Combined oral contraceptives and mental health: Are adolescence and the gut-brain axis the missing links?

Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary-gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.

Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE): A randomized controlled trial.

BACKGROUND: As the prevalence of chemotherapy-related cognitive impairment rises, investigation into treatment options is critical. The objectives of this study were to test the effects of an aerobic exercise intervention initiated during chemotherapy compared to usual care (wait list control condition) on (1) objectively measured cognitive function and self-reported cognitive function, as well as on (2) the impact of cognitive impairment on quality of life (QOL) postintervention (commensurate with chemotherapy completion). METHODS: The Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE) trial was a two-arm, two-center randomized controlled trial conducted in Ottawa and Vancouver (Canada). Fifty-seven women (Mage, 48.8 ± 10 years) diagnosed with stage I-III breast cancer and awaiting chemotherapy were randomized to aerobic exercise initiated with chemotherapy (nEX = 28) or usual care during chemotherapy with aerobic exercise after chemotherapy completion (nUC = 29). The intervention lasted 12-24 weeks and consisted of supervised aerobic training and at-home exercise. The primary outcome was objective cognitive function measured via 13 neuropsychological tests (standardized to M ± SD, 0 ± 1); secondary outcomes of self-reported cognitive function and its impact on QOL were assessed via questionnaires. Data collected pre- and postintervention (the primary end point) were analyzed. RESULTS: Although no significant differences between groups were found for objective cognitive function outcomes postintervention after accounting for multiple testing, four of six self-reported cognitive function outcomes showed significant differences favoring the aerobic exercise group. CONCLUSIONS: Among women initiating chemotherapy for breast cancer, aerobic exercise did not result in significant differences in objective cognitive function postintervention after chemotherapy completion; however, the results do support the use of this intervention for improving self-reported cognitive function and its impact on QOL.

The effect of Transcendental Meditation on self-esteem, self-efficacy, and gratitude, for increasing empowerment of female youth in Uganda.

This longitudinal study with female youth in the slums of Kampala, Uganda (n = 130), explored the impact of the Transcendental Meditation® (TM®) technique on self-esteem, the primary outcome measure, and self-efficacy, gratitude, hope, tiredness, and resilience as secondary outcomes. Quality-of-life behaviors were also assessed, including excessive alcohol use. After baseline testing participants learned TM over five consecutive days. Participants practiced TM at home for 20 min twice a day and attended two follow-up sessions. Post-testing occurred at five months. Significant improvements in self-esteem (p < .001), self-efficacy (p < .001), gratitude (p < .001), and tiredness (p = .05) were found. A decrease in excessive alcohol use was also observed (p = .02). At eight months a short answer questionnaire showed improved physical health, decreased stress and anxiety levels, and improved relationships in the family and community. Our findings have important implications for enhancing the well-being and empowerment of these vulnerable female youth.

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.

Mindfulness-based stress reduction and cognitive function among breast cancer survivors: A randomized controlled trial.

BACKGROUND: Breast cancer (BC) survivors frequently report changes in cognition after chemotherapy. Mindfulness may benefit survivors by mitigating cancer-related cognitive impairment. As part of a larger study investigating the effects of mindfulness-based stress reduction (MBSR) for BC survivors living with neuropathic pain, the authors assessed whether MBSR would have an effect on cognitive outcomes. METHODS: Participants were randomized to an MBSR intervention group (n = 30) or a waitlist control group (n = 30). Cognitive assessments were administered at 3 time points: at baseline, 2 weeks, and 3 months post-MBSR in the intervention group and at equivalent time intervals for the control group. Multilevel models were used to assess whether MBSR significantly improved task performance at each time point. RESULTS: MBSR participants showed a significantly greater reduction in prospective and retrospective memory failures at 2 weeks postintervention. No effects of MBSR were noted for objective assessments. CONCLUSIONS: These results suggest that MBSR training reduces subjective (but not objective) memory-related impairments in BC survivors who receive treatment with chemotherapy. This study provides insight into a noninvasive intervention to ameliorate memory difficulties in BC survivors.

The regulatory roles of progesterone and estradiol on emotion processing in women.

Emotion processing is known to interact with memory. Ovarian steroid hormones, such as progesterone and estradiol, modulate emotion processing and memory. However, it is unclear how these hormones influence brain activity when emotion processing is integrated with working memory (WM). Therefore, the objective of this study was to examine the relationship between endogenous hormonal concentration and brain activity during emotion processing in the context of a WM n-back task in 74 young women using functional magnetic resonance imaging (fMRI). Results show that positive emotion processing activates reward-related areas, such as the caudate and putamen, whereas negative emotion processing activates a corticolimbic network, including the amygdala and hippocampus. Furthermore, our findings provide evidence that progesterone modulates more bottom-up brain activation during both positive and negative emotion processing, whereas estradiol activates lateralized, top-down regulation. These findings provide insight on the neural correlates of emotion processing during an n-back task in young women and highlight how important it is to consider women's endogenous hormonal concentration in neurobiological and cognition research.

A proof-of-concept sub-study exploring feasibility and preliminary evidence for the role of physical activity on neural activity during executive functioning tasks among young adults after cancer treatment.

BACKGROUND: Executive functioning (EF) deficits are troubling for adolescents and young adults (AYAs) after cancer treatment. Physical activity (PA) may enhance neural activity underlying EF among older adults affected by cancer. Establishing whether PA enhances neural activity among AYAs is warranted. As part of a two-arm, mixed-methods pilot randomized controlled trial (RCT), this proof-of-concept sub-study sought to answer the following questions: (1) is it feasible to use neuroimaging with EF tasks to assess neural activity changes following a 12-week PA intervention? And (2) is there preliminary evidence that a 12-week PA intervention enhances neural activity among AYAs after cancer treatment? METHODS: AYAs in the pilot RCT were approached for enrollment into this sub-study. Those who were eligible and enrolled, completed functional magnetic resonance imaging (fMRI) with EF tasks (letter n-back, Go/No Go) pre- and post-PA intervention. Sub-study enrollment, adherence to scheduled fMRI scans, outliers, missing data, and EF task performance data were collected. Data were analyzed with descriptive statistics, blood oxygen level dependent (BOLD) analyses, and paired sample t-tests. RESULTS: Nine eligible participants enrolled into this sub-study; six attended scheduled fMRI scans. One outlier was identified and was subsequently removed from the analytical sample. Participants showed no differences in EF task performance from pre- to post-PA intervention. Increases in neural activity in brain regions responsible for motor control, information encoding and processing, and decision-making were observed post-PA intervention (p < 0.05; n = 5). CONCLUSIONS: Findings  show that fMRI scans during EF tasks detected neural activity changes (as assessed by the BOLD signal) from pre- to post-PA intervention. Results thus suggest future trials confirming that PA enhances neural activity underlying EF are needed, though feasibility issues require careful consideration to ensure trial success. TRIAL REGISTRATION: clinicaltrials.gov, NCT03016728. Registered January 11, 2017, clinicaltrials.gov/ct2/show/NCT03016728.

Study protocol of the Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE) trial: a two-arm, two-centre randomized controlled trial.

BACKGROUND: Up to 75% of women diagnosed with breast cancer report chemotherapy-related cognitive changes (CRCC) during treatment, including decreased memory, attention, and processing speed. Though CRCC negatively impacts everyday functioning and reduces overall quality of life in women diagnosed with breast cancer, effective interventions to prevent and/or manage CRCC are elusive. Consequently, women seldom receive advice on how to prevent or manage CRCC. Aerobic exercise is associated with improved cognitive functioning in healthy older adults and adults with cognitive impairments. Accordingly, it holds promise as an intervention to prevent and/or manage CRCC. However, evidence from randomized controlled trials (RCTs) supporting a beneficial effect of aerobic exercise on CRCC is limited. The primary aim of the ACTIVATE trial is to evaluate the impact of supervised aerobic exercise on CRCC in women receiving chemotherapy for breast cancer. METHODS: The ACTIVATE trial is a two-arm, two-centre RCT. Women diagnosed with stage I-III breast cancer and awaiting neo-adjuvant or adjuvant chemotherapy are recruited from hospitals in Ottawa (Ontario) and Vancouver (British Columbia), Canada. Recruits are randomized to the intervention group (aerobic exercise during chemotherapy) or the wait-list control group (usual care during chemotherapy and aerobic exercise post-chemotherapy). The primary outcome is cognitive functioning as measured by a composite cognitive summary score (COGSUM) of several neuropsychological tests. Secondary outcomes are self-reported cognitive functioning, quality of life, and brain structure and functioning (measured by magnetic resonance imaging (MRI)/functional MRI and electroencephalography). Assessments take place pre-chemotherapy (pre-intervention), mid-way through chemotherapy (mid-intervention/mid-wait period), end of chemotherapy (post-intervention/post-wait period; primary endpoint), 16-weeks post-chemotherapy, and at 1-year post-baseline. DISCUSSION: Aerobic exercise is a promising intervention for preventing and/or managing CRCC and enhancing quality of life among women diagnosed with breast cancer. The ACTIVATE trial tests several novel hypotheses, including that aerobic exercise can prevent and/or mitigate CRCC and that this effect is mediated by the timing of intervention delivery (i.e., during versus post-chemotherapy). Findings may support prescribing exercise during (or post-) chemotherapy for breast cancer and elucidate the potential role of aerobic exercise as a management strategy for CRCC in women with early-stage breast cancer. TRIAL REGISTRATION: The trial was registered with the ClinicalTrials.gov database ( NCT03277898 ) on September 11, 2017.

Oral contraceptive use, especially during puberty, alters resting state functional connectivity.

Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.

Use of the birth control pill affects stress reactivity and brain structure and function.

Millions of women worldwide use oral contraceptives (i.e., birth control pill; OCs), often starting during puberty/adolescence; however, it is unknown how OC use during this critical period of development affects the brain, especially with regard to emotional working memory. Here, we examined stress reactivity, and brain structure and function in OC users using the Trier Social Stress Test and structural and functional magnetic resonance imaging (MRI). Our results show that OC use during puberty/adolescence gives rise to a blunted stress response and alters brain activation during working memory processing. OC use, in general, is also linked to increased prefrontal brain activation during working memory processing for negatively arousing stimuli. OC use is also related to significant structural changes in brain regions implicated in memory and emotional processing. Together, these findings highlight that OC use induces changes to brain structure and function and alters stress reactivity. These findings may provide a mechanistic insight for the increased vulnerability to mood-related mental illness in women after OC use.

Trait Mindfulness and Wellness in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, progressive, autoimmune, neurodegenerative disorder that can interfere with physical and psychological functioning, negatively affecting health-related quality of life (HRQoL). Fostering mindfulness may mitigate the negative consequences of MS on HRQoL. The relationship between mindfulness, mood and MS-related quality of life was investigated. In total, 52 individuals with MS completed questionnaires to examine the relationship between trait mindfulness and wellness. Higher levels of trait mindfulness were associated with better HRQoL, lower depression and anxiety, lower fatigue impact and fewer perceived cognitive deficits. Mindfulness interventions have the potential to enhance wellness in those living with MS.

Objective-subjective disparity in cancer-related cognitive impairment: does the use of change measures help reconcile the difference?

OBJECTIVE: Studies to date have found little correlation between subjective and objective measures of cognitive function in cancer patients, making it difficult to interpret the significance of their cognitive complaints. The purpose of this study was to determine if a stronger correlation would be obtained using measures of cognitive change rather than static scores. METHODS: Sixty women with early stage breast cancer underwent repeated cognitive assessment over the course of chemotherapy with a neuropsychological test battery (objective measure) and with the FACT-Cog (subjective measure). Their results were compared to 60 healthy women matched on age and education and assessed at similar intervals. We used multilevel modeling, with FACT-Cog as the dependent measure and ordinary least squares slopes of a neuropsychological summary score as the independent variable, to evaluate the co-variation between the subjective and objective measures over time RESULTS: Measures of both objective and subjective cognitive function declined over the course of chemotherapy in the breast cancer patients but there was no significant relationship between them, even when using change measures. Change in objective cognitive function was not related to change in anxiety or fatigue scores but the decline in perceived cognitive function was associated with greater anxiety and fatigue. CONCLUSIONS: The discrepancy in objective and subjective measures of cognition in breast cancer patients cannot be accounted for in terms of a failure to use change measures. Although the results are negative, we contend that this is the more appropriate methodology for analyzing cancer-related changes in cognition.

Repetition-lag memory training is feasible in patients with chronic stroke, including those with memory problems.

PRIMARY OBJECTIVE: Repetition-lag memory training was developed to increase individuals' use of recollection as opposed to familiarity in recognition memory. The goals of this study were to examine the feasibility of repetition-lag training in patients with chronic stroke and to explore whether the training might show suggestions of transfer to non-trained tasks. RESEARCH DESIGN: Quasi-experimental. METHODS AND PROCEDURES: Patients (n = 17) took part in six repetition-lag training sessions and their gains on the training and non-trained tasks were compared to those of age-matched healthy controls (n = 30). MAIN OUTCOMES AND RESULTS: All but two patients completed the training, indicating that the method is feasible with a wide range of patients with stroke. The amount patients gained on the training task was similar to that of healthy controls (that is, the Group × Time interactions were by-and-large not significant), suggesting that patients with stroke might benefit to the same degree as healthy adults from this training. Both groups showed some indication of transfer to the non-trained backward digit span task and visuospatial memory. CONCLUSIONS: These findings show that repetition-lag memory training is a possible approach with patients with stroke to enhance recollection. Further research on the method's efficacy and effectiveness is warranted.

Persistent cognitive changes in breast cancer patients 1 year following completion of chemotherapy.

Numerous studies have shown that there are acute cognitive side-effects of chemotherapy for breast cancer. Presumably, patients are more concerned about chronic treatment effects. This report from a prospective longitudinal study compares cognitive functioning in 56 breast cancer patients 1 year after chemotherapy to that of 56 healthy individuals. Neuropsychological test scores were combined into verbal memory, visual memory, working memory, and processing speed scores, as well as an overall summary score, and analyzed using multi-level growth modeling. Frequency of cognitive decline was assessed using regression-based change scores. There was significant rebound in the overall summary score from end of treatment to 1-year follow-up as well as a substantial reduction in the frequency of cognitive decline. However, more than one-third of the breast cancer patients who showed cognitive decline immediately following completion of chemotherapy showed persistent cognitive decline 1 year later. Furthermore, recovery was not seen in all cognitive domains. In fact, the rebound was significant only for working memory. Longer multi-site studies are recommended to explore the risk factors for and the permanence of these longer-term cognitive effects.

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).

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.

Smartphone App-Delivered Mindfulness-Based Intervention for Mild Traumatic Brain Injury in Adolescents: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Concussion in children and adolescents is a significant public health concern, with 30% to 35% of patients at risk for prolonged emotional, cognitive, sleep, or physical symptoms. These symptoms negatively impact a child's quality of life while interfering with their participation in important neurodevelopmental activities such as schoolwork, socializing, and sports. Early psychological intervention following a concussion may improve the ability to regulate emotions and adapt to postinjury symptoms, resulting in the greater acceptance of change; reduced stress; and recovery of somatic, emotional, and cognitive symptoms. OBJECTIVE: The primary objective of this study is to assess the feasibility of conducting a parallel-group (1:1) randomized controlled trial (RCT) to evaluate a digital therapeutics (DTx) mindfulness-based intervention (MBI) in adolescents aged 12 to <18 years. The attention-matched comparator intervention (a math game also used in previous RCTs) will be delivered on the same DTx platform. Both groups will be provided with the standard of care guidelines. The secondary objective is to examine intervention trends for quality of life; resilience; self-efficacy; cognition such as attention, working memory, and executive functioning; symptom burden; and anxiety and depression scores at 4 weeks after concussion, which will inform a more definitive RCT. A subsample will be used to examine whether those randomized to the experimental intervention group have different brain-based imaging patterns compared with those randomized to the control group. METHODS: This study is a double-blind Health Canada-regulated trial. A total of 70 participants will be enrolled within 7 days of concussion and randomly assigned to receive the 4-week DTx MBI (experimental group) or comparator intervention. Feasibility will be assessed based on the recruitment rate, treatment adherence to both interventions, and retention. All outcome measures will be evaluated before the intervention (within 7 days after injury) and at 1, 2, and 4 weeks after the injury. A subset of 60 participants will undergo magnetic resonance imaging within 72 hours and at 4 weeks after recruitment to identify the neurophysiological mechanisms underlying the potential benefits from MBI training in adolescents following a concussion. RESULTS: The recruitment began in October 2022, and the data collection is expected to be completed by September 2024. Data collection and management is still in progress; therefore, data analysis is yet to be conducted. CONCLUSIONS: This trial will confirm the feasibility and resolve uncertainties to inform a future definitive multicenter efficacy RCT. If proven effective, a smartphone-based MBI has the potential to be an accessible and low-risk preventive treatment for youth at risk of experiencing prolonged postconcussion symptoms and complications. TRIAL REGISTRATION: ClinicalTrials.gov NCT05105802; https://classic.clinicaltrials.gov/ct2/show/NCT05105802. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57226.

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.].

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.

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.