Adolescents presenting to either CHEO’s emergency department (ED) or 360cc after sustaining a direct or indirect mild traumatic brain injury (TBI) will be eligible to participate in this study if they (1) are aged 12 to <18 years; (2) have a diagnosed concussion (by a physician), (3) presented to the ED or 360cc within 7 days of TBI; (4) have a score >4 on the Predicting and Preventing Post-Concussive Problems in Pediatrics (5P) clinical risk score, a prediction rule to identify those at risk of poorer outcomes at 4 weeks postinjury [2]; and (5) are proficient in English [38]. To increase the probability of including adolescents with a true concussion, the adapted version of the American Congress of Rehabilitation Medicine [39] framework will be used [40]. Those with either 1 highest level of certainty symptom (dazed, confused, or trouble thinking within minutes after injury, difficulty remembering what happened just before or minutes after injury, and loss of consciousness) or 2 higher level of certainty symptoms (nausea or vomiting, headache, dizziness, clumsy or balance problems, blurred or double or change in vision, difficulty concentrating, and sensitivity to light or noise) immediately or within 1 hour of injury will be included.

Patients will be excluded if they present with TBIs with any of the following: (1) a Glasgow Coma Scale score of ≤13; (2) abnormality on standard neuroimaging studies [41], including positive head computed tomography findings (neuroimaging is not required, but may be performed if clinically indicated); (3) neurosurgical operative intervention, intubation, or intensive care required; (4) multisystem injuries with the treatment requiring hospital admission, operating room, or procedural sedation in ED (hospital admission for observation or management of ongoing concussion symptoms is not an exclusion criteria); (5) severe chronic neurological developmental delay resulting in communication difficulties; (6) intoxication to alcohol or drugs at the time of ED presentation as per clinician judgment; (7) no clear history of trauma as primary event to the concussion (eg, seizure, syncope, and migraine); (8) prior psychiatric hospitalization; (9) inability to obtain written informed consent or assent (eg, language barrier); (10) legal guardian not present (certain forms need to be completed by parents or legal guardians); (11) no internet and mobile or tablet access; and (12) currently in therapy.

In addition, patients will not be included in the magnetic resonance imaging (MRI) component if they present with the following: (1) previous neurological or neurodevelopmental disorder such as epilepsy, intellectual disability, or autism (history of attention-deficit or hyperactivity disorder or learning disability is not exclusionary); (2) previous stroke or transient ischemic attacks; (3) sedation medication (eg, propofol, ketamine, nitrous oxide, midazolam, benzodiazepines, and fentanyl) administered before or during ED visit; (4) inability to be present at the 72-hour (+48 or –48 hours) and 4-week (+5 or –5 days) MRI follow-up visits; and (5) medical contraindications to MRI (eg, claustrophobia, pregnancy, or presence of braces or spacers or other metal implants).

The CHEO Clinical Research Unit will provide data management services for this study and retain randomization codes. The randomization sequence will be created using R software (version 3.1.1; R Foundation for Statistical Computing) [42] and will be stratified by sex, with a 1:1 allocation using random blocks.

A statistician at the CHEO CRU (not involved in the study) will maintain the master list.

The day after enrollment and once all questionnaire data are complete, research assistants (RAs) will call participants over the phone, and RAs will log into REDCap (Research Electronic Data Capture; Vanderbilt University) to obtain the patient’s group allocation. Only the RAs who randomized participants will be unblinded. The research team will be blinded to data acquisition. In case of a serious adverse event, the principal investigator and appropriate research staff will be unblinded to the participant’s group.

To be delivered via the AmDTx platform (Figure 2), the targeted DTx MBI training consists of a 4- to 8-week custom-made program (containing 8-modules) for adolescents with concussion, including setting intentions and check-ins on mood and stress, audio-recorded lectures, guided meditations such as focused attention exercises, and journaling events (Table 1). Each standardized psychoeducation or meditation practice will be unlocked as the participant progresses through the MBI program. Participants will be encouraged to participate in the DTx MBI activities for approximately 10 minutes every day, for a minimum of 4 days a week, over the 4- to-8-week period. Those who choose to end their therapy on the fourth week will be immediately directed to module 8 Reviewing the program and how to maintain practice. Those who choose to continue for an additional 4 weeks will move on to modules 5 through 8. The curriculum is based on previously validated AmDTx MBI app protocols [27,43] and team expertise in youth MBI (Sonia Roth, Craig Mackie, MC, and AAL) and was peer reviewed by experts in the field and parent engagement leaders (Ana Maria Vranceanu, Jonathan Greenberg, and Erin McCarthy). The intervention was piloted on 10 pediatric participants with concussion, and their feedback was integrated into the MBI and protocol [36]. We will track meaningful in-app use time, defined as the time spent engaging in meditation, psychoeducation, self-monitoring, and self-reflection, with a minimum threshold of 3 minutes per day. Any use time <3 minutes will not be counted toward the total weekly minutes spent using the DTx.

To control for daily access to the AmDTx platform, expectation, and clinical attention bias, we created a sham DTx for the control group. The sham DTx will be delivered on the same main interface, within AmDTx; however, these participants will not have access to any of the MBI training or psychoeducational content. Their sham DTx will consist of playing an open-source math game called 2048 developed by Gabriele Cirulli [44]; this will be communicated to the control participants as cognitive training. The game requires participants to slide number tiles on a grid and combine them to create a tile with the number 2048. In a previous study, AmDTx was compared with 2048, revealing that 2048 did not reduce stress or improve psychological well-being in university students with anxiety [27]. Furthermore, 2048 was previously tested in a pediatric population with concussion, and the study found no evidence of harm or symptom improvement at 4 weeks [45]. It is expected that the control intervention will not bother individuals with sensitivity to light or high velocity motion because it lacks fast visuals or movement. The game is programmed to only be accessible for 10 minutes per day.

All participants will be followed weekly by a coach through SMS text messaging. The coaches’ role will be to ensure that the participants adhere to the intervention. All the participants will receive weekly text messages from a coach. These messages will be sent on the same day and time every week and will be limited to 160 characters. The coaches will use a standardized question and answer protocol developed by the team. Coaches will also remind the participants to complete their follow-up surveys.

Furthermore, both interventions are equipped with automated reminders (triggered by inactivity).

All the participants will receive standard of care [46] instructions pamphlet provided by RAs in the ED or at 360cc. The standard of care indicates that the patient refrains from physical and cognitive activities for 24 to 48 hours after injury. After the rest period, it is recommended that low-to-moderate levels of physical and cognitive activity be gradually started, including screen time. The activities should be performed at a level that does not result in the recurrence or exacerbation of symptoms. Adolescents must refrain from any activities that increase the risk of reinjury (eg, contact sports or anything with risk of falls) until fully asymptomatic and cleared by their primary care or other medical providers.

The prespecified thresholds (criteria for success), as outlined in Table 2 for the feasibility, are based on established benchmarks of previous feasibility trials [47,48] and our previous experience in recruiting pediatric patients with concussion from an ED [49]. We will use the traffic light system to determine whether proceeding to a full-scale trial is appropriate [50]. Progression can take place without any changes (green zone), with correctable adjustments (amber zone), or not occur because of issues that cannot be readily addressed (red zone). The decision to progress to a full-scale trial will be contingent on the criterion with the least favorable performance [50].

Table 3 provides an overview of all outcome measures collected and their specific end points.

Information about injuries will be collected from medical records and medical personnel using a standardized case report form. Details regarding the injury and acute signs and symptoms of concussion (ie, loss of consciousness, Glasgow Coma Scale scores, mechanism of injury, neurological status, and other clinical features) will be collected by RAs, with clarification by physicians when necessary. The data will be verified by the site investigator. To calculate the 5P clinical risk score [2], balance will be evaluated by the RA using the balance error scoring system [81], a widely used instrument in the field of sports concussion [82] for objective assessment of postural stability. Pubertal status will be measured using a puberty questionnaire [83]. The questionnaire is a 5-item, self-administered rating scale for pubertal development without pictorial representations or interviews. Demographic data (ie, household annual income and parental education level) will be used as a proxy of socioeconomic status (SES). SES will be collected to assess whether randomization is equally distributed in both groups. If SES is not equally represented in the sample, it will be controlled for in our analysis.

Studies have shown that physical activity can reduce anxiety, improve mood, and help alleviate postconcussive symptoms [84]. We will evaluate physical activity to ensure balance between groups; physical activity levels will be assessed using the Godin-Shepard Leisure-Time Physical Activity Questionnaire [85] on day 1 and then at 2, 4, and 8 weeks after injury.

Recruitment will be conducted similar to the successful Pediatric Concussion Assessment of Rest and Exertion multicenter concussion study [86]. When an adolescent with a mechanism of injury and symptoms consistent with concussion presents to the ED, the nurse will triage the child as per the existing protocols. Once in the ED, a member of the ED clinical team (ie, an ED volunteer) will introduce the study to families of potentially eligible children to inquire whether they are interested in learning more about the study. If so, the electronic charts of potentially eligible participants will be flagged, and the research team will be notified. At 360cc, a health information custodian who is a part of the circle of care will mention to the family that there is a study on children who have head injuries and ask if they are interested in learning more about the study. In both the ED and 360cc, the RA will then approach the family to discuss the research study, and if they are interested, the RA will complete the screening form on an iPad.

During the screening procedure, we will evaluate the likelihood that the patients had a definitive or probable concussion based on the aforementioned inclusion criteria. Their 5P clinical risk score [2] will also be calculated with the following variables: age, sex, prior concussion and length of recovery, history of migraine, slow answers to questions, balance, headache, sensitivity to noise, and feeling fatigued. Only patients with a 5P score >4 will be eligible for the study. Patients who are ineligible based on the initial screening will be thanked for their time. Eligible and willing parents along with adolescents capable of consenting on their own behalf will be asked for written informed consent, and the adolescents who are unable to provide consent on their own behalf will be asked for assent.

Once enrolled in the study, the families will complete a series of questionnaires in an electronic survey format using a portable tablet computer on REDCap [87]. The survey includes questions regarding patient demographics, preinjury and injury characteristics, a symptoms checklist, and diagnostic history.

The day following the ED or 360cc visit, participants will receive a phone call from an RA to randomize the participants to either the experimental or the control group and give instructions to register an account on a study-dedicated landing page using a unique link for each participant. Following registration, participants will install AmDTx on the mobile device of their choice. After creating an account and logging in to AmDTx, each participant will be automatically directed to their assigned intervention (MBI or control).

During this phone call, an MRI appointment will be scheduled for the participants who have agreed to participate in that component of the study. Participants will complete the surveys or questionnaires for day 1 and MRI screener. They will have the option of completing the survey via phone or REDCap.

The proposed duration of the app-based MBI is 4 to 8 weeks. After 4 weeks, all participants in the experimental group will be given the opportunity to pursue the MBI for an additional 4 weeks. At that time, participants in the control group will be offered to cross over and start the MBI intervention.

Participants will complete electronic follow-up questionnaires on REDCap at 1, 2, 4, and 8 weeks after enrollment and will have an in-person follow-up at 4 weeks for the cognitive assessment (and the MRI scan for a subset of participants). Cognitive testing will be conducted before brain scanning.

A subset of 60 participants (30 from each group) will undergo a 45-minute MRI scan at <72 hours and 4 weeks after injury. During the day 1 phone call, participants who have consented to the MRI component of the study will complete the MRI screener and schedule their MRI appointment.

Each scanning session will be approximately 1 hour and will include a high-resolution structural scan, arterial spin labeling, rs-fMRI, and magnetic proton spectroscopy (Table 4).

The CHEO Clinical Research Unit Data Coordinating Centre will be used as a central location for data processing and management. Data will be kept private and secured to industry standards for both clinical and patient-sensitive data in Canada. Data for the study will be collected and managed using REDCap [88] tools hosted and supported by the CHEO Research Institute. REDCap is a secure, web-based application designed to support data capture for research studies. Only members of the research team will be granted access to the database. Users will be assigned to Data Access Groups that will restrict their rights to viewing and entering data. For monitoring purposes, the study coordinator will be able to view the data. Within the Data Access Group, user privileges will be designated by the study coordinator to ensure that the research team members have only the minimum required rights to perform their duties. All identifying information that is collected will be flagged in the database and removed from data export unless the identifying information is required for statistical analysis (eg, date of birth).

Descriptive statistics will be used to summarize patient baseline characteristics and clinical information. The primary objective of this study is to assess the feasibility outcomes of the trial. This will be done by computing the observed points estimates for each criterion (eligibility, recruitment, adherence, credibility, and retention) and comparing them with our predefined red zone upper limits and green zone lower limits. The 3-tiered progression criteria will be used for each criterion (Textbox 1).

Mean and SDs will be computed for each collected measure. Pre-post correlations will be generated to assess preliminary evidence of efficacy signal for QoL, fatigue, symptoms, resiliency, self-efficacy, cognition, anxiety, depression, and mindfulness.

To acquire preliminary data on the association between the interventions and MRI metrics, per-protocol analyses will be conducted. A multivariable linear regression will be performed for each neuroimaging outcome, with age, sex, and handedness (for rs-fMRI) as covariates. If the groups differ at baseline on potentially confounding variables, such as attention-deficit or hyperactivity disorder, anxiety, medication, prior concussion, physical activity, and puberty, these variables will also be entered as covariates in the models. Per-protocol analyses will include only those participants who have adhered to the intervention.

The independent data safety monitoring board (DSMB) will consist of 1 independent pediatric ED physician, 1 neuropsychologist who specializes in pediatric concussion, and 1 statistician who is not involved in the research study. In keeping with the StaRChild Health guidelines [92], the DSMB will, in collaboration with the trial steering committee, establish safety outcomes and termination rules before the start of the study. The DSMB will be immediately advised of severe adverse events, and they will meet in case a serious adverse event occurs. The DSMB will meet annually to review enrollment, study procedures, form completion, data quality, loss to follow-up, and interim safety results. Given the low-risk intervention and no intention to stop the trial for benefit or futility, only an annual meeting will be required. On the basis of negative data trends (increased symptoms) and adverse events, the DSMB may decide to meet earlier than planned and may request unblinding if deemed necessary.

The safety outcomes include (1) severe worsening of symptoms identified on HBI reliable changes or (2) any symptoms requiring an unscheduled visit to the ED or primary care provider. If concussion symptoms worsen during the treatment to the degree that the participant requires an unscheduled visit to the ED or primary care provider, then symptoms will be considered as a possible adverse event. Symptoms could develop into an adverse event if they become unbearable and the patient needs immediate medical attention. Patients will report possible adverse events through REDCap reports, and their responses will be monitored by RAs. In the case of a possible adverse event, defined as the worsening of symptoms requiring an unscheduled visit to the ED or primary care provider, site investigators will be notified to determine if the event is linked to the treatment. If linked, the event will be monitored and the CHEO Research Ethics Board and DSMB will be notified.