depressed (χ2 [1, 260] = 11.46, p < 0.001). CONCLUSION: A notable percentage of youth with continuous headache show initial improvements in headache status. Prospective, longitudinal research is needed to rigorously examine factors associated with continuous headache treatment response.

Impact of preventive pill-based treatment on migraine days: A secondary outcome study of the Childhood and Adolescent Migraine Prevention (CHAMP) trial and a comparison of self-report to nosology-derived assessments.

OBJECTIVE: To examine group differences in self-reported migraine days among youth who completed the Childhood and Adolescent Migraine Prevention (CHAMP) trial prior to its closure and explore the relationship between self-reported and "nosology-derived" (i.e., International Classification of Headache Disorders, 3rd edition [ICHD-3]) migraine days. BACKGROUND: The CHAMP trial compared amitriptyline and topiramate to placebo for migraine prevention in youth and proposed to analyze change in migraine days as a secondary outcome. There is considerable variability in the field regarding what constitutes a "migraine day," how this is determined and reported in trials, and how consistent these measures are with diagnostic nosology. METHODS: CHAMP trial completers (N = 175) were randomized to receive amitriptyline (n = 77), topiramate (n = 63), or placebo (n = 35). Participants maintained daily headache diaries where they reported each day with headache and if they considered that headache to be a migraine. For each headache day, participants completed a symptom record and reported about symptoms such as pain location(s) and presence of nausea/vomiting or photophobia and phonophobia. We examined group differences in self-reported migraine days at trial completion (summed from trial weeks 20-24) compared to baseline. We also used an algorithm to determine whether participants' symptom reports met ICHD-3 criteria for migraine without aura, and examined the association between self-reported and "nosology-derived" migraine days. RESULTS: Results showed no significant differences between groups in self-reported migraine days over the course of the trial. Self-reported and "nosology-derived" migraine days during the baseline and treatment phases were strongly associated (r's = 0.73 and 0.83, respectively; p's < 0.001). CONCLUSION: Regardless of treatment, CHAMP trial completers showed clinically important reductions in self-reported migraine days over the course of the trial (about 3.8 days less). The strong association between self-reported and "nosology-derived" migraine days suggests youth with migraine can recognize a day with migraine and reliably report their headache features and symptoms. Greater rigor and transparency in the calculation and reporting of migraine days in trials is needed.

Trajectory of treatment response in the child and adolescent migraine prevention (CHAMP) study: A randomized clinical trial.

OBJECTIVE: Identify preventive medication treatment response trajectories among youth participating in the Childhood and Adolescent Migraine Prevention study. METHODS: Data were evaluated from 328 youth (ages 8-17). Childhood and Adolescent Migraine Prevention study participants completed headache diaries during a 28-day baseline period and a 168-day active treatment period during which youth took amitriptyline, topiramate, or placebo. Daily headache occurrence trajectories were established across baseline and active treatment periods using longitudinal hierarchical linear modeling. We tested potential treatment group differences. We also compared final models to trajectory findings from a clinical trial of cognitive behavioral therapy plus amitriptyline for youth with chronic migraine to test for reproducibility. RESULTS: Daily headache occurrence showed stability across baseline. Active treatment models revealed decreases in headache frequency that were most notable early in the trial period. Baseline and active treatment models did not differ by treatment group and replicated trajectory cognitive behavioral therapy plus amitriptyline trial findings. CONCLUSIONS: Replicating headache frequency trajectories across clinical trials provides strong evidence that youth can improve quickly. Given no effect for medication, we need to better understand what drives this clinically meaningful improvement. Results also suggest an expected trajectory of treatment response for use in designing and determining endpoints for future clinical trials.Trial Registration. ClinicalTrials.gov Identifier: NCT01581281.

New insight into the neural mechanisms of migraine in adolescents: Relationships with sleep.

OBJECTIVE: This case-control study examines if measures of subjective and objective (actigraphic) sleep difficulties mediate alterations in amygdalar connectivity in adolescents with migraine compared to healthy adolescents. BACKGROUND: Adolescents with migraine have different functional connectivity of the amygdala compared to individuals without migraine. Sleep is often disturbed in adolescents with migraine, and could contribute to the alterations in functional connectivity. METHODS: Twenty adolescents with migraine and 20 healthy controls were recruited from Cincinnati Children's Hospital. Participants completed surveys about their headaches and overall sleep quality, sleep hygiene, and perceived sleep difficulties (Insomnia Severity Scale [ISI]); completed wrist-worn actigraphy; and underwent a magnetic resonance imaging scan. RESULTS: Adolescents with migraine differed from healthy controls only in perceived difficulty in sleep initiation and maintenance (ISI: 8.5 ± 4.7 and 4.5 ± 3.7 [mean ± standard deviation], -4.00 [95% confidence: -6.7 to -1.3], p = 0.005) and had greater functional connectivity between the amygdala and the posterior cingulate cortex, precuneus, dorsolateral prefrontal, sensorimotor, and the occipital cortexes. The differences in functional connectivity of the amygdala were not mediated by the subjective/objective sleep measures (ISI/wake minutes after sleep onset). CONCLUSIONS: Adolescents with migraine have greater connectivity between the amygdala and areas involved in sensory, affective, and cognitive aspects of pain. These alterations may not be due to higher levels of sleep difficulties in adolescents with migraine, suggesting that both amygdala and sleep alterations may play an independent role in migraine pathophysiology. This advances the understanding of the mechanisms underlying pediatric migraine and can potentially advance migraine management.

Multimodal Assessment of Medication Adherence Among Youth With Migraine: An Ancillary Study of the CHAMP Trial.

OBJECTIVE: Examine preventive medication adherence among youth with migraine. METHODS: Adherence (self-report, pill count, and blood serum drug levels) was assessed as an ancillary study that utilized data from 328 CHAMP Study participants (ages 8-17). CHAMP was a multisite trial of preventive medications. Participants completed a prospective headache diary during a six-month active treatment period during which youth took amitriptyline, topiramate, or placebo pill twice daily. Self-reported medication adherence was collected via daily diary. At monthly study visits, pill count measures were captured. At trial month 3 (trial midpoint) and 6 (end of active trial), blood serum drug levels were obtained. Self-report and pill count adherence percentages were calculated for the active trial period, at each monthly study visit, and in the days prior to participants' mid-trial blood draw. Percentages of nonzero drug levels were calculated to assess blood serum drug level data. Adherence measures were compared and assessed in context of several sociodemographic factors. Multiple regression analyses investigated medication adherence as a predictor of headache outcomes. RESULTS: Self-report and pill count adherence rates were high (over 90%) and sustained over the course of the trial period. Serum drug level adherence rates were somewhat lower and decreased significantly (from 84% to 76%) across the trial period [t (198) = 3.23, p = .001]. Adherence measures did not predict headache days at trial end; trial midpoint serum drug levels predicted headache-related disability. CONCLUSIONS: Youth with migraine can demonstrate and sustain relatively high levels of medication adherence over the course of a clinical trial.

Psychological Interventions for Pediatric Headache Disorders: A 2021 Update on Research Progress and Needs.

PURPOSE OF REVIEW: This review summarizes key findings from recent investigations of psychological interventions for pediatric headache disorders and discusses important avenues for future research. RECENT FINDINGS: Cognitive Behavioral Therapy (CBT) is effective in reducing headache days among youth with chronic headache. There is mixed evidence for the benefit of CBT on reducing disability associated with migraine, suggesting that there is room to optimize CBT by leveraging complementary or alternative psychological interventions, such as Acceptance and Commitment Therapy (ACT) and mindfulness-based approaches. Tailoring CBT may be especially important for youth with more impairing or complex clinical presentations, such as those with continuous headache. Using eHealth and novel study designs to expand access to and dissemination of psychological interventions is promising. Although CBT is the gold standard psychological treatment for youth with migraine, we are only beginning to understand how and why it is effective. Other promising psychological treatments are available, and studies are beginning to examine how CBT can be optimized to fit the unique needs of each patient. Improving access and equitability of care for youth with migraine will require tailoring psychological treatments for patients with varying headache presentations and youth from a variety of cultural, racial, ethnic, and linguistic backgrounds.

Predictors of Improvement in Pediatric Chronic Migraine: Results from the Cognitive-Behavioral Therapy and Amitriptyline Trial.

Explore predictors of improvement in headache days and migraine-related disability through a secondary analysis of the cognitive-behavioral therapy plus amitriptyline trial in children and adolescents (Clinical Trials Registration Number: NCT00389038). Participants were 135 youth aged 10-17 years old diagnosed with chronic migraine. Predictor variables included group assignment (treatment or control), baseline scores from depression and quality of life measures, and demographic variables. Criterion variables included headache days and migraine-related disability. Higher baseline depression scores were indicative of more days with headache post-treatment regardless of group assignment. Family income at the higher-end of the low-income range was significantly associated with less migraine-related disability regardless of group assignment (Household Income: HINC-01 in The United States Census Bureau. Bureau, U, 2020). Results from this secondary analysis identify depression symptoms and family income as predictors that can impact headache frequency and migraine-related disability. Self-reported symptoms of depression and family income are important factors to consider as part of the biopsychosocial model of care.

Spatial aspects of pain modulation are not disrupted in adolescents with migraine.

OBJECTIVE: To compare spatial pain modulation capabilities between adolescents with and without migraine. BACKGROUND: Conditioned pain modulation (CPM) responses at the leg are similar in adolescents with versus without migraine. However, the anatomical region of testing may affect spatial pain modulation capabilities as differences in nociceptive processing between patients with migraine and healthy controls are found in local areas that are near the site of clinical pain but not in nonlocal areas. This study aimed to examine spatial pain modulation capabilities tested by the CPM paradigm using test stimulus applied to a local body area. METHODS: Nineteen adolescents with migraine (age 14.9 ± 2.3, mean ± SD; 16 female) and 20 healthy adolescents (age 13.8 ± 2.5, mean ± SD; 16 female) completed this case-control study at Cincinnati Children's Hospital Medical Center. Pressure pain thresholds (PPT) were assessed at the trapezius before and during immersion of the foot in a cold water bath (8°C). RESULTS: In the migraine group (146.0 ± 79.1, mean ± SD), compared to healthy controls (248.0 ± 145.5, mean ± SD), significantly lower PPT (kilopascal) values were found (estimate = 124.28, 95% CI: 58.98, 189.59, p < 0.001; effect size: d = 1.40). No differences between the groups were found for pain intensity and unpleasantness ratings of cold-water immersion nor the CPM response. CONCLUSIONS: This study found altered ascending nociceptive processing of mechanical stimuli at the neck in adolescents with migraine. However, endogenous pain modulatory mechanisms were functional and not altered. In light of other studies, impairments in inhibitory control may not be involved in migraine pathophysiology in pediatric patients regardless of stimulus location.

Learning the full impact of migraine through patient voices: A qualitative study.

OBJECTIVE: To better characterize the ways that migraine affects multiple domains of life. BACKGROUND: Further understanding of migraine burden is needed. METHODS: Adults with migraine randomized to mindfulness-based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in-person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio-recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach. RESULTS: Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties. CONCLUSIONS: Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.

Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine.

BACKGROUND: Which medication, if any, to use to prevent the headache of pediatric migraine has not been established. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. RESULTS: A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. CONCLUSIONS: There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).

Focus group findings on the migraine patient experience during research studies and ideas for future investigations.

OBJECTIVES: We conducted focus groups in people who had participated in mobile health (mHealth) studies of behavioral interventions for migraine to better understand: (a) Participant experience in the recruitment/enrollment process; (b) participant experience during the studies themselves; (c) ideas for improving participant experience for future studies. METHODS: We conducted four focus groups in people who had agreed to participate in one of three studies involving mHealth and behavioral therapy for migraine. Inclusion criteria were being age 18-80, owning a smartphone, and having four or more headache days per month. All participants met the International Classification of Headache Disorders third edition beta version criteria for migraine. Exclusion criteria were not speaking English and having had behavioral therapy for migraine in the past year. Focus groups were audio recorded, fully transcribed and coded using general thematic analysis. RESULTS: The 12 focus group participants had a mean age of 45 ± 15, a mean age of headache onset of 21 ± 13 and mean MIDAS disability score was 39 ± 56. Participants were women (100%), white (50%), Asian (33.3%) or members of other racial groups (16.7%). Certain themes emerged from each topic area. With regard to recruitment/enrollment (a), key themes were: (i) Participants joined their study out of an interest in research and/or a desire to try a new migraine treatment modality (behavioral therapy). (ii) Enrollment should be simple and study requirements should be carefully explained prior to enrollment. When asked about their experiences during the studies (b), the following themes emerged: (i) It is difficult to participate in study follow-up and compliance phone calls; (ii) participants prefer to choose from among various options for contact with the study team; (iii) there are barriers that limit app use related to migraine itself, as well as other barriers; (iv) completing diaries on a daily basis is challenging; (v) technical difficulties and uncertainties about app features limit use; (vi) being part of a research study promoted daily behavioral therapy use; (vii) progressive muscle relaxation (PMR) is enjoyable, and has a positive impact on life; (viii) behavioral therapy was a preferred treatment to reduce migraine pain. Ideas for improving study design or patient experience (c) included: (i) Increased opportunity to interact with other people with migraine would be beneficial; (ii) navigating the app and data entry should be easier; (iii) more varied methods for viewing the data and measures of adherence are needed; (iv) more information on and more varied behavioral treatment modalities would be preferred. CONCLUSION: Though people with migraine are motivated to participate in mHealth and behavioral treatment studies, better communication up front about interventions as well as greater flexibility in interventions and follow-up methods are desired.

Clinic-based characterization of continuous headache in children and adolescents: Comparing youth with chronic migraine to those with new daily persistent headache.

OBJECTIVE: To describe the headache characteristics and functional disability of a large sample of treatment-seeking youth with continuous headache and compare these factors across diagnostic subgroups of chronic migraine and new daily persistent headache. METHODS: This retrospective study utilized clinical information (e.g. diagnosis, headache features, medication overuse, functional disability) from a large data repository of patients initially presenting to a multidisciplinary headache center with continuous headache. Patient inclusion in subgroup analyses for chronic migraine and new daily persistent headache was based on clinician diagnosis using International Classification of Headache Disorders (ICHD) criteria. RESULTS: The current sample included 1170 youth (mean age = 13.95 years, 78.8% female) with continuous headache. The overwhelming majority of these youth had headaches with migrainous features, regardless of their clinical diagnosis. Youth with chronic migraine reported a longer history of continuous headache symptoms and earlier age of headache onset than youth with new daily persistent headache and were more likely to have medication overuse. Most youth with continuous headache experienced severe migraine-related functional disability, regardless of diagnostic subgroup. CONCLUSIONS: Overall, youth with continuous chronic migraine and new daily persistent headache did not have clinically meaningful differences in headache features and associated disability. Findings suggest that chronic migraine and new daily persistent headache may be variants of the same underlying disease.

Alterations in Brain Function After Cognitive Behavioral Therapy for Migraine in Children and Adolescents.

OBJECTIVES: This basic mechanistic study examined the changes in brain activation and resting-state connectivity after 8 weeks of CBT in youth with migraine. BACKGROUND: Cognitive behavioral therapy (CBT) is a psychological intervention that is effective in reducing pain in migraine patients. However, the neural mechanisms underlying CBT in adolescents with migraine are not yet known. METHODS: Eighteen adolescents with migraine (15 females, age 15.1 ± 2.1 years [mean ± SD]) completed 8 weekly CBT sessions. Before the first and after the final CBT session, participants underwent structural and resting-state blood-oxygen-level-dependent contrast MRI scans. Arterial spin labeling was also used to examine brain activation during the resting state. For connectivity analyses, the right and left amygdala were chosen as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. RESULTS: Headache frequency decreased from 15 ± 7.4 headaches per month before CBT to 10 ± 7.4 after CBT (P < .001). After CBT, greater brain activations in frontal regions involved in cognitive regulation of pain were found. In addition, after CBT increased connectivity between the amygdala and frontal regions was observed. Associations between brain activation and amygdalar connectivity with a reduction in headache frequency were also observed. CONCLUSIONS: Alterations in brain function and amygdalar connectivity with areas involved in nociceptive processing, cognitive function, and emotional regulation may underlie the ability of CBT to aid in the prevention of headaches in migraine patients.

The Profile and Prognosis of Youth With Status Migrainosus: Results From an Observational Study.

OBJECTIVE: To characterize the clinical features of a large sample of children, adolescents, and young adults with a history of status migrainosus (SM) and to describe their short-term prognosis. BACKGROUND: Data on the clinical characteristics of children and adolescents with SM are sparse and little is known about the prognosis of this population. METHODS: This was a retrospective clinical cohort study that included patients from the Cincinnati Children's Headache Center if they had a diagnosis of migraine and data available for a 1-3 months follow-up interval. Data extracted from the initial interval visit (visit A) included: age, sex, race, migraine diagnosis, SM history, chronic migraine, medication overuse headache (MOH), body mass index (BMI), headache frequency, headache severity, disability, allodynia and lifestyle habits: caffeine intake, meal skipping, sleep duration, exercise frequency, and fluid intake. Data extracted from the initial consultation visit included: months with headache at initial consultation visit, patient endorsing "feeling depressed" and anxiety symptoms. Headache frequency and visit type were also measured at the second visit (visit B) in the follow-up interval. A multivariate logistic regression model with a backward elimination procedure was created to model the odds of having a diagnosis of SM using the cross-sectional predictor variables above. Second, chi-square tests were used to compare the proportion of patients with SM to the proportion of patients without SM who had each of the following outcomes in the short-term follow-up window: treatment response (50% or greater reduction in headache frequency), overall reduction in headache frequency (reduction of 1 or more headache days/month), minimal change in headache frequency (increase in 0-3 headache days/month), and clinical worsening (increase in 4 or more headache days/month). RESULTS: A total of 5316 youth with migraine were included and 559 (10.5%) had a history of SM. In the multivariate logistic regression model, predictors significantly associated with SM were: older age (OR = 1.13, 95% CI = 1.09-1.17, P < .0001), migraine with aura (MWA) (OR = 1.30, 95% CI = 1.03-1.65, P = .03), MOH (OR = 1.72, 95% CI = 1.30-2.28, P = .0001), headache frequency (OR = 0.99, 95% CI = 0.97-0.99, P = .030), higher headache severity (OR = 1.08, 95% CI = 1.02-1.15, P = .009), months with headache at initial consultation (OR = 1.00, 95% CI = 1.00-1.01, P = .042), and admission to infusion center at visit B (OR = 2.27, 95% CI = 1.38-3.72, P = .001). Patients with a history of SM were more likely to experience an increase in 4 or more headache days per month at follow-up: 15.2% as compared to 11.1% of those without SM, χ2 (1, n = 5316) = 8.172, P = .0043. CONCLUSIONS: Youth with SM represent a distinct subgroup of the migraine population and have an unfavorable short-term prognosis.

The Association Between Glycemic Variability and Macronutrients in Young Children with T1D.

OBJECTIVE: There is limited information regarding the potential effect macronutrients have on postprandial glycemic variability in young children with type 1 diabetes (T1D). To date, studies examining nutrition and glycemic outcomes either assess these factors at a single timepoint, or aggregate large datasets for group level analyses. This study examined how inter- and intraindividual fluctuations in carbohydrate, fat, and protein intake impact glycemic variability in the postprandial period for young children with T1D. METHODS: Thirty-nine young children, aged 2-6 years, wore a continuous glucose monitor for 72 hr, while their parents completed detailed diet records of all food intake. The analyses tested three multilevel models to examine intra- and interindividual differences between food intake and postprandial glycemic variability. RESULTS: The results suggest carbohydrate intake, relates to greater postprandial glycemic variability. In contrast, the results reveal the inverse effect for protein, suggesting a tendency for young children who ate more protein at some meals to have lower postprandial glycemic variability, with the exception of lunch. There was no effect for fat on postprandial glycemic variability. CONCLUSION: These results suggest protein consumption may be an important consideration when aiming for optimal glycemic levels for some meals. When counseling parents of young children with T1D on common behaviors underlying glycemic excursion, pediatric psychologists may consider discussing the nutritional make up of children's meals. Further, the results demonstrate retaining longitudinal data at the person level, versus aggregating individual data for group level analyses, may offer new information regarding macronutrient intake and glycemic outcomes.

Screening Family and Psychosocial Risk in Pediatric Migraine and Tension-Type Headache: Validation of the Psychosocial Assessment Tool (PAT).

OBJECTIVE: To present data on psychometric properties of the Psychosocial Assessment Tool 2.0_General (PAT), a brief screener for psychosocial risk in families of youth with medical conditions, in youth with headache. BACKGROUND: Emotional and behavioral disturbances, parent distress, and poor family functioning are common among youth with recurrent migraine and tension-type headache; however, tools to comprehensively screen family and psychosocial risk in youth with headache are not currently available. The PAT could address an important gap by facilitating identification of psychosocial treatment needs among youth with headache. DESIGN AND METHODS: Youth with recurrent migraine (with and without aura; chronic migraine) or tension-type headache (episodic and chronic) completed the PAT and validated measures of adolescent emotional and behavioral functioning, parent emotional functioning, and family functioning at baseline (n = 239; 157 from neurology clinic, 82 from the community) and 6-month follow-up (n = 221; 146 from neurology clinic, 75 from the community). RESULTS: Internal consistency for the PAT Total score was strong (α = .88). At baseline, the PAT Total score was significantly associated in the expected direction with established measures of child emotional and behavioral functioning (r = .62), parent anxiety and depressive symptoms (r = .49; r = .53, respectively), and family functioning (r = .21). Predictive validity was demonstrated by a significant association between PAT Total scores at baseline with child emotional and behavioral functioning (r = .64), parent anxiety (r = .37), parent depression (r = .42), and family functioning (r = .26) at 6-month follow-up. CONCLUSIONS: The PAT is a promising tool for screening psychosocial risk that could facilitate identification of psychosocial treatment needs among youth with recurrent headache at risk for poor outcomes.

Cognitive Behavioral Therapy for Pediatric Headache and Migraine: Why to Prescribe and What New Research Is Critical for Advancing Integrated Biobehavioral Care.

PURPOSE OF REVIEW: To highlight current evidence supporting the prescription of cognitive behavioral therapy (CBT) as part of first-line preventive treatment for children and adolescents with headache and discuss a research strategy aimed at: (1) understanding how and why CBT works, and (2) developing effective and efficient approaches for integrating CBT into headache specialty, neurology, and primary care settings. RECENT FINDINGS: Although preventive medications for pediatric headache and migraine are commonly prescribed, recent meta-analyses and an NIH-funded, multi-center clinical trial suggests that the effect of pill-taking therapies may be mostly due to a placebo effect. These findings have led to greater consideration of prescription of non-pharmacological therapies as first-line interventions (either alone or in combination with pill-based therapy). A literature that extends back to the 1980s and includes recent clinical trials and meta-analyses demonstrates that CBT decreases headache frequency and related disability in youth with headache and migraine and has a favorable benefit to risk profile with almost no negative side effects. SUMMARY: CBT has been repeatedly demonstrated as effective in treating pediatric headache and migraine. As such, it should be considered as part of first-line preventive treatment for pediatric headache (either alone or in combination with a pill-based therapy). We need to better understand how this therapy works and what makes it distinct (if anything) from the placebo effect. What we need to achieve is empirical support for efficient access to this evidence-based treatment and clarity on how to match the intensity of non-pharmacological intervention to the needs of our patients at the time they present for care.