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.

Assessment of sleep parameters in adults with persistent post-concussive symptoms.

OBJECTIVES: The primary aim of this study was to characterize sleep in adults with persistent post-concussive symptoms (PPCS). Secondary aims explored relationships between sleep parameters, injury characteristics, and symptom questionnaires. METHODS: This case-controlled, cross-sectional study recruited adults (18-65yrs) diagnosed with PPCS and age and sex-matched controls. Participants wore a wrist-worn actigraph for 3-7 nights and completed daily sleep diaries. Participants completed questionnaires examining daytime sleepiness, fatigue, anxiety/depressive symptoms, and sedentariness. Sleep parameters were compared between groups using Mann-Whitney U tests. Secondary analyses used two-way ANOVA and Spearman's rank correlations. RESULTS: Fifty adults with PPCS (43.7 ± 10.6yrs, 78 % female) and 50 controls (43.6 ± 11.0yrs) were included in this study. Adults with PPCS had significantly longer sleep onset latency (PPCS 16.99 ± 14.51min, Controls 8.87 ± 6.44min, p < 0.001) and total sleep time (PPCS 8.3 ± 1.0hrs, Control 7.6 ± 0.9hrs, p = 0.030) compared to controls, but woke up later (PPCS 7:57:27 ± 1:36:40, Control 7:17:16 ± 0:50:08, p = 0.026) and had poorer sleep efficiency (PPCS 77.9 ± 7.5 %, Control 80.8 ± 6.0 %, p = 0.019) than controls. Adults with PPCS reported more daytime sleepiness (Epworth Sleepiness Scale: PPCS 8.70 ± 4.61, Control 4.28 ± 2.79, p < 0.001) and fatigue (Fatigue Severity Scale: PPCS 56.54 ± 12.92, Control 21.90 ± 10.38, p < 0.001). Injury characteristics did not significantly affect sleep parameters in adults with PPCS. Actigraphy parameters were not significantly correlated to questionnaire measures. CONCLUSION: Several actigraphy sleep parameters were significantly altered in adults with PPCS compared to controls, but did not correlate with sleep questionnaires, suggesting both are useful tools in characterizing sleep in PPCS. Further, this study provides potential treatment targets to improve sleep difficulties in adults with PPCS.

The Impact of the Early COVID-19 Global Pandemic on Children Undergoing Active Cancer Treatment and Their Parents.

(1) Background: The COVID-19 global pandemic has impacted people worldwide with unique implications for vulnerable groups. In this cross-sectional study, we examined the impact of the early pandemic on children undergoing active cancer treatment and their parents. (2) Methods: In May 2020, 30 parents of children undergoing active cancer treatment completed an online survey regarding the impact of COVID-19 on their child's cancer care, perceived utility of telemedicine, and child and parent mental health status. (3) Results: Most participants (87%) reported that they did not experience any changes to major cancer treatments. Among those who reported using telemedicine, 78% reported this to be beneficial. Over half of the participants reported that their child's mental health status was worse now than prior to the COVID-19 global pandemic. Parent-reported child anxiety scores were significantly higher for those who reported changes to mental health care for their child compared to those who did not report the same, t(25.99) = -3.04, p = 0.005. (4) Conclusion: Child and parent mental health status were affected when compared to pre-pandemic. Telemedicine appears to be a promising complement to face-to-face meetings for some families and warrants further exploration.

Pediatric Hematopoietic Cell Transplantation: A Longitudinal Assessment of Health-Related Quality of Life of Pediatric Donors.

Pediatric donors may be at increased risk of psychological and social challenges following hematopoietic cell transplantation (HCT). Through a retrospective chart review, we evaluated the health-related quality of life (HRQL) of pediatric donors over time and examined facilitators and barriers to implementing a longitudinal psychosocial assessment. Fifty-one pediatric donors (M = 10.7 years, SD = 3.7) completed an HRQL questionnaire across six time points (T1 to T6) from prior to donation to 2 years after. Change in mean scores was assessed using a linear mixed-effect model for repeated measures design. Facilitators and barriers to implementation were examined. HRQL of pediatric donors improved between T1 and T6 with significant change in physical, emotional, and overall functioning. Facilitators to retention included the support of a clinical coordinator. Barriers to implementation included the absence of infrastructure to maintain contact with pediatric and their families. HRQL of pediatric donors of HCT improved steadily over time. Pattern of results suggests a need to further explore factors that contribute to change across time. Development of a longitudinal standardized assessment protocol that can be prospectively and feasibly implemented is integral to supporting the well-being of this group.

Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms.

Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism.

The Perceived Impact of COVID-19 on the Mental Health Status of Adolescent and Young Adult Survivors of Childhood Cancer and the Development of a Knowledge Translation Tool to Support Their Information Needs.

Background: Adolescent and young adult (AYA; 13 to 39 years) survivors of childhood cancer may be especially vulnerable to physical health and mental health concerns during the pandemic. We investigated the impact of COVID-19 on the mental health status of AYA survivors (Aim 1) and shared tailored, evidence-based health-related information on COVID-19 (Aim 2). Methods: Between May and June 2020, participants completed a cross-sectional online survey assessing their cancer history, current mental health status, and their COVID-19 information needs. Results: Ninety-four participants (78 females, 13 males, 2 non-binary) with a mean age of 26.9 years (SD = 6.2) were included in the final sample. Participants reported residing from 10 countries and 94% identified as White. Nearly half of the participants (49%) described their mental health status as worse now than before the pandemic. Thirty-nine participants (41%) that indicated their current mental health status was tied to fears/worries about their past cancer and treatment experienced a higher level of anxiety and PTSS than those who did not report the same. Most participants (77%) had not received any information related to the potential risks of COVID-19 and expressed an interest in receiving this information. In response, an infographic detailing recommended strategies for coping with mental health problems in the pandemic, along with preliminary study findings, was developed. Discussion: AYA survivors reporting their mental health status was linked to their past cancer experienced poorer mental health. There is a value to educating survivors on their potential health risks, but accounting for their perceived mental health vulnerabilities should be considered when disseminating knowledge. The use of an infographic is a unique contribution towards the development of innovative and personalized means of sharing health education to this vulnerable yet resilient group. This research on the mental health status of AYA survivors very early in the pandemic informs continued initiatives investigating the rapidly changing nature of how COVID-19 may impact AYA survivors today and in the future.

Nonlinear age effects in tactile processing from early childhood to adulthood.

BACKGROUND: Tactile processing plays a pivotal role in the early stages of human development; however, little is known about tactile function in young children. An understanding of how tactile processing changes with age from early childhood to adulthood is fundamental in understanding altered tactile experiences in neurodevelopmental disorders, such as autism spectrum disorder. METHODS: In this cross-sectional study, 142 children and adults aged 3-23 years completed a vibrotactile testing battery consisting of 5 tasks, which rely on different cortical and cognitive mechanisms. The battery was designed to be suitable for testing in young children to investigate how tactile processing changes from early childhood to adulthood. RESULTS: Our results suggest a pattern of rapid, age-related changes in tactile processing toward lower discrimination thresholds (lower discrimination thresholds = greater sensitivity) across early childhood, though we acknowledge limitations with cross-sectional data. Differences in the rate of change across tasks were observed, with tactile performance reaching adult-like levels at a younger age on some tasks compared to others. CONCLUSIONS: While it is known that early childhood is a period of profound development including tactile processing, our data provides evidence for subtle differences in the developmental rate of the various underlying cortical, physical, and cognitive processes. Further, we are the first to show the feasibility of vibrotactile testing in early childhood (<6 years). The results of this work provide estimates of age-related differences in performance, which could have important implications as a reference for investigating altered tactile processing in developmental disorders.

Health related quality of life in children with sickle cell disease: A systematic review and meta-analysis.

This review had three aims: 1) describe the measures used to assess health-related quality of life (HRQL) in pediatric patients diagnosed with sickle cell disease (SCD); 2) document the biopsychosocial factors related to HRQL in pediatric patients diagnosed with SCD; and 3) complete a meta-analysis comparing HRQL in pediatric patients diagnosed with SCD to healthy controls. Included studies were published in English, quantitatively assessed HRQL as a primary aim, in both SCD and controls, and included participants between 0 and 21 years of age. The final review included 66 articles, with a total of 8642 participants with SCD, 4 months-21 years of age, and 62,458 controls, 5-27 years of age. HRQL was predominately measured using the Pediatric Quality of Life Inventory Generic Core and Sickle Cell Disease Module. Meta-analyses revealed children with SCD had significantly worse HRQL compared to healthy controls (standardized mean difference = -0.93, 95% CI = -1.25, -0.61, p < 0.00001). Worse HRQL was associated with more severe SCD, female sex, and pain. The findings indicate that children with SCD are at risk for worse HRQL compared to their healthy peers and their HRQL may be impacted by several biopsychosocial factors. Future research is needed to examine how sociocultural factors uniquely impact this population and their overall quality of life.

Autism interest intensity in early childhood associates with executive functioning but not reward sensitivity or anxiety symptoms.

LAY ABSTRACT: Personal interests in autism are a source of joy, pride, and assist with the formation of social relationships. However, highly intense engagement can also interfere with other activities including activities of daily living. Theories have suggested that intense interests relate to executive functioning, reward sensitivity, and anxiety symptoms; but none of these theories have been tested in early childhood. Understanding which behavioral traits relate to intense interests in early childhood could help understand how intense interests may emerge, while also providing clues for how to manage interest intensity and best promote the many benefits of personal interests. We recruited families with autistic and non-autistic children aged 3-6 years. Parents completed questionnaires to assess children's interest diversity and intensity, executive functioning, reward sensitivity, and anxiety symptoms. We found that for autistic and non-autistic children, greater difficulty shifting attention between activities related to more intense interests. In autistic children only, difficulty with inhibitory control of attention also related to more intense interests. However, reward sensitivity and anxiety symptoms did not relate to interest intensity. Based on these observations, assisting young children with developing executive functioning skills could help with mediating the interference of interests in daily life to ultimately promote the many benefits of personal interests.

Characterizing pain in long-term survivors of childhood cancer.

Many long-term survivors of childhood cancer (LTSCC), individuals at least 5 years post-diagnosis or 2 years post-treatment, experience late- and long-term effects from their treatments, including pain. Yet, pain is poorly understood among LTSCC. The current study aimed to (1a) describe rates and multiple dimensions of pain; (1b) identify patterns of chronic pain; and (2) test correlates of chronic pain in LTSCC. Survivors (n = 140; 48.6% male, Mage = 17.3 years (range = 8-25)) were recruited from across Canada. Between 2017 and 2019, participants completed the Pain Questionnaire, Pain Catastrophizing Scale, Pediatric Quality of Life Inventory, Patient-Reported Outcome Measurement Information System (PROMIS)-Pain Interference, Anxiety, and Depression scales, Child Posttraumatic Stress Scale, the Posttraumatic Stress Disorder Checklist for the DSM-V, and the Cancer Worry Scale. RESULTS: Twenty-six percent of LTSCC reported experiencing chronic pain. Exploratory cluster analysis showed 20% of survivors had moderate to severe chronic pain based on measures of pain intensity and interference. The combination of higher posttraumatic stress symptoms, older current age, more pain catastrophizing, and sex (being female) significantly predicted the presence of chronic pain in logistic regression, χ2 (4, N = 107) = 28.10, p < .001. Higher pain catastrophizing (OR = 1.09; 95% CI = 1.02-1.16), older current age (OR = 1.20; 95% CI = 1.07-1.34), and higher posttraumatic stress (OR = 1.92; 95% CI = 1.01-3.63) were significant predictors of chronic pain. LTSCC should be screened for the presence and magnitude of chronic pain during long-term follow-up visits so appropriate interventions can be offered and implemented. Future research should investigate pain interventions tailored for this population. RELEVANCE: Findings support regular screening for the presence and magnitude of chronic pain in survivors of childhood cancer in long-term follow-up care.

Age-related differences in resting state functional connectivity in pediatric migraine.

BACKGROUND: Migraine affects roughly 10% of youth aged 5-15 years, however the underlying mechanisms of migraine in youth are poorly understood. Multiple structural and functional alterations have been shown in the brains of adult migraine sufferers. This study aims to investigate the effects of migraine on resting-state functional connectivity during the period of transition from childhood to adolescence, a critical period of brain development and the time when rates of pediatric chronic pain spikes. METHODS: Using independent component analysis, we compared resting state network spatial maps and power spectra between youth with migraine aged 7-15 and age-matched controls. Statistical comparisons were conducted using a MANCOVA analysis. RESULTS: We show (1) group by age interaction effects on connectivity in the visual and salience networks, group by sex interaction effects on connectivity in the default mode network and group by pubertal status interaction effects on connectivity in visual and frontal parietal networks, and (2) relationships between connectivity in the visual networks and the migraine cycle, and age by cycle interaction effects on connectivity in the visual, default mode and sensorimotor networks. CONCLUSIONS: We demonstrate that brain alterations begin early in youth with migraine and are modulated by development. This highlights the need for further study into the neural mechanisms of migraine in youth specifically, to aid in the development of more effective treatments.

Perceived Health among Adolescent and Young Adult Survivors of Childhood Cancer.

Survivors of childhood cancer (SCCs) are at increased risk of late effects, which are cancer- and treatment-related side-effects that are experienced months to years post-treatment and encapsulate a range of physical, cognitive and emotional problems including secondary malignancies. Perceived health can serve as an indicator of overall health. This study aims to (1) understand how a patient reported outcome (PRO) of perceived health of SCCs compares to controls who have not had a cancer diagnosis and (2) examine the relationships between perceived health and demographic and clinical variables, and health behavior. A total of 209 SCCs (n = 113 (54.10%) males; median age at diagnosis = 6.50 years; median time off treatment = 11.10 years; mean age at study = 19.00 years) were included. SCCs completed annual assessments as part of Long-Term Survivor Clinic appointments, including a question on perceived health answered on a five-point Likert scale. Data were collected retrospectively from medical charts. Perceived health of SCCs was compared to a control group (n = 836) using data from the 2014 Canadian Community Health Survey. Most SCCs (67%) reported excellent or very good health. The mean perceived health of SCCs (2.15 ± 0.91) was not statistically different from population controls (2.10 ± 0.87). Pain (B = 0.35; p < 0.001), physical activity (B = -0.39; p = 0.013) and concerns related to health resources (B = 0.59; p = 0.002) were significant predictors of perceived health. Factors shown to influence SCCs' perceived health may inform interventions. Exploration into how SCCs develop their conception of health may be warranted.

Macromolecule suppressed GABA levels show no relationship with age in a pediatric sample.

The inhibitory neurotransmitter γ-Aminobutyric acid (GABA) plays a crucial role in cortical development. Therefore, characterizing changes in GABA levels during development has important implications for the study of healthy development and developmental disorders. Brain GABA levels can be measured non-invasively using GABA-edited magnetic resonance spectroscopy (MRS). However, the most commonly used editing technique to measure GABA results in contamination of the GABA signal with macromolecules (MM). Therefore, GABA measured using this technique is often referred to as GABA+ . While few in number, previous studies have shown GABA+ levels increase with age during development. However, these studies are unable to specify whether it is specifically GABA that is increasing or, instead, if levels of MM increase. In this study, we use a GABA-editing technique specifically designed to suppress the MM signal (MM-supp GABA). We find no relationship between MM-supp GABA and age in healthy children aged 7-14 years. These findings suggest that the relationship between GABA+ and age is driven by changes in MM levels, not by changes in GABA levels. Moreover, these findings highlight the importance of accounting for MM levels in MRS quantification.

GABA and glutamate in pediatric migraine.

Migraine is one of the top 5 most prevalent childhood diseases; however, effective treatment strategies for pediatric migraine are limited. For example, standard adult pharmaceutical therapies are less effective in children and can carry undesirable side effects. To develop more effective treatments, improved knowledge of the biology underlying pediatric migraine is necessary. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions in adults with migraine; however, they have yet to be assessed in children with migraine. Using MRS and GABA-edited MRS, we show that children (7-13 years) with migraine and aura had significantly lower glutamate levels in the visual cortex compared to controls, the opposite to results seen in adults. In addition, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together, this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to pediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in development of more effective treatments.

The Intergenerational Transmission of Chronic Pain from Parents to Survivors of Childhood Cancer.

BACKGROUND: Among youth with chronic non-cancer pain, 50% have parents with chronic pain. These youth report significantly more pain interference and posttraumatic stress symptoms (PTSS), and worse health-related quality of life (HRQL) than youth whose parents do not have chronic pain. Additionally, parent chronic pain is linked to increased child anxiety and depressive symptoms. Survivors of childhood cancer (SCCs) are at risk of pain and negative psychosocial outcomes and therefore may be especially vulnerable if their parents have chronic pain. Thus, the aims of the current study were to (1) identify rates of chronic pain among parents of SCCs, (2) test group differences in psychological symptoms in parents with chronic pain versus without, and (3) test group differences in pain interference, HRQL, anxiety, depression, and PTSS in SCCs with parents with chronic pain versus without. METHODS: 122 SCCs (Mean age = 15.8, SD = 4.8, 45.7% male, Mean age at diagnosis = 5.9, SD = 4.7) and their parents were recruited from across Canada to complete online questionnaires. Parents were asked if they have had pain for at least three consecutive months and completed the brief symptom inventory (BSI) as a measure of psychological symptomatology. Survivors completed the pain questionnaire, patient reported outcomes measurement information system (PROMIS)-pain interference, anxiety, and depression measures, child posttraumatic stress scale, posttraumatic stress disorder checklist for the Diagnostic and Statistical Manual of Mental Disorders, and the pediatric quality of life inventory. RESULTS: Forty-three (39%) parents of SCCs reported having chronic pain. Of the 29 survivors who had chronic pain, 14 (48%) also had parents with chronic pain. Parents with chronic pain reported significantly higher scores on the BSI than parents without chronic pain, F(1, 116) = 5.07, p = 0.026. SCCs with parents with versus without chronic pain reported significantly higher PTSS F(1, 105) = 10.53, p = 0.002 and depressive symptoms F(1, 102) = 6.68, p = 0.011. No significant differences were found across the other variables tested. CONCLUSIONS: Findings suggest that survivors' parents' own pain is prevalent and is related to survivors' increased depressive symptoms and PTSS, but not anxiety, pain interference, or HRQL. Future research should explore whether parents may benefit from psychological intervention after their child has been diagnosed with cancer and how this could improve outcomes for their child.