Remote electrical neuromodulation to treat children and adolescents with migraine in the emergency department: A randomized double-dummy pilot trial.

OBJECTIVE: Using a double-dummy pilot randomized controlled trial design, we aimed to determine the feasibility and acceptability of comparing remote electrical neuromodulation (REN) to typical care intravenous pharmacologic interventions for the treatment of children and adolescents visiting the emergency department (ED) with migraine, and to compare parallel-group versus crossover trial designs. BACKGROUND: There are limited data to guide the management of migraine in the ED. Children and adolescents are interested in neuromodulation, and specifically REN, for treatment in this setting, but there are no existing data on this approach. METHODS: We employed a double-dummy, double-blind, pilot randomized controlled trial that tested two designs in two phases: a parallel-group design and a crossover design (ClinicalTrials.gov identifier: NCT05102591). The intervention arms consisted of: (i) active REN stimulation with matched normal saline placebo intravenously, and (ii) matched sham REN stimulation, intravenous metoclopramide (0.15 mg/kg, maximum 10 mg), and intravenous ketorolac (0.5 mg/kg, maximum 30 mg). Youth aged 8.0-<18.0 years visiting a Canadian tertiary care pediatric ED with migraine attacks as per criteria B-E of the International Classification of Headache Disorders third edition were eligible. Primary outcomes were focused on trial feasibility and acceptability, and preliminary efficacy and safety data were also collected. RESULTS: A total of 34% (22/65) of those who screened eligible were enrolled. Three participants (14%) withdrew prior to receiving any study interventions. In all, 10 participants were allocated to typical care, and nine to REN. All treated participants (19/19) completed all assessments. Recruitment was higher during the parallel-group phase: 1.1 participants/month versus 0.6 participants/month, and 36% (17/47) versus 28% (five of 18) of screened eligible were enrolled in the parallel-group and crossover phases, respectively. Participants reported positive impressions of REN use in the ED, e.g., higher mean (standard deviation [SD]) levels of interest in using REN only at 3.7 (1.0) versus 2.8 (1.0) in using intravenous interventions only for a future ED visit. Participants and clinical staff reported overall positive impressions regarding the study protocol. Employing an 11-point pain numerical rating scale, the mean (SD) reduction in pain severity score was 2.1 (1.3) and 2.9 (2.9) from baseline to 1 h, and 2.4 (1.6) and 4.0 (3.5) from baseline to 2 h for REN and intravenous interventions, respectively. One participant in the typical care group and none in the REN group experienced adverse events. CONCLUSION: We demonstrated the feasibility and acceptability of our trial protocol and of using REN to treat youth presenting to the ED with migraine. The parallel-group design generated a higher recruitment rate than the crossover design. Our preliminary efficacy and safety data suggest that REN could be non-inferior to typical care, but we were not powered for these outcomes. Further research on REN's use in the ED setting is warranted.

The safety and efficacy of onabotulinumtoxinA injections for children and adolescents with chronic migraine: A systematic review and meta-analysis.

OBJECTIVE: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine. BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence. METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively. RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred. CONCLUSION: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.

Region-specific changes in brain glutamate and gamma-aminobutyric acid across the migraine attack in children and adolescents.

ABSTRACT: In patients with migraine, an excitation-inhibition imbalance that fluctuates relative to attack onset has been proposed to contribute to the underlying pathophysiology of migraine, but this has yet to be explored in children and adolescents. This prospective, observational, cohort study examined glutamate and gamma-aminobutyric acid (GABA) levels across the phases of a migraine attack and interictally in children and adolescents using magnetic resonance spectroscopy. Macromolecule-suppressed GABA (sensorimotor cortex and thalamus) and glutamate (occipital cortex, sensorimotor cortex, and thalamus) were measured in children and adolescents (10-17 years) with a migraine diagnosis with or without aura 4 times over 2 weeks. Linear mixed-effects models examined changes in glutamate and GABA during the 72 hours leading up to, and after the onset of an attack. We found significant region-specific changes in glutamate and GABA. Specifically, sensorimotor GABA significantly increased leading up to the headache phase, whereas glutamate significantly decreased following the headache onset in the occipital cortex and the thalamus. Post hoc analyses examined the 24 hours leading up to or following the onset of the headache phase. In the 24 hours before the headache onset, sensorimotor glutamate, occipital glutamate, and thalamic GABA decreased. In the 24 hours post headache onset, sensorimotor glutamate continued to decrease. Our results suggest changes in glutamate and GABA that are consistent with the thalamocortical dysrhythmia hypothesis. These findings provide insight into developmental migraine pathophysiology and may open future avenues for treatment targets specific to children and adolescents.

Evaluating patient and family preferences for acute and preventive pediatric headache treatment.

OBJECTIVE: To describe acute and preventive treatment preferences among youth with migraine and their parents/guardians, and to describe the degree of youth-parent/guardian preference agreement. BACKGROUND: Headache disorders are common in youth, but little is known about patient and family preferences for headache treatments and outcomes. METHODS: In this cross-sectional survey, a headache treatment preferences questionnaire was co-created with stakeholders, piloted, and distributed to consenting youth with migraine aged 9-18 years and parents/guardians at a tertiary care headache clinic in western Canada. Response data were summarized for youth and parents/guardians separately, and agreement rates within a youth-parent/guardian pair were compared to a hypothesized agreement rate of 80% for the primary questionnaire items. RESULTS: Seventy-two youth and n = 94 parents/guardians participated, with n = 63 in youth-parent/guardian pairs. Freedom from pain and rapid relief, and reducing pain severity and headache frequency were top acute and preventive treatment priorities, respectively. More than 90% (69/72) agreed that ≥ 50% reduction in headache frequency was a good target. For both acute and preventive interventions, swallowed pill-based options were most often selected as the preferred first-line treatment, with neuromodulation selected as the preferred second-line treatment. The level of agreement within youth-parent/guardian pairs on preferred treatment modalities was lower than hypothesized for acute (63% [40/63], 95% confidence interval [CI] = 52-75%, χ2 = 10.73, p = 0.001) but not for preventive treatment (73% [46/63], 95% CI = 62-84%, χ2 = 1.92, p = 0.166). Regarding which treatment modalities were perceived as most effective, youth-parent agreement was lower than hypothesized for both acute (48% [30/63], 95% CI = 35-60%, χ2 = 41.29, p < 0.001) and preventive treatment (46% [29/63], 95% CI = 34-58%, χ2 = 45.43, p < 0.001). CONCLUSION: Youth and family preferences aligned qualitatively, but sometimes diverged quantitatively, from typical clinical trial outcomes. The level of agreement within youth-parent/guardian pairs on treatment preferences and perceptions was low. Clinicians should consider both perspectives as they may be divergent.

The moving wave: Applications of the mobile EEG approach to study human attention.

Although historically confined to traditional research laboratories, electroencephalography (EEG) paradigms are now being applied to study a wide array of behaviors, from daily activities to specialized tasks in diverse fields such as sports science, neurorehabilitation, and education. This transition from traditional to real-world mobile research can provide new tools for understanding attentional processes as they occur naturally. Early mobile EEG research has made progress, despite the large size and wired connections. Recent developments in hardware and software have expanded the possibilities of mobile EEG, enabling a broader range of applications. Despite these advancements, limitations influencing mobile EEG remain that must be overcome to achieve adequate reliability and validity. In this review, we first assess the feasibility of mobile paradigms, including electrode selection, artifact correction techniques, and methodological considerations. This review underscores the importance of ecological, construct, and predictive validity in ensuring the trustworthiness and applicability of mobile EEG findings. Second, we explore studies on attention in naturalistic settings, focusing on replicating classic P3 component studies in mobile paradigms like stationary biking in our lab, and activities such as walking, cycling, and dual-tasking outside of the lab. We emphasize how the mobile approach complements traditional laboratory paradigms and the types of insights gained in naturalistic research settings. Third, we discuss promising applications of portable EEG in workplace safety and other areas including road safety, rehabilitation medicine, and brain-computer interfaces. In summary, this review explores the expanding possibilities of mobile EEG while recognizing the existing challenges in fully realizing its potential.

Anxiety and depressive symptoms and migraine-related outcomes in children and adolescents.

OBJECTIVE: The objective of this study was to explore the longitudinal relationship between anxiety and depressive symptoms and migraine outcomes in children and adolescents. BACKGROUND: Children and adolescents with migraine experience more anxiety and depressive symptoms than their peers without migraine, but it is unknown if these symptoms are associated with differential migraine outcomes. METHODS: In this prospective clinical cohort study, children and adolescents aged 8.0-18.0 years with migraine completed headache questionnaires and validated measures of anxiety and depressive symptoms (Patient-Reported Outcomes Measurement Information System) at an initial consultation and at their first follow-up visit with a neurologist. Changes in monthly headache frequency and changes in migraine-related disability (Pediatric Migraine Disability Assessment) were tracked at each time point. The relationships between these migraine outcomes and anxiety and depressive symptoms were estimated using models controlling for sex, age, headache frequency, and treatment type. RESULTS: There were 123 consenting participants. In models adjusted for age, sex, baseline disability score, and treatment type, baseline anxiety and depressive symptom levels were not significantly associated with change in headache frequency (for anxiety symptoms: ß = -0.05, 95% confidence interval [CI] = -0.268 to 0.166, p = 0.639; for depressive symptoms: ß = 0.14, 95% CI = -0.079 to 0.359, p = 0.209). Similarly, in models adjusted for age, sex, baseline headache frequency, and treatment type, the change in disability was not associated with baseline anxiety (ß = -0.45, 95% CI = -1.69 to 0.78, p = 0.470), nor with baseline depressive symptom scores (ß = 0.16, 95% CI = -1.07 to 1.40, p = 0.796). In post hoc exploratory analyses (N = 84 with anxiety and N = 82 with depressive symptom data at both visits), there were also no significant associations between change in mental health symptoms and change in headache frequency (for anxiety symptoms: ß = -0.084, 95% CI = -0.246 to 0.078, p = 0.306; for depressive symptoms: ß = -0.013, 95% CI = -0.164 to 0.138, p = 0.865). Similarly, the change in disability scores between visits was not related to the change in anxiety (ß = 0.85, 95% CI = -0.095 to 1.78, p = 0.077) nor depressive symptom scores (ß = 0.32, 95% CI = -0.51 to 1.15, p = 0.446). CONCLUSION: Baseline anxiety and depressive symptom levels were not associated with longitudinal migraine outcomes and neither were longitudinal changes in anxiety and depressive symptom levels; this contradicts popular clinical belief that mental health symptoms predict or consistently change in tandem with migraine outcomes.

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.

EEG in motion: Using an oddball task to explore motor interference in active skateboarding.

Recent advancements in portable computer devices have opened new avenues in the study of human cognition outside research laboratories. This flexibility in methodology has led to the publication of several electroencephalography studies recording brain responses in real-world scenarios such as cycling and walking outside. In the present study, we tested the classic auditory oddball task while participants moved around an indoor running track using an electric skateboard. This novel approach allows for the study of attention in motion while virtually removing body movement. Using the skateboard auditory oddball paradigm, we found reliable and expected standard-target differences in the P3 and MMN/N2b event-related potentials. We also recorded baseline electroencephalography activity and found that, compared to this baseline, alpha power is attenuated in frontal and parietal regions during skateboarding. In order to explore the influence of motor interference in cognitive resources during skateboarding, we compared participants' preferred riding stance (baseline level of riding difficulty) versus their non-preferred stance (increased level of riding difficulty). We found that an increase in riding difficulty did not modulate the P3 and tonic alpha amplitude during skateboard motion. These results suggest that increases in motor demands might not lead to reductions in cognitive resources as shown in previous literature.

Predicting stroke severity with a 3-min recording from the Muse portable EEG system for rapid diagnosis of stroke.

In this study, we demonstrated the use of low-cost portable electroencephalography (EEG) as a method for prehospital stroke diagnosis. We used a portable EEG system to record data from 25 participants, 16 had acute ischemic stroke events, and compared the results to age-matched controls that included stroke mimics. Delta/alpha ratio (DAR), (delta + theta)/(alpha + beta) ratio (DBATR) and pairwise-derived Brain Symmetry Index (pdBSI) were investigated, as well as head movement using the on-board accelerometer and gyroscope. We then used machine learning to distinguish between different subgroups. DAR and DBATR increased in ischemic stroke patients with increasing stroke severity (p = 0.0021, partial η2 = 0.293; p = 0.01, partial η2 = 0.234). Also, pdBSI decreased in low frequencies and increased in high frequencies in patients who had a stroke (p = 0.036, partial η2 = 0.177). Using classification trees, we were able to distinguish moderate to severe stroke patients and from minor stroke and controls, with a 63% sensitivity, 86% specificity and accuracy of 76%. There are significant differences in DAR, DBATR, and pdBSI between patients with ischemic stroke when compared to controls, and these effects scale with severity. We have shown the utility of a low-cost portable EEG system to aid in patient triage and diagnosis as an early detection tool.

A ride in the park: Cycling in different outdoor environments modulates the auditory evoked potentials.

In this study, we investigated the effect of environmental sounds on ERPs during an auditory task, by having participants perform the same dual task in two different outdoor environments. Participants performed an auditory oddball task while cycling outside both in a quiet park and near a noisy roadway. While biking near the roadway, an increased N1 amplitude was observed when evoked by both standard and target tones. This may be due to attentional processes of enhancing sound processing in the noisier environment. No behavioural differences were found. Future directions include investigating auditory ERPs in more realistic studies outside of laboratory.

The ecological cocktail party: Measuring brain activity during an auditory oddball task with background noise.

Most experiments using EEG recordings take place in highly isolated and restricted environments, limiting their applicability to real-life scenarios. New technologies for mobile EEG are changing this by allowing EEG recording to take place outside of the laboratory. However, before results from experiments performed outside the laboratory can be fully understood, the effects of ecological stimuli on brain activity during cognitive tasks must be examined. In this experiment, participants performed an auditory oddball task while also listening to concurrent background noises of silence, white noise, and outdoor ecological sounds, as well as a condition in which the tones themselves were at a low volume. We found a significantly increased N1 and decreased P2 when participants performed the task with outdoor sounds and white noise in the background, with the largest differences in the outdoor sound condition. This modulation in the N1 and P2 replicates what we have previously found outside while people rode bicycles. No behavioral differences were found in response to the target tones. We interpret these modulations in early ERPs as indicative of sensory filtering of background sounds and that ecologically valid sounds require more filtering than simple synthetic sounds. Our results reveal that much of what we understand about the brain will need to be updated as cognitive neuroscience research begins to step outside of the lab.

Taking off the training wheels: Measuring auditory P3 during outdoor cycling using an active wet EEG system.

Mobile EEG allows the investigation of brain activity in increasingly complex environments. In this study, EEG equipment was adapted for use and transportation in a backpack while cycling. Participants performed an auditory oddball task while cycling outside and sitting in an isolated chamber inside the lab. Cycling increased EEG noise and marginally diminished alpha amplitude. However, this increased noise did not influence the ability to measure reliable event related potentials (ERP). The P3 was similar in topography, and morphology when outside on the bike, with a lower amplitude in the outside cycling condition. There was only a minor decrease in the statistical power to measure reliable ERP effects. Unexpectedly, when biking outside significantly decreased P2 and increased N1 amplitude were observed when evoked by both standards and targets compared with sitting in the lab. This may be due to attentional processes filtering the overlapping sounds between the tones used and similar environmental frequencies. This study established methods for mobile recording of ERP signals. Future directions include investigating auditory P2 filtering inside the laboratory.

Two-Layered and Stretchable e-Textile Patches for Wearable Healthcare Electronics.

Wearable healthcare systems require skin-adhering electrodes that allow maximal comfort for patients as well as an electronics system to enable signal processing and transmittance. Textile-based electronics, known as "e-textiles," is a platform technology that allows comfort for patients. Here, two-layered e-textile patches are designed by controlled permeation of Ag-particle/fluoropolymer composite ink into a porous textile. The permeated ink forms a cladding onto the nanofibers in the textile substrate, which is beneficial for mechanical and electrical properties of the e-textile. The printed e-textile features conductivity of ≈3200 S cm-1 , whereas 1000 cycles of 30% uniaxial stretching causes the resistance to increase only by a factor of ≈5, which is acceptable in many applications. Controlling over the penetration depth enables a two-layer design of the e-textile, where the sensing electrodes and the conducting traces are printed in the opposite sides of the substrate. The formation of vertical interconnected access is remarkably simple as an injection from a syringe. With the custom-developed electronic circuits, a surface electromyography system with wireless data transmission is demonstrated. Furthermore, the dry e-textile patch collects electroencephalography with comparable signal quality to commercial gel electrodes. It is anticipated that the two-layered e-textiles will be effective in healthcare and sports applications.

Increasing the mobility of EEG data collection using a Latte Panda computer.

BACKGROUND: Electroencephalography (EEG) experiments often require several computers to ensure accurate stimulus presentation and data collection. However, this requirement can make it more difficult to perform such experiments in mobile settings within, or outside, the laboratory. NEW METHOD: Computer miniaturisation and increasing processing power allow for EEG experiments to become more portable. Our goal is to show that a Latte Panda, a small Windows 10 computer, can be used to accurately collect EEG data in a similar manner to a laptop. Using a stationary bike, we also suggest that the Latte Panda will allow for more portable EEG experiments. RESULTS: Significant and reliable MMN and P3 responses, event-related potentials (ERPs) typically associated with auditory oddball tasks, were observed and were consistent when using either the laptop or Latte Panda for EEG data collection. Similar MMN and P3 ERPs were also measured in the sitting and stationary biking conditions while using a Latte Panda for data collection. COMPARISON WITH EXISTING METHOD: Data recorded by the Latte Panda computer produced comparable and equally reliable results to the laptop. As well, similar ERPs during sitting and biking would suggest that EEG experiments can be conducted in more mobile situations despite the increased noise and artifacts associated with muscle movement. CONCLUSIONS: Our results show that the Latte Panda is a low-cost, more portable alternative to a laptop computer for recording EEG data. Such a device will further allow for more portable and mobile EEG experimentation in a wider variety of environments.

Transitioning EEG experiments away from the laboratory using a Raspberry Pi 2.

BACKGROUND: Electroencephalography (EEG) experiments are typically performed in controlled laboratory settings to minimise noise and produce reliable measurements. These controlled conditions also reduce the applicability of the obtained results to more varied environments and may limit their relevance to everyday situations. NEW METHOD: Advances in computer portability may increase the mobility and applicability of EEG results while decreasing costs. In this experiment we show that stimulus presentation using a Raspberry Pi 2 computer provides a low cost, reliable alternative to a traditional desktop PC in the administration of EEG experimental tasks. RESULTS: Significant and reliable MMN and P3 activity, typical event-related potentials (ERPs) associated with an auditory oddball paradigm, were measured while experiments were administered using the Raspberry Pi 2. While latency differences in ERP triggering were observed between systems, these differences reduced power only marginally, likely due to the reduced processing power of the Raspberry Pi 2. COMPARISON WITH EXISTING METHOD: An auditory oddball task administered using the Raspberry Pi 2 produced similar ERPs to those derived from a desktop PC in a laboratory setting. Despite temporal differences and slight increases in trials needed for similar statistical power, the Raspberry Pi 2 can be used to design and present auditory experiments comparable to a PC. RESULTS: Our results show that the Raspberry Pi 2 is a low cost alternative to the desktop PC when administering EEG experiments and, due to its small size and low power consumption, will enable mobile EEG experiments unconstrained by a traditional laboratory setting.