Associations Between Changes in Psychological Resilience and Resting-State Functional Connectivity Throughout Pediatric Concussion Recovery.

Purpose: This study investigated the association between psychological resilience and resting-state network functional connectivity of three major brain networks in pediatric concussion. Methods: This was a substudy of a randomized controlled trial, recruiting children with concussion and orthopedic injury. Participants completed the Connor-Davidson Resilience 10 Scale and underwent magnetic resonance imaging at 72 h and 4-weeks postinjury. We explored associations between resilience and connectivity with the default mode network (DMN), central executive network (CEN), and salience network (SN) at both timepoints and also any change that occurred over time. We also explored associations between resilience and connectivity within each network. Results: A total of 67 children with a concussion (median age = 12.87 [IQR: 11.79-14.36]; 46% female) and 30 with orthopedic injury (median age = 12.27 [IQR: 11.19-13.94]; 40% female) were included. Seed-to-voxel analyses detected a positive correlation between 72-h resilience and CEN connectivity in the concussion group. Group moderated associations between resilience and SN connectivity at 72 h, as well as resilience and DMN connectivity over time. Regions-of-interest analyses identified group as a moderator of longitudinal resilience and within-DMN connectivity. Conclusions: These results suggest that neural recovery from concussion could be reliant on resilience. Resilience was related to functional connectivity with three of the main networks in the brain that are often impacted by concussion. Improving resilience might be investigated as a modifiable variable in children as both a protective and restorative in the context of concussion. Clinical Trial Registration Identifier: NCT05105802. PedCARE+MRI team (see Supplementary Appendix S1).

Correction: Development of Therapeutic Alliance and Social Presence in a Digital Intervention for Pediatric Concussion: Qualitative Exploratory Study.

[This corrects the article DOI: 10.2196/49133.].

Acceptability, usability, and credibility of a mindfulness-based digital therapeutic for pediatric concussion: A mixed-method study.

Background: The ability to cope with concussion symptoms and manage stress is an important determinant of risk for prolonged symptoms. Objective: This open-label mixed-methods pilot study assessed the acceptability and credibility of a mindfulness-based intervention delivered through a digital therapeutic (DTx; therapeutic smartphone app) for pediatric concussion. Methods: Participants aged 12 to 18 years were recruited from an emergency department within 48 hours of a concussion (acute cohort) or from a tertiary care clinic at least 1-month post-concussion (persisting symptoms cohort). Participants completed a novel 4-week mindfulness-based intervention, for 10 to 15 minutes/day, at a minimum of 4 days/week. At 2 weeks, participants completed a credibility and expectancy questionnaire. At 4 weeks, participants completed questionnaires assessing satisfaction, usability and working alliance, as well as a semi-structured phone interview. Results: Ten participants completed the study outcomes (7 acute; 3 persisting symptoms). The intervention was perceived as credible (median/max possible = 6.50/9.00 [6.83,8.75]) and DTx was usable (median/max possible = 70.00/100.00 [55.00,82.50]). Participants rated their satisfaction with the DTx (median/max possible = 27.00/32.00 [24.50,29.50]) and the working alliance with the digital mindfulness guides (median/max possible = 3.92/5.00 [3.38-4.33]) as high. Four themes were identified from the qualitative data: (a) positive attributes; (b) negative attributes; (c) ideas for modifications; and (d) technical issues. Conclusion: Results show modifications to the DTx, instructions and mindfulness intervention, and potential ways to increase adherence by leveraging positive attributes. A randomized control trial will assess the effectiveness of the DTx MBI to decrease the risk of persisting symptoms and reduce the symptom burden following pediatric concussion.

Development of Therapeutic Alliance and Social Presence in a Digital Intervention for Pediatric Concussion: Qualitative Exploratory Study.

BACKGROUND: Despite the promising benefits of self-guided digital interventions for adolescents recovering from concussion, attrition rates for such interventions are high. Evidence suggests that adults can develop therapeutic alliance with self-guided digital interventions, which is in turn associated with intervention engagement. However, no research has examined whether adolescents develop therapeutic alliance with self-guided digital interventions and what factors are important to its development. Additionally, social presence-the extent to which digital encounters feel like they are occurring in person-may be another relevant factor to understanding the nature of the connection between adolescents and a self-guided digital intervention, though this has yet to be explored. OBJECTIVE: This qualitative study explored the extent to which adolescents recovering from concussion developed therapeutic alliance and social presence during their use of a self-guided digital mindfulness-based intervention. Additionally, this study aimed to determine factors important to adolescents' development of therapeutic alliance and social presence with the intervention. METHODS: Adolescents aged between 12 and 17.99 years who sustained a concussion were recruited from 2 sites: a pediatric emergency department up to 48 hours after a concussion and a tertiary care clinic over 1 month following a concussion to capture adolescents who had both acute and persisting symptoms after concussion. Participants (N=10) completed a 4-week mindfulness-based intervention delivered through a smartphone app. Within the app, participants listened to audio recordings of mindfulness guides (voice actors) narrating psychoeducation and mindfulness practices. At 4 weeks, participants completed questionnaires and a semistructured interview exploring their experience of therapeutic alliance and social presence with the mindfulness guides in the intervention. RESULTS: Themes identified within the qualitative results revealed that participants developed therapeutic alliance and social presence by "developing a genuine connection" with their mindfulness guides and "sensing real people." Particularly important to the development of therapeutic alliance and social presence were the mindfulness guides' "personal backgrounds and voices," such that participants felt more connected to the guides by knowing information about them and through the guides' calm tone of voice in audio recordings. Quantitative findings supported qualitative results; participants' average score for therapeutic alliance was far above the scale midpoint, while the mixed results for social presence measures aligned with qualitative findings that participants felt that the mindfulness guides seemed real but not quite as real as an in-person connection would. CONCLUSIONS: Our data suggest that adolescents can develop therapeutic alliance and social presence when using digital interventions with no direct human contact. Adolescents' development of therapeutic alliance and social presence with self-guided digital interventions can be bolstered by increasing human-like qualities (eg, real voices) within interventions. Maximizing therapeutic alliance and social presence may be a promising way to reduce attrition in self-guided digital interventions while providing accessible treatment.

Longitudinal Brain Perfusion and Symptom Presentation Following Pediatric Concussion: A Pediatric Concussion Assessment of Rest and Exertion+MRI (PedCARE+MRI) Substudy.

Emerging evidence suggests that advanced neuroimaging modalities such as arterial spin labelling (ASL) might have prognostic utility for pediatric concussion. This study aimed to: 1) examine group differences in global and regional brain perfusion in youth with concussion or orthopedic injury (OI) at 72 h and 4 weeks post-injury; 2) examine patterns of abnormal brain perfusion within both groups and their recovery; 3) investigate the association between perfusion and symptom burden within concussed and OI youths at both time-points; and 4) explore perfusion between symptomatic and asymptomatic concussed and OI youths. Youths ages 10.00-17.99 years presenting to the emergency department with an acute concussion or OI were enrolled. ASL-magnetic resonance imaging scans were conducted at 72 h and 4 weeks post-injury to measure brain perfusion, along with completion of the Health Behavior Inventory (HBI) to measure symptoms. Abnormal perfusion clusters were identified using voxel-based z-score analysis at each visit. First, mixed analyses of covariance (ANCOVAs) investigated the Group*Time interaction on global and regional perfusion. Post hoc region of interest (ROI) analyses were performed on significant regions. Second, within-group generalized estimating equations investigated the recovery of abnormal perfusion at an individual level. Third, multiple regressions at each time-point examined the association between HBI and regional perfusion, and between HBI and abnormal perfusion volumes within the concussion group. Fourth, whole-brain one-way ANCOVAs explored differences in regional and abnormal perfusion based on symptomatic status (symptomatic vs. asymptomatic) and OIs at each time-point. A total of 70 youths with a concussion [median age (interquartile range; IQR) = 12.70 (11.67-14.35), 47.1% female] and 29 with an OI [median age (IQR) = 12.05 (11.18-13.89), 41.4% female] were included. Although no Group effect was found in global perfusion, the concussion group showed greater adjusted perfusion within the anterior cingulate cortex/middle frontal gyrus (MFG) and right MFG compared with the OI group across time-points (ps ≤ 0.004). The concussion group showed lower perfusion within the right superior temporal gyrus at both time-points and bilateral occipital gyrus at 4 weeks, (ps ≤ 0.006). The number of hypoperfused clusters was increased at 72 h compared with 4 weeks in the concussion youths (p < 0.001), but not in the OIs. Moreover, Group moderated the HBI-perfusion association within the left precuneus and superior frontal gyrus at both time-points, (ps ≤ 0.001). No association was found between HBI and abnormal perfusion volume within the concussion group at any visits. At 4 weeks, the symptomatic sub-group (n = 10) showed lower adjusted perfusion within the right cerebellum and lingual gyrus, while the asymptomatic sub-group (n = 59) showed lower adjusted perfusion within the left calcarine, but greater perfusion within the left medial orbitofrontal cortex, right middle frontal gyrus, and bilateral caudate compared with OIs. Yet, no group differences were observed in the number of abnormal perfusion clusters or volumes at any visit. The present study suggests that symptoms may be associated with changes in regional perfusion, but not abnormal perfusion levels.

Associations between psychological resilience and metrics of white matter microstructure in pediatric concussion.

This study investigated associations between psychological resilience and characteristics of white matter microstructure in pediatric concussion. This is a case control study and a planned substudy of a larger randomized controlled trial. Children with an acute concussion or orthopedic injury were recruited from the emergency department. Participants completed both the Connor-Davidson Resilience Scale 10 and an MRI at 72 h and 4-weeks post-injury. The association between resiliency and fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) at both timepoints were examined. We examined whether these associations were moderated by group. The association between resiliency captured at 72 h and diffusion tensor imaging metrics at 4 weeks was also investigated. Clusters were extracted using a significance threshold of threshold-free cluster enhancement corrected p < .05. A total of 66 children with concussion (median (IQR) age = 12.88 (IQR: 11.80-14.36); 47% female) and 29 children with orthopedic-injury (median (IQR) age = 12.49 (IQR: 11.18-14.01); 41% female) were included. A negative correlation was identified in the concussion group between 72 h resilience and 72 h FA. Meanwhile, positive correlations were identified in the concussion group with concussion between 72 h resilience and both 72 h MD and 72 h RD. These findings suggest that 72 h resilience is associated with white matter microstructure of the forceps minor, superior longitudinal fasciculus, and anterior thalamic radiation at 72 h post-concussion. Resilience seems to be associated with neural integrity only in the acute phase of concussion and thus may be considered when researching concussion recovery.

Adolescents with a concussion have altered brain network functional connectivity one month following injury when compared to adolescents with orthopedic injuries.

Concussion is a mild traumatic brain injury (mTBI) with increasing prevalence among children and adolescents. Functional connectivity (FC) within and between the default mode network (DMN), central executive network (CEN) and salience network (SN) has been shown to be altered post-concussion. Few studies have investigated connectivity within and between these 3 networks following a pediatric concussion. The present study explored whether within and between-network FC differs between a pediatric concussion and orthopedic injury (OI) group aged 10-18. Participants underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scan at 4 weeks post-injury. One-way ANCOVA analyses were conducted between groups with the seed-based FC of the 3 networks. A total of 55 concussion and 27 OI participants were included in the analyses. Increased within-network FC of the CEN and decreased between-network FC of the DMN-CEN was found in the concussion group when compared to the OI group. Secondary analyses using spherical SN regions of interest revealed increased within-network FC of the SN and increased between-network FC of the DMN-SN and CEN-SN in the concussion group when compared to the OI group. This study identified differential connectivity patterns following a pediatric concussion as compared to an OI 4 weeks post-injury. These differences indicate potential adaptive brain mechanisms that may provide insight into recovery trajectories and appropriate timing of treatment within the first month following a concussion.

Association Between Preinjury Symptoms and Postconcussion Symptoms at 4 Weeks in Youth.

OBJECTIVE: To investigate whether preinjury physical, emotional, cognitive, and sleep symptoms on the Post-Concussion Symptoms Inventory (PCSI) are associated with persistent postconcussion symptoms (PPCS) at 4 weeks and whether any associations are moderated by sex or age. STUDY SETTING AND PARTICIPANTS: A total of 3063 participants with acute concussion, presenting to 9 Canadian pediatric emergency departments, were enrolled from August 2013 to June 2015. DESIGN: A planned secondary analysis of a prospective, multicenter cohort study (Predicting Persistent Post-concussive Problems in Pediatrics or 5P). Primary outcome was PPCS at 4 weeks, defined as 3 or more new or worsening individual symptoms compared with the preinjury score at 28 days on the PCSI. The association between preinjury scores and PPCS was analyzed with a multivariable logistic regression analysis that included preinjury, sex, age, sex × preinjury, and age × preinjury interactions as predictors. Missing baseline covariates were imputed. RESULTS: A total of 2123 (n = 844 [39.8%] girls; median [IQR] age = 12.9 [10.7, 15.0] participants were included in the analysis. Preinjury physical symptom score was associated with PPCS at 4 weeks (χ2 = 13.87, df = 6, P = .031). The preinjury emotional score also contributed to the variability in PPCS (χ2 = 11.79, df = 6, P = .067). While girls reported higher preinjury physical, emotional, and cognitive scores than boys, neither sex nor age interacted with preinjury to predict PPCS at 4 weeks. Independent of age and sex, preinjury physical symptoms were associated with PPCS at 4 weeks (OR = 1.40; 95% CI, 1.15-1.70). CONCLUSION: Preinjury physical symptoms are associated with the probability of having PPCS at 4 weeks postconcussion independent of age and sex. Providers should consider preinjury symptoms to inform prognosis and recovery management.

The mutagenicity of urban particulate matter in an enzyme free system is associated with the generation of reactive oxygen species.

Urban particulate matter (UPM) contributes to lung cancer incidence. UPM has been shown to be genotoxic to mammalian cells and to induce mutations in the Ames assay. Here, we have studied the induction of mutations generated by direct acting mutagenic components of UPM, using the supF forward mutation assay. Plasmid pSP189 was exposed to UPM in aqueous solution in the presence of sucrose buffer, to reduce strand breaks. The mutation frequency induced by 1 microg/microl UPM was 4.99 mutants per 10(4) colonies. This was reduced to 0.84 and 1.48 mutants per 10(4) colonies by addition of mannitol (1 mM) or EDTA (1 mM), respectively. A large percentage of mutant plasmids contained frameshift mutations (57%), and 31% of mutant plasmids contained multiple mutations. Of the base substitution mutations, 88% were at GC pairs, with twice as many transversions as transitions. The types of mutations induced, the reduction of mutagenicity by the inclusion of the free radical scavenger, mannitol, or the metal chelator, EDTA, and the sequence context of the induced mutations all support the conclusion that the majority of mutations were induced by reactive oxygen species generated by metal ions present in the UPM. Most mutation studies with UPM have focused on organic carcinogens present on UPM. Our results highlight the potential contribution of metal ions to the mutagenicity of UPM.

Genotoxicity of size-fractionated samples of urban particulate matter.

Urban particulate matter (UPM) includes particles of size smaller than 10 microm (PM10), which may impact on human respiratory and cardiovascular health. It has been reported previously that PM10 can induce DNA damage. We have collected size-fractionated PM10 at the roadside and measured the induction of DNA damage by different-sized UPM using the alkaline Comet assay and the plasmid strand-break assay. We found that foil disks were more suitable for collecting UPM than quartz fiber filters, as the UPM could be easily extracted from the foil disks and accurately weighed. Using the Comet assay, all size fractions induced DNA damage in A549 lung epithelial cells, with the finer fractions (D50% = 0.65 microm and lower) inducing the most damage. In the plasmid strand-break assay, in which DNA damage is induced by free-radical species generated in solution, the most damage was also induced by the finer fractions, although the finest fraction (D50% < 0.43 microm) did not induce as much damage as D50% = 0.65 and 0.43 microm. When an organic extract of a standard UPM sample was compared to the whole particles and the washed particles in the Comet assay, it was found that around 75% of the damage induced by the whole UPM could be induced by the organic extract. These results show that finer particulates have the greatest ability to induce DNA damage in lung epithelial cells and naked DNA, and that both organic and inorganic components of the UPM contribute to its genotoxic effects.