Study design {2, 8, 13, 18b}
The study will be conducted as a two parallel-group randomized controlled trial (RCT) with an active control group. Participants will be randomized into either VR-training or a control group, after baseline assessment (figure 1). During the intervention period, participants in both groups will be followed up with a ten-minute phone call once per week, with standardized questions to each of the study conditions. This aims to increase fidelity and adherence to protocol, and adverse events will be monitored. For the participants in the intervention group, the phone call will also include technical issues if needed, and assessment of sense of presence (Multi Modal Presence Scale (Makransky et al., 2017)) during the intervention. Participants in both groups will answer weekly questionnaires regarding motivation (Situational Motivation Scale (Guay et al., 2000)) and fatigue (Fatigue Severity Scale (Lerdal, 2021)).
The primary and secondary outcome measures will be re-administered after the intervention period, which is 5 (T2) and 16 weeks (T3) after baseline. After T3, the first ten participants from the VR group will be asked to take part in individual qualitative interviews to gain in-depth understanding of their experience with the use of VR as a training method and participation in the intervention.
The RCT will follow the CONSORT statement (Eldridge et al., 2016) and is registered in ClinicalTrials.gov (NCT05443542) and Open Science Framework (osf.io/6gphy).
Study setting {9}
T1 (week 0), T2 (week 5) and T3 (week 16) assessments will be performed at Sunnaas Rehabilitation hospital, the largest rehabilitation hospital in Norway and the owner of the study. Participants will receive tutorials in use of the VR-technology at baseline, and the interventions will be carried out in the participant’s homes.
Participants {15}
Patients with ABI who have been admitted to Sunnaas Rehabilitation hospital will be considered for inclusion, and screened for eligibility. Eligible participants will receive a letter with an invitation to participate in the study. If participants have not responded to the letter within fourteen days, the project members will call them and ask whether they are interested in participating. A next of kin nominated by the patient will be included to obtain comparative information of the participants’ everyday functioning.
Eligibility criteria {10}
Inclusion criteria:
- Patients with ABI (traumatic brain injury, cerebrovascular incidents, anoxia, encephalitis and non-progressive brain tumors)
- At least 12 months post injury
- Aged 18-65 years
- Impairments of processing speed, working memory and/or sustained attention (self-reported and/or documented in medical journal).
- Participants need to:
- Be physically able to operate VR-equipment
- Understand instructions in Norwegian or English
- Be able to provide informed consent
Exclusion criteria:
- Aphasia affecting the ability to understand instructions
- Apraxia affecting the ability to operate the VR equipment
- Visual neglect
- Photosensitive epilepsy
- Severe mental illness or active substance use disorder
- Comorbid neurological disorders
Descriptive and outcome measures {12, 18a, 22}
All outcome measures will be administered at T1, T2, and at T3. Primary outcome is sustained attention and will be measured by coefficient of variation (CoV) on the Conners Continuous Performance Test 3rd (CPT 3) (Conners, 2013). See table 1 for an overview of all primary and secondary outcome measures, respondents and time points.
Table 1: Outcome measures, respondents and time points
|
Outcome domain
|
Measure
|
Respondent
|
Time point
|
Sustained Attention
|
Conners Continuous Performance Test 3rd, coefficient of variation
|
All participants
|
T1, T2, T3
|
Processing speed
|
Conners Continuous Performance Test 3rd, Mean hit Reaction time
|
All participants
|
T1, T2, T3
|
Working memory
|
Weschler Adult intelligence Scale IV, Backwards Digit Span and Digit Sequencing
|
All participants
|
T1, T2, T3
|
Everyday functioning
|
Behavior Rated Inventory of Executive Functioning – Adult, working memory scale
|
All participants and next of kin
|
T1, T2, T3
|
Patient Competency Rating Scale
|
All participants
|
T1, T2, T3
|
Motivation
|
Situational Motivation Scale
|
All participants
|
Weekly during intervention period
|
Fatigue
|
Fatigue severity scale
|
All participants
|
Weekly during intervention period
|
Cybersickness
|
Simulator sickness questionnaire
|
Participants in VR-group
|
Weekly during intervention period
|
Sense of presence
|
Multi modal presence scale
|
Participants in VR-group
|
Weekly during intervention period
|
At baseline (T1), neuropsychological test measures and questionnaires will be used for descriptive purposes. The following neuropsychological test battery will be applied; The Trail Making Test 4 (shifting) and subtest 3 of the Color Word Interference Test (inhibition) from the Delis-Kaplan Executive Function System test battery (Ellis, 2001). Abstract reasoning will be measured with Similarities and Matrices from WAIS IV (Wechsler, 2008). Furthermore, we will include Coding from the WAIS IV as a measure of processing speed (Wechsler, 2008). Immersive tendencies questionnaire will be administered at baseline to assess personality traits that may impact the level of experienced immersion (Witmer & Singer, 1998).
Demographic data such as marital status, length and type of education and work status, will be gathered. In addition, injury related data such as type and localization of injury will be collected.
Randomization and allocation concealment {11b, 16a, b, c, 17a}
After the baseline assessment, the participants will be randomized into either the intervention or the control group. The randomization sequence will be generated electronically by an independent statistician, using block randomization (Lim & In, 2019) with a 1:1 ratio containing variable block sizes of 4 or 6. Participants will be randomized after baseline assessment. The allocation sequence will be stored in a database that can only be accessed by the study principal investigator. Allocation will not be modified if the participant do not tolerate the intervention.
Blinding of participants and the researchers carrying out the intervention is impossible, but outcomes will be assessed by blinded assessors. Participants will be instructed to not reveal their group allocation to the outcome assessors. Data analysis will also be blinded as fake ID-numbers will be assigned in the final database.
Study interventions {11a, c}
Virtual reality
The experimental intervention is playing a commercially available VR game 30 minutes per day, for 5 weeks. The game selected is BeatSaber (Beat games, Undated), which is a rhythm-based VR game that requires the player to react to colored blocks presented at the rhythm beats. As the game progresses the requirements of the game increases as the blocks are presented faster thus taxing both processing speed, sustained attention, and working memory. In addition to its cognitive requirements, the game was chosen due to availability on different platforms, which may ease implementation. It also has many users globally, securing the availability of the game in the future. The participants will be provided with a VR headset in order to conduct the VR training sessions at home. Throughout the intervention period they will have access to support, either by phone or video conference. Each 30-minute session will be scheduled individually, with the instruction to use an alarm system to keep track of time. There are no existing clinical guidelines regarding recommended dosage and intensity of VR training; thus, the session length is based on clinical experience at SRH.
The VR game tracks the actual time each participant has spent playing the game during the intervention period. The amount of time spent playing will be recorded and used as a measure of intervention adherence.
Control group {6b}
An information booklet has been developed based on best practice evidence with information regarding compensatory strategies that participants can easily practice in their everyday lives. In addition to strategies, the booklet includes general information on topics that can affect cognitive functioning; national recommendation of physical exercise and physical activity, leisure activities (crossword puzzles, Sudoku, games and reading), sleep and nutrition. The control group will not be given a specific dosage, however they will be encouraged to choose one or two topics to focus on during the intervention period. The control group will receive the same amount of therapist follow-up as the intervention group.
Qualitative data collection {18}
To investigate the participant’s experiences with VR as a method of cognitive training, semi-structured interviews will be conducted. An interview guide has been developed as recommended by Creswell (2017), based on the acceptability framework developed by Sekhon and colleagues (Sekhon et al., 2017). This includes questions regarding how participants feel about the intervention, perceived amount of effort required to partake in the intervention, to what extent the participants understood the intervention, whether the participants perceived the intervention to result in its intended purpose and the participant’s own belief that they can participate in the intervention. Interviews will be transcribed verbatim after each interview.
A pilot interview with one participant with previous experience with utilizing VR will be performed. After this an evaluation of the interview guide will be performed to assess whether amendments to the interview guide is needed.
Technical solutions and data management {19, 27, 29}
The intervention will be provided using the Oculus Quest 2 (Facebook Technologies, LLC). The Oculus Quest 2 is a wireless standalone VR-headset that delivers the commercial VR game to the participants, creating the virtual environment through visual and auditory stimuli. The VR-headset utilizes two motion-controlled hand controls that detects hand movements of the participants in the virtual environment and provides haptic stimuli to the user. Oculus Quest 2 requires Meta accounts to set up the headset and to download and play the VR-games. We will set up 20 Meta accounts, one for each headset.
Questionnaire data will be gathered using University of Oslo’s solution for managing data, Services for Sensitive Data (University of Oslo, Undated). The TSD is an IT-platform with a secure server that is approved for storing sensitive data for research purposes (University of Oslo, Undated). Questionnaires will be set up electronically using Nettskjema, which is a tool for designing and conducting online surveys (University of Oslo, 2023).
All physical forms and test results will be kept in a locked cabinet. All data material will be recorded with participant ID and will be deidentified. Only the researchers working in the project will have access to the list that connects participant IDs with name. Data will be stored electronically on a secure research server at SRH and will be deleted 5 years after the project period has ended.
Statistical analyses {20a, b, c}
Descriptive statistics will be performed to describe demographics, cognitive functioning and injury severity. Effect analysis of primary and secondary outcomes will be performed according to intention-to-treat analysis using data from all randomized participants, regardless of whether they complete the intervention. To determine changes in continuous outcome measures over time (T1, T2, and T3) between the groups, linear mixed-effects models will be used. Time and time-by-group interaction will be used as fixed effects and their interactions as indicator of the intervention effect. The main effect of group will be removed from the models to adjust for potential baseline differences (Twisk et al., 2018). In the same manner, we aim to explore associations between motivation, cybersickness, fatigue and sense of presence and interaction with time within the mixed-model framework. Estimated mean between group changes from baseline to T2 and T3 with 95% confidence intervals will be provided. For all outcomes an alpha level of p=0.05 will be applied.
Sub-group analyses of i.e differences in duration since injury, age, educational levels will be performed. Differences in continuous variables between groups will be tested using independent sample t-test for normally distributed data, or by Mann-Whitney U test for very skewed data. Linear regressions analysis will be performed with registered adherence data as a possible predictor of treatment efficacy.
Sample size and power calculation {14}
The sample size was calculated based on coefficient of variation (CoV) of CPT as primary outcome. A mean difference in change in CoV of CPT of 3 % between baseline and follow up between the groups was defined as a clinically important difference. With equal allocation to both treatment groups and with an SD of 5%, power of 80%, and a significance level of 5%, the sample size was calculated to be 45 patients in each group. Allowing for 10% drop out, we aim to include a total of 100 patients.
The sample for qualitative interviews will be selected using selective sampling, meaning selecting individuals who are knowledgeable about the intervention or phenomenon being studied (Gill, 2020) . In this study, the sample will be the first ten participants that finish the VR intervention period.
Qualitative analyses
After all the interviews have been conducted, thematic analysis will be applied, following these six steps: (1) Organizing and preparing data, including transcribing and sorting field notes. (2) Reading through all the data, to obtain a general sense of what the information given by the participants. (3) Coding the data and organizing the material into segments of texts to start bring meaning to the information. (4) Separate the information into “descriptions” and “themes”. (5) Check for interrelating themes and descriptions. (6) Interpret the meaning of the themes and descriptions (Clarke et al., 2015).
Dissemination plan {31a}
The study plans for at least three publications in international peer-reviewed journals. We expect the novelty and innovative aspects of the study to allow for publication in high-impact journals within the field of neurology/rehabilitation and health innovation. Results will be disseminated in relevant expert forums, national meetings, conferences and popular scientific journals and reports. Members of the local research group all have central positions within research, clinical management, and innovation at SRH. Implementation of study findings into clinical practice will thus be highly feasible. SRH plays a major role in spreading knowledge and contributing to implementation of new knowledge throughout the rehabilitation sector, i.e. through hosting the South Eastern Regional Competency Centre for Rehabilitation. This will provide ample opportunity for national dissemination of results. The international collaborators will help to improve international dissemination of the results. We also expect study findings to be of interest for the general public.