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Remotely delivered environmental enrichment intervention for traumatic brain injury: A randomised controlled trial

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-039767 review only Article Type: Protocol

Date Submitted by the 27-Apr-2020 Author:

Complete List of Authors: Belchev, Zorry; University of Toronto, Psychology; Rotman Research Institute, Boulos, Mary Ellene; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Rybkina, Julia; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Johns, Kadeen; Toronto Rehabilitation Institute, KITE Jeffay, Eliyas; Rotman Research Institute, ; Toronto Rehabilitation Institute, KITE Colella, Brenda; Toronto Rehabilitation Institute, KITE Ozubko, Jason; State University of New York College at Geneseo, Psychology Bray, Michael; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE

Di Genova, Nicholas; Toronto Rehabilitation Institute, KITE; McMaster http://bmjopen.bmj.com/ University, Computing and Software Levi, Adina; Rotman Research Institute, ; York University, Psychology Changoor, Alana; Toronto Rehabilitation Institute, KITE; McMaster University Faculty of Health Sciences, Global Health Program Worthington, Thomas; Toronto Rehabilitation Institute, KITE; York University, Psychology Gilboa, Asaf; University of Toronto, Psychology; Rotman Research Institute, Green, Robin; Toronto Rehabilitation Institute, KITE; University of on October 2, 2021 by guest. Protected copyright. Toronto, Psychiatry

REHABILITATION MEDICINE, Neurological injury < NEUROLOGY, Keywords: THERAPEUTICS

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4 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 2, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Running head: REMOTE ENRICHMENT IN TBI 1 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 Title: Remotely delivered environmental enrichment intervention for traumatic brain injury: A 7 randomised controlled trial 8 9 Authors: 1,2Belchev, Zorry, 3,4Boulos, Mary E., 3,4Rybkina, Julia, 4Johns, Kadeen, 1,2,4Jeffay, 10 Eliyas, 4Colella, Brenda, 5Ozubko, Jason, 3,4Bray, Michael J. C., 4,6Di Genova, Nicholas, 2,7Levi, 11 Adina, 4,8Changoor, Alana, 4,7Worthington, Thomas, 1,2,4Gilboa, Asaf*, 4,9Green, Robin E.* 12 *Co-senior authors 13 14 15 1Department of Psychology, University of Toronto, Toronto, ON, Canada 16 2Rotman Research InstituteFor at peer Baycrest, Toronto, review ON, Canada only 17 3Graduate Department of Rehabilitation Science, University of Toronto, Toronto, ON, Canada 18 4Toronto Rehabilitation Institute (KITE), Toronto, ON, Canada 19 5Department of Psychology, The State University of New York, Geneseo, NY, USA 20 6 21 Department of Computing and Software, McMaster University, Hamilton, ON, Canada 7 22 Department of Psychology, York University, Toronto, ON, Canada 23 8Global Health Program, Faculty of Health Sciences, McMaster University, Hamilton, ON, 24 Canada 25 9Department of Psychiatry, University of Toronto, ON, Canada 26 27 28 29 Corresponding Author Information: 30 Zorry Belchev 31 (t) 416-785-2500 x3354. (e) [email protected] 32 Rotman Research Institute at Baycrest 33 3460 Bathurst St., North York, Ontario, Canada M6A 2E1 34 http://bmjopen.bmj.com/ 35 Word Count (between Article Summary and Acknowledgments): 4557 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI 2 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 ABSTRACT 4 5 6 Introduction: Individuals with moderate-severe traumatic brain injury (m-sTBI) experience 7 8 progressive brain and behavioural declines in the chronic stages of injury. Longitudinal studies 9 10 found that a majority of m-sTBI patients exhibit significant hippocampal atrophy from 5-12 11 12 months post-injury, associated with decreased cognitive environmental enrichment (EE). 13 14 15 Encouragingly, engaging in EE has been shown to lead to neural improvements, suggesting it is 16 For peer review only 17 a promising avenue for offsetting hippocampal neurodegeneration in m-sTBI. Allocentric spatial 18 19 navigation (i.e., flexible, bird’s eye view approach), is a good candidate for EE in m-sTBI 20 21 22 because it is associated with hippocampal activation and reduced aging-related volume loss. 23 24 Efficacy of EE requires intensive daily training, prohibitive within most current health delivery 25 26 systems. The present protocol is a novel, remotely delivered and self-administered intervention 27 28 29 designed to harness principles from EE and allocentric spatial navigation to offset hippocampal 30 31 atrophy and potentially improve hippocampal functions such as navigation and memory for m- 32 33 sTBI patients. 34 http://bmjopen.bmj.com/ 35 Methods and Analysis: Seventy chronic m-sTBI participants are being recruited from an urban 36 37 38 rehabilitation hospital and randomised into a 16-week intervention (five hours/week; total: 80 39 40 hrs.) of either targeted spatial navigation or an active control group. The spatial navigation group 41 on October 2, 2021 by guest. Protected copyright. 42 engages in structured exploration of different cities using Google Street View that includes daily 43 44 45 navigation challenges. The active control group watches and answers subjective questions about 46 47 educational videos. Following a brief orientation, participants remotely self-administer the 48 49 intervention on their home computer. In addition to feasibility and compliance measures, clinical 50 51 52 and experimental cognitive measures as well as MRI scan data are collected pre- and post- 53 54 intervention to determine behavioural and neural efficacy. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 51

REMOTE ENRICHMENT IN TBI 3 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Ethics and Dissemination: Ethics approval has been obtained from ethics boards at the 4 5 6 University Health Network and University of Toronto. Findings will be presented at academic 7 8 conferences and submitted to peer-reviewed journals. 9 10 Trial registration: Version 1 (2 April 2020), ClinicalTrials.gov: NCT04331392 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI 4 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 ARTICLE SUMMARY 4 5 6 Strengths and limitations of this study 7 8 ● A remote, self-administered intervention will allow patients greater access to clinically 9 10 relevant resources regardless of physical and economical restrictions, and increase 11 12 current telerehabilitation offerings. 13 14 15 ● The inclusion of neuroimaging outcomes allow for the examination of structural 16 For peer review only 17 changes that may occur alongside potential cognitive improvements associated with 18 19 targeted behavioural training, increasing our understanding of the mechanisms of these 20 21 22 potential changes in humans. 23 24 ● The inclusion of an active control group is critical in determining whether targeted 25 26 rather than generalised training is effective in improving hippocampal-dependent 27 28 29 abilities, but introduces a conservative bias in observing these effects more than if it 30 31 only included a waitlisted control group. 32 33 ● Although the present protocol builds on the principles of successful environmental 34 http://bmjopen.bmj.com/ 35 enrichment observed in rodents in terms of targeted training and high dose, a potential 36 37 38 component that may mediate the benefit is the addition of vigorous physical exercise, 39 40 which will be a consideration for future studies. 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 51

REMOTE ENRICHMENT IN TBI 5 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 INTRODUCTION 4 5 6 Traumatic brain injury (TBI) is a significant global public health problem, with an 7 8 estimated worldwide incidence rate of 874-1005 cases per 100,000[1]. Contrary to typical 9 10 models of the recovery trajectory, recent longitudinal studies show that degeneration continues at 11 12 least up to 2 years post-injury[2–4]. These recent lines of evidence have signaled a shift from 13 14 15 viewing TBI as a single event, to treating it as a chronic neurodegenerative disorder[5,6], 16 For peer review only 17 necessitating a need for appropriate long-term treatments for patients past their acute phase of 18 19 recovery. 20 21 22 Neurodegeneration and cognitive impairment in chronic TBI 23 24 There is evidence that moderate-severe TBI (m-sTBI) results in chronic volumetric 25 26 decline in both white matter (WM) and gray matter (GM) through the first and up to at least the 27 28 29 second year post-injury. Structures affected include the fornix[7] corpus callosum[3] (CC), and 30 31 temporal, frontal, and occipital regions[2]. Notably, the hippocampus (HPC) tends to be 32 33 particularly vulnerable to chronic degeneration, where Green and colleagues[3] found over 70% 34 http://bmjopen.bmj.com/ 35 of patients showed significant declines (over 2 standard deviations away from controls) in the 36 37 38 HPC. In another study, specific degeneration was found in the HPC, in addition to sub-cortical 39 40 regions that included the thalamus, putamen, amygdala, and caudate[2]. The heightened 41 on October 2, 2021 by guest. Protected copyright. 42 vulnerability of the HPC has been attributed to its sensitivity to excitotoxicity[8], and Wallerian 43 44 45 degeneration through damage distal to the site of the injury[9–11]. 46 47 In addition to neural declines, patients with TBI also exhibit chronic cognitive deficits, 48 49 including in spatial abilities[12] and memory[13,14]. These types of cognitive deficits have been 50 51 52 linked to the underlying degeneration in the HPC, including memory[15]. Furthermore, these 53 54 cognitive deficits may generalise to daily functioning, as lower acute volumes in areas known to 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI 6 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 be associated with cognitive deficits in TBI (i.e., HPC, thalamus), predict poorer functional 4 5 6 outcome measured in the chronic stage[16]. 7 8 Impact of external factors on recovery 9 10 Tertiary factors can also negatively contribute to the continued degeneration in the 11 12 chronic stages of TBI in addition to or by compounding the persistent underlying 13 14 15 neuropathology[17,18]. As outlined by the negative neuroplasticity framework[19,20], three 16 For peer review only 17 factors can have a negative impact on neural recovery from a TBI, including: 1) reduced 18 19 schedules of activity following rehabilitation regimen in the acute periods; 2) noisy processing 20 21 22 from sensory deficits, and; 3) weakened neuromodulatory control due to neurotransmitter 23 24 dysfunction. These factors can contribute to negative learning through preference for low-level, 25 26 low-effort cognitive tasks, leading to negative neuroplasticity. Thus, the chronic period that 27 28 29 follows in-patient rehabilitative treatments is critical for ensuring continued cognitive and neural 30 31 stimulation, with therapeutic support during this period that can be scalable and does not 32 33 necessitate extensive therapist involvement. 34 http://bmjopen.bmj.com/ 35 Harnessing environmental enrichment to improve post-injury outcomes 36 37 38 The HPC is commonly impacted by TBI[2–4,16], yet also holds an innate affinity for 39 40 neurogenesis and neuroplasticity[21–23], highlighting it as a good candidate for targeted 41 on October 2, 2021 by guest. Protected copyright. 42 interventions. Evidence from animal studies show that environmental enrichment (EE) through 43 44 45 extensive maze training can support positive neuroplasticity in the HPC[24]. Support for this 46 47 intervention approach has also been shown in humans, particularly when focusing on allocentric 48 49 spatial navigation, involving flexible navigation from a bird’s eye view perspective[25,26]. For 50 51 52 example, an intensive 90 hours of training on a video game associated with allocentric 53 54 navigation resulted in increased HPC volume in those who generally use the opposite strategy 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 51

REMOTE ENRICHMENT IN TBI 7 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 (i.e., egocentric[27]). Another study showed that intensive virtual navigation training in healthy 4 5 6 older adults resulted in successfully offsetting expected age-related volume declines in the 7 8 HPC[28] and increased hippocampal neural density which was moderated by genotype[29]. 9 10 Informed by the efficacy of such interventions, here we designed a novel intervention 11 12 focused on three factors: 1) targeting the HPC through training on allocentric navigation; 2) 13 14 15 high-intensity and high-dose schedules, and; 3) scalability and convenience through remote 16 For peer review only 17 training online. Google Street View (GSV) was chosen as the navigation platform because it is 18 19 easily accessible from patients’ homes and does not require specialised software, allowing 20 21 22 intensive training of allocentric navigation with only a browser and internet. Based on current 23 24 experimental evidence, we created a website with set virtual environments (cities) consisting of 25 26 routes learning and associated navigation tasks such as vector mapping, distance judgments, 27 28 29 reverse and blocked routes and landmark mapping known to significantly engage hippocampal 30 31 function. The dose of the structured navigation training is 80 hours based on previous findings 32 33 that produced significant benefits[28,29]. Different levels of difficulty are available to 34 http://bmjopen.bmj.com/ 35 adjustment to patients’ ability and maintain an appropriate challenge level. To ensure 36 37 38 compliance, intrinsic and extrinsic rewards are embedded into the intervention, and remote 39 40 progress tracking allows for immediate assistance. 41 on October 2, 2021 by guest. Protected copyright. 42 Study objectives and hypotheses 43 44 45 The present study examines the efficacy and feasibility of a novel, remotely-delivered 46 47 and self-administered intervention designed to offset HPC atrophy following m-sTBI. The 48 49 primary objective includes two sub-goals examining the intervention’s ability to: 1) 50 51 52 behaviourally improve spatial abilities and memory, and; 2) reduce chronic HPC 53 54 neurodegeneration. By comparing the navigation intervention to an active control intervention 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI 8 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 that provides generalised EE, we predict that the navigation intervention will lead to more HPC- 4 5 6 specific neural and behavioural improvements. The secondary objective takes an exploratory 7 8 approach to assess the feasibility of this intervention in this population. For a broad overview of 9 10 the trial registration data set, please refer to Supplementary Table 1. 11 12 METHODS 13 14 15 Participants 16 For peer review only 17 M-sTBI patients from Toronto Rehabilitation Institute’s Acquired Brain Injury Inpatient 18 19 Unit, Outpatient clinics, and Day Hospital program are in the process of being recruited, with a 20 21 22 projected recruited sample size of N = 70. This sample size accounts for an estimated 20% 23 24 attrition rate, with an expected resultant sample size of N = 56. This target sample size will 25 26 provide enough statistical power when factoring in attrition, based on a previous study that 27 28 29 employed 22-26 participants per group and found significant pre- vs. post- intervention 30 31 interactions for HPC volume change between treatment and control participants with moderate- 32 33 large effect sizes (Cohen’s d = 0.84)[28]. 34 http://bmjopen.bmj.com/ 35 Inclusion criteria include: 1) acute care diagnosis of m-sTBI; 2) PTA of 24 hours or more 36 37 38 and/or lowest GCS <13; 3) positive CT or MRI; 4) between 18 to 55 years of age; 5) fluency in 39 40 English; 6) competency to provide informed consent or availability of a legal substitute decision 41 on October 2, 2021 by guest. Protected copyright. 42 maker; 7) basic computer skills (use of internet/email, mouse and arrow keys); 8) functional use 43 44 45 of at least one upper extremity for computer use, and; 9) resident of Greater Toronto Area (to 46 47 facilitate access to the MRI). Exclusion criteria include: 1) neurological disorder other than TBI 48 49 (e.g., dementia, stroke); 2) diagnosis of a neurodevelopmental disorder; 3) TBI sustained before 50 51 52 age 18; 4) systemic comorbidities (e.g., lupus, diabetes); 5) current diagnosis of aphasia, and; 6) 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 51

REMOTE ENRICHMENT IN TBI 9 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 presence of metal inside the body (e.g., surgical clips, pacemaker) leading to ineligibility for an 4 5 6 MRI. 7 8 Inclusion criteria pertaining to the participant’s medical history are assessed using a chart 9 10 review. During recruitment, patients are informed that they do not need to discontinue ongoing 11 12 rehabilitative activities to participate in the study. Basic computer skills are evaluated at the pre- 13 14 15 intervention assessment. Participants are compensated for their participation by receiving 16 For peer review only 17 $75CAD following the completion of each of the pre- and post-intervention assessments, and 18 19 $75CAD in electronic gift cards (i.e., Amazon) for each month of intervention completion. To 20 21 22 maximise retention and compliance to intervention dose, participants also have the opportunity 23 24 to receive an additional $40CAD in coffee cards ($2.50 for each completed week). 25 26 Patient and Public Involvement 27 28 29 Patients were not involved in the initial design and development of the research questions 30 31 and outcome measures. Once the intervention was developed, pilot patients were recruited to 32 33 complete three to five weeks of the designed intervention to gauge the feasibility of the format 34 http://bmjopen.bmj.com/ 35 and intensity of remote training; the patients were able to complete the training as designed and 36 37 38 showed improvements on the targeted training tasks. Patients in the present study will be asked 39 40 to assess the burden of the intervention through the weekly administration of the How Much Is 41 on October 2, 2021 by guest. Protected copyright. 42 Too Much Scale[30]. As part of a post-intervention semi-structured interview they will also be 43 44 45 asked to identify any facilitators and barriers they encountered to completing the intervention, as 46 47 well as the average amount of time they required to participate in the intervention. The public 48 49 was not involved in the design of the study, but a number of public organizations were engaged 50 51 52 for recruitment strategies and aid (e.g., March of Dimes, Community Brain Injury Services). 53 54 Study Design 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 10 3 The present study is a randomised, controlled, patient and (partially) observer blinded, 4 5 6 parallel group, two arm, superiority trial with a 1:1 allocation. Participants are randomly assigned 7 8 to either the experimental targeted navigation intervention or to active control training 9 10 (educational videos), and are blinded to their assigned experimental vs. active control condition. 11 12 Note that although the experimenter is not blind to group assignments, as they need to train the 13 14 15 participant on the task, the study team member conducting the in-person outcome measure 16 For peer review only 17 assessments, as well as the MRI technologist, are blinded to group assignments. Randomisation 18 19 is conducted using the rand() function in Microsoft Excel by the study coordinator, who then 20 21 22 enrolls and assigns participants to the allocated intervention. Participants complete their assigned 23 24 intervention online, using their computer at home. In the event that a participant does not have 25 26 access to a computer or internet connection, they are lent to them at no cost for the duration of 27 28 29 the study. 30 31 Cognitive assessments are conducted at pre-intervention (week 0) and post-intervention 32 33 (week 17) by the study team and are each split over two days (for a CONSORT study flow 34 http://bmjopen.bmj.com/ 35 diagram, see Figure 1). Pre-intervention assessment occurs one week prior to beginning the 36 37 38 intervention, in-person at the University of Toronto Neuroimaging Facility, and over the phone. 39 40 At the end of the pre-intervention assessments, participants receive an orientation to their 41 on October 2, 2021 by guest. Protected copyright. 42 assigned intervention by completing a sample level on the respective intervention’s website, 43 44 45 guided by the experimenter over the phone. Participants assigned to the navigation intervention 46 47 are provided with instructions on how to develop their allocentric navigation strategy, conducive 48 49 to flexible navigation and linked to HPC activation[31,32]. 50 51 52 Reminder emails are sent out immediately following the orientation, and on day 1 of the 53 54 intervention in order to support participants when they are beginning the intervention. For the 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 11 3 remainder of the 16-week intervention, participants receive reminder emails if they miss three 4 5 6 days of training, and a phone call if they miss an entire week of training, in order to follow-up 7 8 and work through any potential barriers to participation. If required, daily text-message or email 9 10 reminders are implemented. A month before the end of the intervention period, the post- 11 12 intervention assessments are scheduled to ensure that it is conducted a maximum of one to two 13 14 15 weeks following intervention completion. 16 For peer review only 17 Targeted navigation intervention 18 19 The targeted navigation intervention involves virtual navigation training with a focus on 20 21 22 allocentric navigation, which is highly associated with the HPC[33,34]). The dose and intensity 23 24 match the design of a previous study with successful outcomes[28,29], with a modified format: 25 26 approximately one hour a day, five days a week, for 16 weeks on the designated website hosted 27 28 29 within the University Health Network’s (UHN) secure servers. Each week, participants learn a 30 31 section of a new city through basic to more challenging navigation tasks, with the goal of being 32 33 able to independently navigate the assigned section by the end of the week. During task 34 http://bmjopen.bmj.com/ 35 development, cities were selected based on availability of GSV, presence of English street 36 37 38 names, sufficient size (i.e., a city centre at least 1 square kilometre), and availability of notable 39 40 landmarks. Participants are asked to complete tasks in new cities with increasingly challenging 41 on October 2, 2021 by guest. Protected copyright. 42 layouts each week. The challenge level of the tasks within each week vary based on the selected 43 44 45 level, ranging from Level 1 to 4, which differ in number of streets, turns, and landmarks (see 46 47 below) . All participants are initially placed in Level 1, and levels for subsequent weeks are 48 49 based on performance of at least 80% on all of the main task measures during the previous week. 50 51 52 If participants are performing less than 60% on any of the main task measures in subsequent 53 54 weeks, they will be placed in a lower level the following week. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 12 3 Inspired by the format of the study maps used in another study[35], each week of training 4 5 6 begins with studying a map stripped of all labelling except for pre-selected landmarks and street 7 8 names. Based on the challenge level, an initial three landmarks and 8-10 street names were 9 10 selected for Level 1 to 3, and an initial five landmarks and 11-13 street names were selected for 11 12 Level 4. Throughout the week, participants learn additional landmarks and street names, where 13 14 15 by the end of the week they will have learned five landmarks and 11-13 street names for Level 1 16 For peer review only 17 and 2, seven landmarks and 14-16 street names for Level 3, and nine landmarks and 17-20 street 18 19 names selected for Level 4. 20 21 22 Learning is scaffolded using two types of activities that increase in difficulty throughout 23 24 the week. The first activity is navigation, which requires participants to navigate routes of 25 26 increasing difficulty, including: 1) passive routes, where participants are shown videos of route 27 28 29 navigation in GSV between each of the new landmarks; 2) active routes, which require them to 30 31 independently navigate the same routes shown in the videos; 3) reverse routes, which require 32 33 them to navigate to and from landmarks in the opposite direction from what was learned in the 34 http://bmjopen.bmj.com/ 35 videos; 4) alternate/new routes, which involves finding routes to learned landmarks or 36 37 38 intersections that had not been previously paired, and; 5) blocked routes, where participants are 39 40 instructed to find detours to landmarks or intersections when certain streets are identified as 41 on October 2, 2021 by guest. Protected copyright. 42 inaccessible. When navigating each route, participants are provided a dual-map view earlier in 43 44 45 the week, with a map inset on one half of the screen, and GSV on the other half. Later in the 46 47 week, participants are required to navigate solely using GSV. Dual-maps and GSV are embedded 48 49 in a new page within the website using scripts incorporating Google Maps javascript API, which 50 51 52 collects participant path data. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 13 3 The second activity used to scaffold and to test learning involves an end-of-day multiple- 4 5 6 choice task based on information learned during the day and throughout the week. Participants 7 8 are asked three types of spatial mapping questions previously used to test both egocentric and 9 10 allocentric spatial knowledge[36–39], including: 1) landmark sequencing (e.g., You’re walking 11 12 along X St. from Y St. to Z St. Which landmark do you most closely pass?); 2) distance 13 14 15 judgment (e.g., Which is closer to X?), and; 3) vector mapping (e.g., Facing X St. from Y, which 16 For peer review only 17 degree represents the direction of Z?). Participants also complete a map placement task, which 18 19 involves presenting two reproductions of the study map stripped of all information; letters and 20 21 22 numbers representing landmarks and streets, respectively, need to be matched to a list of learned 23 24 landmark and street names. 25 26 To increase compliance and engagement, in addition to earning potential coffee cards, 27 28 29 auditory and written rewards are provided throughout training. Auditory rewards are presented in 30 31 the form of short audio clips about each new landmark, with information about the landmark that 32 33 is part of a greater fictional narrative created for each city. Written rewards are in the form of 34 http://bmjopen.bmj.com/ 35 eight different encouraging pop-up messages appearing randomly throughout the week (e.g., 36 37 38 “Good work, keep it up!”). Placement of written and coffee card rewards are based on four 39 40 randomised schedules, with a maximum of four combined rewards, at approximately 25%, 50%, 41 on October 2, 2021 by guest. Protected copyright. 42 75%, and 100% of the way into the day. The four schedules were additionally randomised to 43 44 45 each be the set reward schedules of four different weeks. 46 47 Active control training 48 49 Participants randomly assigned to an active control counterpart to the experimental 50 51 52 intervention complete a 16-week educational video intervention at the same intensity as the 53 54 navigation training, also on a designated website hosted on the secure UHN server. Training 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 14 3 involves watching TED Talks on educational topics, to control for placebo effects and for the 4 5 6 effects of generalised environmental enrichment of the same dose as the targeted navigation 7 8 training. For each day of training, participants are asked to select one of two possible videos, 9 10 watching a total of three videos. Videos were selected by two raters, basing their decisions on the 11 12 educational and engagement level. The videos were further screened for coarse language, sexual 13 14 15 content, and highly political, religious or polarising topics. To ensure compliance and sufficient 16 For peer review only 17 attention to the videos, at the end of each video, participants rate five aspects of the content 18 19 (relevance, interest, comprehensibility, complexity, informative), and speaker (persuasiveness, 20 21 22 quality of delivery, facial expression, convincingness, captivation), on a scale of 1 (lowest) to 5 23 24 (highest). Additionally, as with navigation participants, they are given written rewards of 25 26 encouragement with the same randomised placement as described above. 27 28 29 Outcome measures 30 31 Brain structural changes using Magnetic Resonance Imaging 32 33 A Siemens Prisma 3 Tesla scanner with a 32 channel head coil is used for imaging 34 http://bmjopen.bmj.com/ 35 acquisition. The primary imaging measures include total HPC volumes, and HPC sub-structures. 36 37 38 The secondary imaging measures include the integrity of white matter tracts involving the HPC 39 40 (i.e., fimbria-fornix pathway). 41 on October 2, 2021 by guest. Protected copyright. 42 Cognitive changes: Experimental measures 43 44 45 The primary cognitive outcome measures include near-, medium-, and far-transfer 46 47 measures. Near-transfer outcome measures (navigation intervention only) are performance 48 49 outcomes in a city on which participants were not trained following the intervention. Medium- 50 51 52 transfer measures are used to assess changes to spatial abilities that were not trained: 1) 53 54 Cognitive Map Formation Test (CMFT; earlier version described in [40]); 2) Different Approach 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 15 3 Task[41], and; 3) Path Integration Task[42]. Far-transfer measures include memory tasks 4 5 6 sensitive to HPC integrity to assess generalizability of training to HPC-dependent abilities that 7 8 were not directly trained: 1) Memory Image Completion Task[43,44] (MIC), and; 2) Mnemonic 9 10 Similarity Test[45] (MST). Additional secondary outcome measures include subjective changes 11 12 to navigation and memory in daily life with the following self-report measures; 1) Santa Barbara 13 14 15 Sense of Direction Scale[46] (SBSOD); 2) Navigational Strategies Questionnaire[47] (NSQ), 16 For peer review only 17 and; 3) Everyday Memory Questionnaire[48] (EMQ). Alternate forms of the primary tasks are 18 19 used (i.e., MST, MIC, CMFT, Different Approach Task, Path Integration Task), with the specific 20 21 22 form used for the pre- and post-intervention assessments counterbalanced across participants. To 23 24 maintain consistency in administration, data collection, and data entry, experimenters will 25 26 undergo matched training and utilize scripts and detailed instructions. Coding of the key 27 28 29 components of the measures will be entered and checked by multiple experimenters. 30 31 Cognition: Clinical measures 32 33 A comprehensive neuropsychological assessment battery validated for use with 34 http://bmjopen.bmj.com/ 35 individuals with TBI will be administered by a trained neuropsychologist blind to group 36 37 38 allocation, to characterise the participants at baseline, and determine changes to performance on 39 40 traditional clinical measures following the intervention. The tests administered include: 1) the 41 on October 2, 2021 by guest. Protected copyright. 42 Wechsler Test of Adult Reading[49]; 2) Digit Span forwards and backwards[50]; Visual Spatial 43 44 45 Span (forwards and backwards); 4) the Rey Auditory Verbal Learning Test[51] (RAVLT); 5) the 46 47 Rey Visual Design Learning Test[52] (RVDLT); 6) the Sustained Attention to Response 48 49 Test[53] (SART); the Symbol Digit Modalities Test[54], and; 7) select sub-tests of the NIH 50 51 52 toolbox[55], including the picture sequence memory test, flanker inhibitory control and attention 53 54 test, dimensional change card sort test, and pattern comparison processing speed test. An 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 16 3 alternate form of the picture sequence memory test is used for the post-intervention assessment. 4 5 6 The cognitive and mood assessments are employed to provide clinical neuropsychological 7 8 feedback to patients at baseline and post-treatment. 9 10 Training-related outcome measures 11 12 To assess improvements in navigation-related, within-task intervention components, the 13 14 15 following measures are collected for navigation training patients only: 1) spatial learning ability 16 For peer review only 17 based on end-of-day questions; 2) overall spatial ability improvement based on the difference in 18 19 performance of end-of-week end-of-day questions, between earlier to later weeks of training; 3) 20 21 22 independent navigation ability improvement on GSV-only reverse, alternate, and blocked routes, 23 24 based on differences in performance between earlier to later weeks of training, and; 4) cognitive 25 26 map formation ability, based on differences in end-of-week performance between earlier and 27 28 29 later weeks of training. Because the complexity of the cities increases throughout the 16 weeks 30 31 of training, and participants may switch challenge levels, this is not a direct comparison of pre- 32 33 and post-intervention ability. Therefore, performance is also compared between the first week of 34 http://bmjopen.bmj.com/ 35 training, and an additional week following the completion of the intervention, based on a novel 36 37 38 city of similar complexity as the first city. 39 40 Assessments of feasibility 41 on October 2, 2021 by guest. Protected copyright. 42 General feasibility of the intervention will be determined by the recruitment rate, 43 44 45 retention rate (including factors influencing retention), and adherence rates (objective and 46 47 through a daily, weekly, and bi-weekly self-reported questionnaires). The degree of burden to the 48 49 patients in completing the intervention will be assessed by The How Much is Too Much 50 51 52 Scale[30], administered each week to measure physical, mental, and mood symptom onset 53 54 following intervention participation. Patients placed in the targeted navigation intervention group 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 17 3 also complete a semi-structured interview following the intervention for a qualitative assessment 4 5 6 of their experiences to inform the feasibility of the method of delivery and content of the 7 8 intervention. 9 10 Control variables 11 12 Demographic information, injury history, and hours of therapy for all participants are 13 14 15 collected using a secure, online survey prior to the pre-intervention assessment. At the pre- 16 For peer review only 17 intervention assessment, a personal interview is conducted to validate the contents of the survey 18 19 and gather additional information. Current symptoms of anxiety and depression are assessed 20 21 22 using the Beck Anxiety Inventory and the Beck Depression Inventory, respectively[56,57]. 23 24 Participants’ current level of physical activity are assessed using the International Physical 25 26 Activity Questionnaire - Short Form[58] (IPAQ). For individuals in the targeted navigation 27 28 29 group, a survey of cities visited are administered to ensure all cities are novel to participants. If a 30 31 participant has visited a test city, a replacement city is assigned. 32 33 PLANNED STATISTICAL ANALYSES 34 http://bmjopen.bmj.com/ 35 Primary objective: Efficacy 36 37 38 To address the first sub-goal of the primary objective of determining whether our 39 40 intervention can improve cognitive domains related to the HPC, descriptive and inferential 41 on October 2, 2021 by guest. Protected copyright. 42 statistics will be employed to examine group-level changes in the following experimental 43 44 45 outcomes: far-transfer tasks associated with memory (MIC, MST), medium-transfer associated 46 47 with spatial abilities (CMFT, Different Approach Task, Path Integration Task); near-transfer of 48 49 navigating using GSV, and subjective measures (SBSOD, NSQ, EMQ). A series of between- 50 51 52 group (targeted navigation and active control) analyses will be conducted to estimate the average 53 54 causal treatment effect. Secondary outcome measures will then be introduced individually to test 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 18 3 for interactions that, if present, indicate that the corresponding variable acts as a moderator of the 4 5 6 treatment effect, including depression (BDI-II), anxiety (BAI), age, sex, injury severity (i.e., 7 8 GCS), hours of therapy, physical activity (IPAQ), and cognition (clinical measures). If so, 9 10 specific effects will be estimated. Within the targeted navigation group, changes to near-transfer 11 12 outcomes will be assessed using single-group analyses on the training-related outcome measures. 13 14 15 The analyses will be carried out with mixed models using information available from all 16 For peer review only 17 participants, including those with partially missing data (combining mixed models with multiple 18 19 imputation for longitudinal data) to reduce potential bias due to attrition. Analyses will be carried 20 21 22 out “as randomised” (intent-to-treat analyses) as well as “per protocol” taking the degree of 23 24 compliance into account. We anticipate group effects and group by time interactions, with 25 26 improvements in the navigation group at post-intervention (vs. control). For navigation 27 28 29 participants, we also anticipate improvements on the training-related outcome measures. 30 31 To test our second sub-goal of determining the efficacy of the intervention to reduce HPC 32 33 degeneration, the same analyses described above for the cognitive measures will be undertaken 34 http://bmjopen.bmj.com/ 35 for our imaging outcomes. We expect specific HPC degeneration in controls and stable or 36 37 38 increased volumes in the navigation group. Additional HPC sub-field analyses will be completed 39 40 based on manual segmentation of the T2 volumes, where data analysts will be blinded to the 41 on October 2, 2021 by guest. Protected copyright. 42 allocation of the participant. We expect the dentate gyrus and CA1 sub-regions to most strongly 43 44 45 express degeneration and preservation trajectories due to roles in allocentric navigation and 46 47 neurogenesis. For DTI, we expect an offset of previously reported fornix degeneration following 48 49 navigation training[7]. Cingulum integrity could also be expected to be modulated with 50 51 52 improved HPC function and/or structure. 53 54 Secondary objective: Feasibility 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 19 3 This secondary objective will be achieved by assessing recruitment and retention in the 4 5 6 study, by measuring compliance of patients in the completion of the interventions and the 7 8 completion of all behavioural outcome measures of the study, and by assessing scores on the 9 10 How Much is Too Much Scale. A semi-structured interview will help identify barriers to 11 12 completion and to elicit suggestions for improvement. Descriptive statistics will be used to 13 14 15 summarise the outcomes of the feasibility component of the study. 16 For peer review only 17 ETHICS AND DISSEMINATION 18 19 This study has been approved by the University Health Network Research Ethics Board 20 21 22 and the Research Oversight and Compliance Office at the University of Toronto. This study will 23 24 be conducted in accordance with the Declaration of Helsinki and the Tri-Council Policy 25 26 Statement: Ethical Conduct for Research Involving Humans, 2nd edition[59]. The present study 27 28 29 began on October 20, 2018 and recruitment is ongoing. Any modifications to the present 30 31 protocol will be submitted as formal amendments to the original ethics application and reviewed 32 33 by the above ethics boards prior to their implementation. All participants will be recruited 34 http://bmjopen.bmj.com/ 35 through an informed consent protocol in-person and by telephone (please see online 36 37 38 supplemental material for a model consent form). At the time of consent, participants are assured 39 40 that withdrawing from the study will not affect the care they receive at Toronto Rehabilitation 41 on October 2, 2021 by guest. Protected copyright. 42 Institute. Participants may leave the study at any time. The protocol follows the guidelines 43 44 45 prescribed by the Standard Protocol Items: Recommendations for Interventional Trials 46 47 Statement[60]. All collected physical data will be stored securely in locked cabinets, and 48 49 electronic data will be stored on a secure server at Toronto Rehabilitation Institute. Only the 50 51 52 direct study team will have access to identifying information, which will be kept confidential, 53 54 and to the final dataset. Results summarizing the anonymised data will be presented at academic 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 20 3 and clinical conferences and findings will be submitted to peer-reviewed journals. Authorship for 4 5 6 publications will be determined based on the uniform requirements for manuscripts submitted to 7 8 biomedical journals[61]. Key findings will be shared directly with patients who have participated 9 10 in the study, and will be made accessible to the public through media releases shared through the 11 12 Marketing and Communications departments at Toronto Rehabilitation Institute and the Rotman 13 14 15 Research Institute at Baycrest. 16 For peer review only 17 SIGNIFICANCE AND IMPACT 18 19 The strength and novelty of the present study is the unique design of an intervention that 20 21 22 can be completed by patients in their own homes using widely available software, which can 23 24 therefore be delivered with minimal resources, anywhere in the world. This enhances the 25 26 scalability and reach of the intervention, allowing the study to be replicated and the intervention 27 28 29 to be available to large samples and other patient populations with similar neuropathology. 30 31 Furthermore, using the principles of EE, the intervention is designed to be continuously novel 32 33 and challenging, allowing participants to remain engaged while stimulating the HPC through 34 http://bmjopen.bmj.com/ 35 tasks known to be hippocampal-dependent. Additionally, the study employs an active control to 36 37 38 allow more robust conclusions to be made regarding the effectiveness of a targeted navigation 39 40 intervention for m-s TBI, compared to generalised EE. Finally, the online setting of the 41 on October 2, 2021 by guest. Protected copyright. 42 intervention allows for real-time data collection to monitor adherence and performance while 43 44 45 maintaining accurate records. 46 47 Importantly, the proposed research aims to develop infrastructure for ongoing 48 49 neurorehabilitation in remote communities, and for individuals who may face other barriers to 50 51 52 obtaining necessary resources (e.g., reduced mobility, or financial burden). The self-administered 53 54 feasibility questionnaire as well as the post-intervention interview will help to ascertain barriers 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 21 3 and facilitators to retention and compliance for computerised cognitive tasks for individuals with 4 5 6 m-sTBI, to ultimately expand the availability of treatment options for individuals in this 7 8 population. 9 10 ACKNOWLEDGMENTS 11 12 We would like to thank all of the volunteers, research assistants and undergraduate 13 14 15 project students who graciously offered their time to assist in the development of the 16 For peer review only 17 intervention: Taha Arshad, Marta Bogacki, Priyanka Prince, Sonia Persaud, Michelle Gomez, 18 19 Robert Dydynsky, Alexander Drohobycky, Mikael Salnikov, Reid Syrydiuk, Ginelle Feliciano, 20 21 22 Roy Kuo, Maleeha Khan, Gina D'Souza, Mubina Butt, Samreen Aziz, Madison Fraser. Finally, 23 24 we would also like to acknowledge our recruitment contacts and partners who are central in 25 26 strengthening our recruitment reach in order to assess the feasibility and efficacy of this 27 28 29 intervention in patients: Dr. Matthew Burke (Sunnybrook Health Sciences Center), Dr. Karl F. 30 31 Gunnarsson (West Park Healthcare Centre), Kamilah Francis and Crystal McCollum (March of 32 33 Dimes Canada), and Michelle Pangilinan (Community Brain Injury Services). 34 http://bmjopen.bmj.com/ 35 COMPETING INTERESTS 36 37 38 The authors declare no competing interests related to this study. 39 40 FUNDING 41 on October 2, 2021 by guest. Protected copyright. 42 This work is supported and funded by the Ontario Neurotrauma Foundation (ONF; 2017- 43 44 45 ABI-INFRA-1035), the Canadian Centre for Aging & Brain Health Innovation (CABHI), the 46 47 Canadian Traumatic Brain Injury Research Consortium (CTRC), the Branch Out Neurological 48 49 Foundation, and the Canada Research Chairs (950-230647). None of the funding sources had any 50 51 52 role in the design of the protocol nor will be involved in its execution, analyses, data 53 54 interpretation, or dissemination of results. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 22 3 AUTHOR CONTRIBUTIONS 4 5 6 AG and REG conceived the original idea for the intervention, with BC as study manager. 7 8 AG and REG are also supervising the study, are helping maintain recruitment avenues, and 9 10 contributed to the final manuscript. ZB developed the materials for the intervention with 11 12 assistance and supervision by AG and REG, and with the aid of AL and AC. ZB, MEB and JR 13 14 15 all contributed to the implementation of the intervention on the training website, with JO 16 For peer review only 17 completing the initial methodology for GSV and overseeing ND as programmer, and with 18 19 assistance from TW and AL. MJCB and MEB developed the semi-structured interview that will 20 21 22 be administered to patients following completion of the study. KJ oversees the recruitment and 23 24 screening of patients, with help from EJ, JR, MEB, and ZB, as well as all other administrative 25 26 aspects of the study. ZB, JR, and MEB oversee data collection and training patients on the 27 28 29 intervention, with EJ completing the administration of neuropsychological assessments and 30 31 reports, and TW assisting in data collection and training. ZB, MEB, and JR wrote the manuscript 32 33 with consultation from AG and REG. 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 23 3 REFERENCES 4 5 6 1 World Health Organization. World Health Statistics 2015. 7 8 2015.https://www.who.int/gho/publications/world_health_statistics/2015/en/ (accessed 22 9 10 Apr 2020). 11 12 2 Cole JH, Jolly A, de Simoni S, et al. Spatial patterns of progressive brain volume loss 13 14 15 after moderate-severe traumatic brain injury. Brain 2018;141:822–36. 16 For peer review only 17 doi:10.1093/brain/awx354 18 19 3 Green REA, Colella B, Maller JJ, et al. Scale and pattern of atrophy in the chronic stages 20 21 22 of moderate-severe TBI. Front Hum Neurosci 2014;8:67. doi:10.3389/fnhum.2014.00067 23 24 4 Ng K, Mikulis DJ, Glazer J, et al. Magnetic Resonance Imaging Evidence of Progression 25 26 of Subacute Brain Atrophy in Moderate to Severe Traumatic Brain Injury. Arch Phys Med 27 28 29 Rehabil 2008;89:S35–44. doi:10.1016/j.apmr.2008.07.006 30 31 5 Green REA. Editorial: Brain Injury as a Neurodegenerative Disorder. Front Hum 32 33 Neurosci 2016;9:615. doi:10.3389/fnhum.2015.00615 34 http://bmjopen.bmj.com/ 35 6 Masel BE, DeWitt DS. Traumatic brain injury: A disease process, not an event. J. 36 37 38 Neurotrauma. 2010;27:1529–40. doi:10.1089/neu.2010.1358 39 40 7 Adnan A, Crawley A, Mikulis D, et al. Moderate–severe traumatic brain injury causes 41 on October 2, 2021 by guest. Protected copyright. 42 delayed loss of white matter integrity: Evidence of fornix deterioration in the chronic 43 44 45 stage of injury. Brain Inj 2013;27:1415–22. doi:10.3109/02699052.2013.823659 46 47 8 Mccarthy MM. Stretching the truth Why hippocampal neurons are so vulnerable following 48 49 traumatic brain injury. Published Online First: 2003. doi:10.1016/j.expneurol.2003.08.020 50 51 52 9 Mckee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin 53 54 Neurol 2015;127:45–66. doi:10.1016/B978-0-444-52892-6.00004-0 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 51 BMJ Open

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REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 25 3 18 Jullienne A, Obenaus A, Ichkova A, et al. Chronic cerebrovascular dysfunction after 4 5 6 traumatic brain injury. J Neurosci Res 2016;94:609–22. doi:10.1002/jnr.23732 7 8 19 Tomaszczyk JC, Green NL, Frasca D, et al. Negative Neuroplasticity in Chronic 9 10 Traumatic Brain Injury and Implications for Neurorehabilitation. Neuropsychol. Rev. 11 12 2014;24:409–27. doi:10.1007/s11065-014-9273-6 13 14 15 20 Mahncke HW, Bronstone A, Merzenich MM. Brain plasticity and functional losses in the 16 For peer review only 17 aged: scientific bases for a novel intervention. Prog Brain Res 2006;157:81–109. 18 19 doi:10.1016/S0079-6123(06)57006-2 20 21 22 21 Aimone JB, Li Y, Lee SW, et al. Regulation and Function of Adult Neurogenesis: From 23 24 Genes to Cognition. Physiol Rev 2014;94:991–1026. doi:10.1152/physrev.00004.2014.- 25 26 Adult 27 28 29 22 Boldrini M, Fulmore CA, Tartt AN, et al. Human Hippocampal Neurogenesis Persists 30 31 throughout Aging. Cell Stem Cell 2018;22:589-599.e5. doi:10.1016/J.STEM.2018.03.015 32 33 23 Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, et al. Adult hippocampal 34 http://bmjopen.bmj.com/ 35 neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients 36 37 38 with Alzheimer’s disease. Nat. Med. 2019;25:554–60. doi:10.1038/s41591-019-0375-9 39 40 24 Scholz J, Allemang-Grand R, Dazai J, et al. Environmental enrichment is associated with 41 on October 2, 2021 by guest. Protected copyright. 42 rapid volumetric brain changes in adult mice. Neuroimage 2015;109:190–8. 43 44 45 doi:10.1016/J.NEUROIMAGE.2015.01.027 46 47 25 Konishi K, Bohbot VD. Spatial navigational strategies correlate with gray matter in the 48 49 hippocampus of healthy older adults tested in a virtual maze. Front Aging Neurosci 50 51 52 2013;5:1. doi:10.3389/fnagi.2013.00001 53 54 26 Lithfous S, Dufour A, Després O. Spatial navigation in normal aging and the prodromal 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 26 3 stage of Alzheimer’s disease: Insights from imaging and behavioral studies. Ageing Res. 4 5 6 Rev. 2013;12:201–13. doi:10.1016/j.arr.2012.04.007 7 8 27 West GL, Konishi K, Bohbot VD. Video Games and Hippocampus-Dependent Learning. 9 10 Curr Dir Psychol Sci 2017;26. doi:10.1177/0963721416687342 11 12 28 Lövdén M, Schaefer S, Noack H, et al. Spatial navigation training protects the 13 14 15 hippocampus against age-related changes during early and late adulthood. Neurobiol 16 For peer review only 17 Aging 2012;33:620.e9-620.e22. doi:10.1016/J.NEUROBIOLAGING.2011.02.013 18 19 29 Lövdén M, Schaefer S, Noack H, et al. Performance-related increases in hippocampal N- 20 21 22 acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val 23 24 homozygotes. Cereb Cortex 2011;21:1435–42. doi:10.1093/cercor/bhq230 25 26 30 Tomaszczyk JC, Sharma B, Chan AA, et al. Measuring cognitive assessment and 27 28 29 intervention burden in patients with acquired brain injury: Development of the ‘how Much 30 31 Is Too Much?’ questionnaire. J Rehabil Med 2018;50:519–26. doi:10.2340/16501977- 32 33 2344 34 http://bmjopen.bmj.com/ 35 31 Iaria G, Petrides M, Dagher A, et al. Cognitive strategies dependent on the hippocampus 36 37 38 and caudate nucleus in human navigation: Variability and change with practice. J 39 40 Neurosci 2003;23:5945–52. doi:10.1523/jneurosci.23-13-05945.2003 41 on October 2, 2021 by guest. Protected copyright. 42 32 Ohnishi T, Matsuda H, Hirakata M, et al. Navigation ability dependent neural activation 43 44 45 in the human brain: An fMRI study. Neurosci Res 2006;55:361–9. 46 47 doi:10.1016/J.NEURES.2006.04.009 48 49 33 O’Keefe J, Dostrovsky J. The hippocampus as spatial map: Preliminary evidence from 50 51 52 unit activity in the freely-moving rat. Brain Res 1971;34:171–5. 53 54 34 Bohbot VD, Lerch J, Thorndycraft B, et al. Gray Matter Differences Correlate with 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 27 3 Spontaneous Strategies in a Human Virtual Navigation Task. Published Online First: 4 5 6 2007. doi:10.1523/JNEUROSCI.1763-07.2007 7 8 35 Howard LR, Javadi AH, Yu Y, et al. The Hippocampus and Entorhinal Cortex Encode the 9 10 Path and Euclidean Distances to Goals during Navigation. Curr Biol 2014;24:1331–40. 11 12 doi:10.1016/J.CUB.2014.05.001 13 14 15 36 Hirshhorn M, Grady C, Rosenbaum RS, et al. The hippocampus is involved in mental 16 For peer review only 17 navigation for a recently learned, but not a highly familiar environment: A longitudinal 18 19 fMRI study. Hippocampus 2012;22:842–52. doi:10.1002/hipo.20944 20 21 22 37 Rosenbaum RS, Ziegler M, Winocur G, et al. ‘I have often walked down this street 23 24 before’: fMRI studies on the hippocampus and other structures during mental navigation 25 26 of an old environment. Hippocampus 2004;14:826–35. doi:10.1002/hipo.10218 27 28 29 38 Rosenbaum RS, Cassidy BN, Herdman KA. Patterns of preserved and impaired spatial 30 31 memory in a case of developmental amnesia. Front Hum Neurosci 2015;9:196. 32 33 doi:10.3389/fnhum.2015.00196 34 http://bmjopen.bmj.com/ 35 39 Waller D, Hodgson E. Transient and enduring spatial representations under disorientation 36 37 38 and self-rotation. J Exp Psychol Learn Mem Cogn 2006;32:867–82. doi:10.1037/0278- 39 40 7393.32.4.867 41 on October 2, 2021 by guest. Protected copyright. 42 40 Corrow JC, Corrow SL, Lee E, et al. Getting lost: Topographic skills in acquired and 43 44 45 developmental prosopagnosia. Cortex 2016;76:89–103. 46 47 doi:10.1016/J.CORTEX.2016.01.003 48 49 41 Wiener JM, Carroll D, Moeller S, et al. A novel virtual-reality-based route-learning test 50 51 52 suite: Assessing the effects of cognitive aging on navigation. Behav Res Methods 2019;:1– 53 54 11. doi:10.3758/s13428-019-01264-8 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 28 3 42 Persson J, Herlitz A, Engman J, et al. Remembering our origin: Gender differences in 4 5 6 spatial memory are reflected in gender differences in hippocampal lateralization. Behav 7 8 Brain Res 2013;256:219–28. doi:10.1016/j.bbr.2013.07.050 9 10 43 Vieweg P, Stangl M, Howard LR, et al. Changes in pattern completion – A key 11 12 mechanism to explain age-related recognition memory deficits? Cortex 2015;64:343–51. 13 14 15 doi:10.1016/J.CORTEX.2014.12.007 16 For peer review only 17 44 Vieweg P, Riemer M, Berron D, et al. Memory Image Completion: Establishing a task to 18 19 behaviorally assess pattern completion in humans. Hippocampus 2018;:1–18. 20 21 22 doi:10.1002/hipo.23030 23 24 45 Stark SM, Yassa MA, Lacy JW, et al. A task to assess behavioral pattern separation (BPS) 25 26 in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia 27 28 29 2013;51:2442–9. doi:10.1016/J.NEUROPSYCHOLOGIA.2012.12.014 30 31 46 Hegarty M, Richardson AE, Montello DR, et al. Development of a self-report measure of 32 33 environmental spatial ability. Intelligence 2002;30:425–47. doi:10.1016/S0160- 34 http://bmjopen.bmj.com/ 35 2896(02)00116-2 36 37 38 47 Brunec IK, Bellana B, Ozubko JD, et al. Multiple Scales of Representation along the 39 40 Hippocampal Anteroposterior Axis in Humans. Curr Biol 2018;28:2129-2135.e6. 41 on October 2, 2021 by guest. Protected copyright. 42 doi:10.1016/J.CUB.2018.05.016 43 44 45 48 Sunderland A, Harris JE, Baddeley AD. Do laboratory tests predict everyday memory? A 46 47 neuropsychological study. J Verbal Learning Verbal Behav 1983;22:341–57. 48 49 doi:10.1016/S0022-5371(83)90229-3 50 51 52 49 Wechsler D. Wechsler Test of Adult Reading (WTAR). San Antonio, TX: : The 53 54 Psychological Corporation 2001. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 29 3 50 Wechsler D. Manual for the Wechsler Adult Intelligence Scale - Revised. 1981. 4 5 6 doi:Thesis_references-Converted #317 7 8 51 Rey A. L’examen Clinique en Psychologie. 2e ed. Paris: : Presses universitaires de France 9 10 1964. doi:10.1176/appi.psychotherapy.1959.13.4.989 11 12 52 Rey A. L’examen Clinique en Psychologie. 1. éd. Paris: : Presses universitaires de France 13 14 15 1958. doi:10.1176/appi.psychotherapy.1959.13.4.989 16 For peer review only 17 53 Robertson IH, Manly T, Andrade J, et al. ‘Oops!’: Performance correlates of everyday 18 19 attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 20 21 22 1997;35:747–58. doi:10.1016/S0028-3932(97)00015-8 23 24 54 Smith A. Symbol Digits Modalities Test. Los Angeles: : Western Psychological Sciences 25 26 1982. 27 28 29 55 Gershon RC, Cella D, Fox NA, et al. Assessment of neurological and behavioural 30 31 function: the NIH Toolbox. Lancet Neurol. 2010;9:138–9. doi:10.1016/S1474- 32 33 4422(09)70335-7 34 http://bmjopen.bmj.com/ 35 56 Beck AT, Epstein N, Brown G, et al. An Inventory for Measuring Clinical Anxiety: 36 37 38 Psychometric Properties. J Consult Clin Psychol 1988;56:893–7. doi:10.1037/0022- 39 40 006X.56.6.893 41 on October 2, 2021 by guest. Protected copyright. 42 57 Beck AT, Steer RA, Brown GK. Manual for the Beck depression inventory-II. San 43 44 45 Antonio, TX Psychol Corp 1996;:1–82. 46 47 58 Craig CL, Marshall AL, Sjöström M, et al. International physical activity questionnaire: 48 49 12-Country reliability and validity. Med Sci Sports Exerc Published Online First: 2003. 50 51 52 doi:10.1249/01.MSS.0000078924.61453.FB 53 54 59 Canadian Institute of Health Research, Natural Sciences and Engineering Research 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 51 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 30 3 Council of Canada SS and HRC. Tri-Council Policy Statement: Ethical Conduct for 4 5 6 Research Involving Humans. 2018. 7 8 60 Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: Defining standard 9 10 protocol items for clinical trials. Ann. Intern. Med. 2013;158:200–7. doi:10.7326/0003- 11 12 4819-158-3-201302050-00583 13 14 15 61 International Committee of Medical Journal Editors. Uniform Requirements for 16 For peer review only 17 Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 18 19 Publication. 2010. www.ICMJE.org (accessed 22 Apr 2020). 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 51

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 31 3 Figure 1 4 5 6 CONSORT study flow diagram of the present protocol 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 Figure 1. CONSORT study flow diagram of the present protocol on October 2, 2021 by guest. Protected copyright. 43 200x219mm (300 x 300 DPI) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 1 4 5 6 Trial registration data for the study protocol based on World Health Organization Trial 7 Registration Data Set guidelines 8 9 10 Data category Information 11 Primary registry and trial identifying number ClinicalTrials.gov: NCT04331392 12 Date of registration in primary registry 2 April, 2020 13 14 Source(s) of monetary or material support Ontario Neurotrauma Foundation (ONF); 15 Canadian Centre for Aging & Brain Health 16 For peer reviewInnovation only(CABHI); Canadian Traumatic 17 Brain Injury Research Consortium (CTRC); 18 Branch Out Neurological Foundation 19 Primary sponsor ONF; CABHI 20 21 Name and Contact Information for Primary Judy Gargaro, ABI Program Director, ONF - 22 sponsors [email protected] 23 James Mayer, Portfolio Manager, CABHI - 24 [email protected] 25 Secondary sponsor(s) CTRC; Branch Out Neurological Foundation 26 27 Contact for public queries REG, AG, ZB, MB, JR 28 Contact for scientific queries REG, AG, ZB, MB, JR 29 Public title Remotely Delivered Environmental 30 Enrichment Intervention for Traumatic Brain 31 Injury: A Randomized Controlled Trial 32 33 Scientific title Remotely Delivered Environmental 34 Enrichment Intervention for Traumatic Brain http://bmjopen.bmj.com/ 35 Injury: A Randomized Controlled Trial 36 Countries of recruitment Canada 37 Health condition(s) or problem(s) studied Traumatic brain injury 38 Intervention(s) Experimental: Spatial navigation intervention 39 40 Active Comparator: Educational Videos 41 Key inclusion and exclusion criteria Inclusion: 1) acute care diagnosis of m-sTBI; on October 2, 2021 by guest. Protected copyright. 42 2) PTA of 24 hours or more and/or lowest 43 44 GCS <13; 3) positive CT or MRI; 4) between 45 18 to 55 years of age; 5) fluency in English; 46 6) competency to provide informed consent or 47 48 availability of a legal decision maker; 7) basic 49 computer skills (use of internet/email, mouse 50 and arrow keys); 8) functional use of at least 51 52 one upper extremity for computer use, and; 9) 53 resident of Greater Toronto Area (to facilitate 54 access to the MRI) 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Exclusion: 1) neurological disorder other than 4 TBI (e.g., dementia, stroke); 2) diagnosis of a 5 6 neurodevelopmental disorder; 3) TBI 7 sustained before age 18; 4) systemic 8 comorbidities (e.g., lupus, diabetes); 5) 9 current diagnosis of aphasia, and; 6) presence 10 of metal inside the body (e.g., surgical clips, 11 pacemaker) leading to ineligibility for an MRI 12 13 Study type Interventional (Clinical Trial), Randomized 14 Parallel Assignment Masking (Participant, 15 Investigator, Outcomes Assessor) 16 For peer review only 17 Primary purpose: Treatment 18 Date of first enrolment 9 January, 2019 19 Target sample size 70 20 Recruitment status Recruiting 21 Primary outcome(s) Brain structural changes; cognitive changes 22 (memory: pattern separation, pattern 23 24 completion; near- and medium-transfer spatial 25 abilities; self-reported spatial abilities) 26 Key secondary outcome(s) Feasibility (recruitment, retention, 27 compliance, self-reported barriers) 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 2 4 5 6 Roles and responsibilities for study protocol members 7 8 9 Teams Roles 10 Principal investigators  Protocol design and revisions 11  AG  Preparing annual reports for funding sponsors 12  REG 13  Recruitment strategy aid and initiation of 14 recruitment contacts 15 Trial management  Participant randomisation and enrolment 16 For peer review only 17  AG  Participant recruitment and screening 18  REG  Budgeting and financial administration 19  KJ  Participant payments 20  ZB  Participant support for completion of online 21  JR assessments and intervention 22 23  EJ  Assistance with ethics committee applications and 24  MB amendments 25  Assistance with study reports 26 Data management and analyses  Data compiling and storage 27  ZB 28  Data organization 29  JR  Data entry 30  EJ  Data verification 31  ND  Consultation with biostatisticians at Toronto 32  JO Rehabilitation and Rotman Research Institutes 33 34  Other student assistants http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Model Consent Form 4 5 6 7 8

9 10 11 12 CONSENT FORM TO PARTICIPATE IN A RESEARCH STUDY 13 14 Study Title: Remotely delivered Environmental Enrichment interventions for acquired brain 15 16 injury For peer review only 17 18 Principal Investigators/Study Doctors: Dr. Robin Green & Dr. Asaf Gilboa 19 20 Contact Information: 21 22 Dr. Robin Green 23 Research Scientist, Toronto Rehabilitation Institute 24 550 University Avenue, Room 11-207 25 Toronto, ON, M5G 2A2 26 Phone: 416-597-3422, extension 7606 27 28 Dr. Asaf Gilboa 29 Research Scientist, Rotman Research Institute at Baycrest 30 31 Centre for Stroke Recovery 32 3560 Bathurst St. 33 Toronto, ON, M6A 2E1 http://bmjopen.bmj.com/ 34 Phone: 416-785-2500, extension 2908 35 36 37 Funding Source: The study is financed by a grant from the Ontario Neurotrauma Foundation 38 39 40 Introduction: 41

You are being asked to take part in a research study. Please read the information about the on October 2, 2021 by guest. Protected copyright. 42 43 study presented in this form. The form includes details on the study’s risks and benefits that you 44 should know before you decide if you would like to take part. You should take as much time as 45 you need to make your decision. You should ask the study doctor or study staff to explain 46 anything that you do not understand and make sure that all of your questions have been 47 answered before signing this consent form. Before you make your decision, feel free to talk 48 49 about this study with anyone you wish including your friends, family, and family doctor. 50 Participation in this study is voluntary. 51 52 Background/Purpose: 53 54 You have been asked to participate in this study because you have sustained a traumatic brain 55 injury (TBI). Past research has shown that “environmental enrichment” - engaging in effortful 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 cognitive activities on a regular basis - can have beneficial effects on recovery from brain injury. 4 For example, it can improve cognitive difficulties and maximize brain health after brain injury. 5 6 The purpose of this research project is to investigate the feasibility (i.e., the ability for us to re- 7 run the same study with a larger number of people) and effectiveness of two “environmental 8 enrichment” therapies delivered to participants online in their homes for a period of 16 weeks. 9 Up to 134 individuals may participate in this study over the course of 2 years. Through your 10 participation you will receive additional therapy which may be helpful to your rehabilitation. 11 12 13 Study Visits and Procedures: 14 15 If you agree to participate in the study, you will participate in a pre-therapy assessment while 16 you are an in-patient.For This will peer take about anreview extra day of your only time, however it will not affect 17 your length of stay at Toronto Rehab.) You will participate in a second pre-therapy 18 assessment, in-person and by phone, when you are approximately 7 months post- brain injury. 19 We will contact you 2 – 3 months prior to your assessment window to schedule an appointment, 20 21 and we will contact you 1 month prior to confirm your appointment). This assessment has two 22 components: 23 24  A Cognitive Assessment: You will be asked to complete some computerized tasks 25 and some pencil and paper tasks to measure cognitive functioning. Some of the 26 computerized tasks you will do will train you on the intervention tasks that you will be 27 28 doing at home during the intervention phase of the study. You will also be asked to 29 complete some questionnaires about your cognitive function, mood, and level of 30 physical activity. This assessment will last for approximately 3 - 6 hours and will be 31 completed over two (2) days, consecutively. The assessment will take place at the 32 Toronto Neuroimaging Facility at the University of Toronto (325 Huron St.) on the 33 first day, and by phone on the second day. 34 http://bmjopen.bmj.com/ 35  A Magnetic Resonance Imaging (MRI) scan of your brain: The MRI scanner takes 36 signals emitted by the brain and turns them into pictures of the brain using magnetic 37 field. The MRI scanning will be carried out at the Toronto Neuroimaging Facility at 38 the University of Toronto (325 Huron St.). This will involve lying down on a table. 39 Foam pads will be placed around your head to limit head movement during the 40 study. The table will then be slid into the magnet. While in the scanner, you will be 41

asked to lie still for approximately 1.5 hours, during which time several scans will on October 2, 2021 by guest. Protected copyright. 42 43 take place. For obtaining some of the images, you don’t have to do any specific task, 44 other than relaxing while keeping your head and body still. Before the scan, you will 45 be asked some questions to ensure you do not have any magnetically sensitive 46 metal materials in your body. (This does not include dental fillings.) You cannot 47 participate in the rest of the study if you cannot participate in the MRI scan. 48 49 Once you have completed the above assessment you will move onto the therapy phase of the 50 study. The therapies we are investigating in this study are “environmental enrichment” exercise 51 programs to maximize brain health. The therapy phase involves: 52 53  Completing 1 hour of “environmental enrichment” exercises daily for 5 days per week 54 (e.g., Monday - Friday). You will be given online access to intervention materials at 55 home each day over the course of 16 weeks. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3  There are two forms of environmental enrichment therapy: 4 5 o Allocentric spatial navigation therapy (or ‘bird’s eye view’ navigation therapy) 6 involving finding various landmarks while navigating different cities around the 7 world using Google Street View. 8 9 o Educational video viewing in which you will view several short educational 10 videos each day and will learn about a wide range of topics. 11 12  Study Design: this is a “randomized control trial” which means that we will compare 13 the two treatments to each other by assigning participants randomly (i.e., by chance) 14 15 to either the allocentric spatial navigation intervention or the educational video 16 intervention.For Once peer you have agreedreview to enter the only trial, a computer will perform the 17 equivalent of tossing a coin to allocate you to one of the two treatments. 18 19  Once you are assigned to one of the two treatments, you will be provided with login 20 information to access the intervention activities on a secure Toronto Rehab –UHN 21 study website. 22 23  We will provide you with a laptop and a high-speed internet connection for the duration 24 of the therapy program (i.e., 16 weeks) if you do not have or do not wish to use your 25 own equipment. 26 27  We ask that you adhere as closely as possible to the recommended schedule for the 28 entire 16 weeks. You will be receiving reminders and be provided training support as 29 necessary 30 31  Your participation in the exercises online and your performance over time will be 32 monitored by a therapy assistant at Toronto Rehab. The therapy assistant will access 33 your activity information via the website. 34 http://bmjopen.bmj.com/ 35  You will be asked to answer some questions on a daily basis and on a weekly basis. 36 On a daily basis, you will be asked to answer 3 online questions about how you are 37 finding the activities (1-2 minutes to complete); at the end of each week of training, 38 you will also be asked to answer 3-6 online questions about the intervention (2-3 39 minutes to complete); once a month you will be asked to complete a questionnaire 40 about cognitive, physical and emotional symptoms that you may experience in 41 42 response to completing the cognitive intervention. on October 2, 2021 by guest. Protected copyright. 43 44  At the end of the program, some participants will also be invited to participate in a 45 15-30 minute, telephone administered, semi-structured interview with our team so 46 that we can better understand your experiences with the environmental enrichment 47 intervention. Up to 30 participants will be randomly selected from all participants in 48 the study to be invited to participate in the interview. We will also ask you for 49 permission to contact your caregiver or significant other to invite him/her to 50 participate in a similar 15-30 minute, telephone administered, semi-structured 51 interview with our team to further understand your experiences with the 52 environmental enrichment intervention. 53 54 55 ☐ I agree to being invited to participate in the telephone interview. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 ☐ I agree to having my caregiver/significant other invited to participate in the 4 5 telephone interview. 6 7 8 At the end of the 16 week therapy phase you will be asked to return to the University of Toronto 9 for a post-therapy assessment. This assessment is identical to the pre-therapy assessment 10 11 described above. 12 13 Risks: 14 15 Taking part in this study has risks. Some of these risks we know about. 16 For peer review only 17 The cognitive assessments that occur pre-and post- therapy phase involve no more risk to you 18 than there are in your routine cognitive assessments. You may get tired during the assessment 19 20 and if this occurs, please tell the researcher and a break will be provided or if necessary the 21 task will be discontinued. 22 23 The study therapies involve a time commitment of 5 hours per week which could cause you to 24 be more tired than usual. If fatigue prevents you from completing the specified amount of 25 26 therapy, you can discuss this with your study therapists and a modified schedule can be 27 arranged. 28 29 The risks involved in this MRI study are minimal, and are limited to the risks present during 30 31 routine MRI examinations. The MRI scan is painless but noisy. There is no radiation associated 32 with the scan. When near an MRI scanner, there is a potential for the powerful magnetic field 33 to attract metallic objects toward the magnet. For this reason, you will be carefully screened for http://bmjopen.bmj.com/ 34 previous exposure to metallic fragments or clips that may be inside your body. Similarly, you will 35 be asked to place all metallic and magnetic objects in your possession (e.g. keys, jewelry, credit 36 37 cards) in a locker outside the magnet room. 38 39 Some people may feel a little ‘closed-in’ the MRI machine, but you will be able to speak with 40 someone at all times and can stop the test at any time. 41

on October 2, 2021 by guest. Protected copyright. 42 43 To reduce potential back or neck pain due to lying still in the scanner, cushions and pads 44 designed to better disperse your weight for the scan duration will be used under your knees and 45 neck and around your body. 46 47 Benefits: 48 49 You may not receive any direct benefit from being in this study. However, information learned 50 from this study may help with the development of a novel post-injury cognitive intervention. 51 52 53 Reminders and Responsibilities: 54 55  Tell your study team if you change your mind about being in the study. 56  Ask your study team about anything related to the study that worries you. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3  Tell study staff of any health changes that you experience during the course of the study. 4 5 6 Confidentiality: 7 Personal Health Information 8 If you agree to join this study, the Principal Investigators and their study team will collect only 9 10 the information they need for the study which may include personal health information: 11  Name 12  address 13  email 14  telephone number 15  partial date of birth (month and year) 16 For peer review only 17  name of a family member/significant other (who could fill out a questionnaire for this 18 study) 19  New or existing medical records, that includes types, dates and results of medical tests 20 or procedures 21 22 Representatives of either the University of Toronto or the University Health Network (UHN) 23 including the University of Toronto or UHN Research Ethics Board may look at the study 24 records and at your personal health information to check that the information collected for the 25 study is correct and to make sure the study is following proper laws and guidelines. 26 27 28 The study doctor will keep any personal health information about you in a secure and 29 confidential location for 10 years. A list linking your study number with your name 30 will be kept by the study doctor in a secure place, separate from your study file. 31 32 Study Information that Does Not Identify You: 33

Any information about you that is sent out of the hospital will have a code and will not show your http://bmjopen.bmj.com/ 34 35 name or address, or any information that directly identifies you. 36 37 All information collected during this study, including your personal health information, will be 38 kept confidential and will not be shared with anyone outside the study unless required by law. 39 40 You will not be named in any reports, publications, or presentations that may come from this 41 42 What happens with the results of the study? on October 2, 2021 by guest. Protected copyright. 43 44 Primarily, the results will be used to inform the ideas and design of future studies, these 45 additional future studies may build on the findings of this study to advance healthcare or 46 treatment options of relevance. It is very likely that a report will be published about this research 47 study and the results will be published in scientific journals or presented at scientific 48 49 conferences, but you will not be able to be identified. Your identity will always be kept 50 confidential. In addition, anonymous images may be provided to third parties (such as the 51 manufacturer of the scanner for use in connection with its product development and marketing 52 activities). All identifying information about you is removed from the images so that they are 53 anonymized before they are sent to this third party. The third party may keep the images for up 54 55 to 5 years. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Voluntary Participation: 4 5 Your participation in this study is voluntary. You may decide not to be in this study, or to be in 6 the study now and then change your mind later. You may leave the study at any time. You will 7 not be required to give reasons for your decision to leave the study. 8 9 10 We will give you new information that is learned during the study that might affect your decision 11 to stay in the study. 12 13 Withdrawal from the Study: 14 15 The researchers can take you off the study if: 16  You are unableFor to comply peer with the reviewinstructions for participation only given to you 17  You no longer meet the criteria for participation 18 19 20 If you wish to leave the study, please let study staff know. If you leave the study, the information 21 that was collected before you left the study will still be used in order to help answer the research 22 question. No new information will be collected without your permission. However, you have the 23 right to request withdrawal of information collected about you. Let the Principal Investigator 24 25 know. 26 27 Costs and Reimbursement: 28 29 You will receive $75 for your participation in each of the 2 in-person and phone assessments 30 (pre- and post- therapy) to cover travel expenses incurred to attend the in-person session. 31 32 The therapy phase of the study will last 16 weeks (i.e., 4 months). At the end of each month of 33 34 therapy, you will receive $75 in the form of a gift card (which can be sent to you electronically). http://bmjopen.bmj.com/ 35 You will have an additional opportunity to receive a bonus $5 electronic gift card to a coffee 36 shop for every 2 weeks of completed training, to be sent biweekly or monthly. 37 38 Rights as a Participant: 39 40 If you are harmed as a direct result of taking part in this study, all necessary medical treatment 41 will be made available to you at no cost. 42 on October 2, 2021 by guest. Protected copyright. 43 By signing this form you do not give up any of your legal rights against the investigators, or 44 involved institutions for compensation, nor does this form relieve the investigators, sponsor or 45 involved institutions of their legal and professional responsibilities. 46

47 48 Incidental Findings: 49 The magnetic resonance imaging (MRI) scan you will receive during the course of this study is 50 for research purposes only. It is not a clinical scan intended for diagnostic or therapeutic 51 52 purposes. The Brain Imaging Facility is a research center. It is NOT a clinical MRI facility in a 53 hospital. There are no neuroradiologists at the Brain Imaging Facility, therefore the staff are 54 unable to make any medical comments about your scan. Should you want to know if your scan 55 is normal or abnormal, the staff will not be able to tell you. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 There is a chance, however, that, in the course of this research scanning protocol, we observe 5 6 an anomaly (e.g. tumor or cyst) in one or more of the MRI images. If this happens, your images 7 will be sent to a trained neuroradiologist for further investigation and you may be informed of the 8 results. An anomaly does not necessarily indicate the presence of any disorder. Because our 9 MRI scans are for research purposes only, they may be inadequate for the purpose of clinical 10 diagnosis. Additionally, as researchers, we are not trained to clinically interpret MRI data. 11 12 However, we feel it is important to inform you of any observations, as we cannot rule out the 13 possibility that this anomaly may require medical advice. If you prefer not to be informed of 14 anomalous findings, you must check the box below. 15 ☐ I prefer NOT to be informed of any anomalous findings. 16 For peer review only 17 18 Conflict of Interest: 19 20 The researchers report no potential conflicts of interest. They have an interest in completing this 21 study. Their interest should not affect your consideration for participating. 22 23 Future Studies: 24 25 I authorize the MRI facility to contact me about future research within the MRI research facility in 26 the Department of Psychology. If I agree, a researcher may contact me and tell me about the 27 research. At that time, I can decide whether or not I am interested in participating in a particular 28 29 study. 30 ☐ I agree to be contacted about research studies conducted at the MRI facility. 31 ☐ I authorize the MRI facility to use my data in future research within the MRI research facility 32 33 in the Department of Psychology. 34 http://bmjopen.bmj.com/ 35 Questions about the Study: 36 If you have any questions, concerns or would like to speak to the study team for any reason, 37 please call: Dr. Robin Green (416) 597-3422 ext. 7871 38 39 If you have any questions about your rights as a research participant or have concerns about 40 this study, call the Chair of the University Health Network Research Ethics Board (UHN REB) or 41 the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee on October 2, 2021 by guest. Protected copyright. 42 the ethical conduct of research studies. The UHN REB is not part of the study team. Everything 43 that you discuss will be kept confidential. 44 45 46 You will be given a signed copy of this consent form. 47 48 Consent: 49 50 This study has been explained to me and any questions I had have been answered. 51 52 I know that I may leave the study at any time. I agree to the use of my information as described 53 in this form. I agree to take part in this study. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Print Study Participant’s Name Signature Date 4 5

6 7 Or for substitute decision maker: 8 9 10 This study has been explained to me and any questions I had have been answered. 11 I know that ______may leave the study at any time. I agree to the use of 12 his or her information as described in this form. I agree to have ______take 13 part in this study. 14

15

16 For peer review only 17 ______18 Print Name of Substitute decision maker Signature Date 19 20 21 22 ______23 Relationship to participant 24 25 26 Person who obtained consent: 27 My signature means that I have explained the study to the participant named above and/or his 28 or her substitute decision maker named above. I have answered all questions. 29 30 31 32 Print Name of Person Signature Date 33 Obtaining Consent 34 http://bmjopen.bmj.com/ 35 36 Was the participant assisted during the consent process? YES NO 37 If YES, please check the relevant box and complete the signature space below: 38 39 The person signing below acted as an interpreter, and attests that the study as set out in the 40 consent form was accurately sight translated and/or interpreted, and that interpretation was 41

provided on questions, responses and additional discussion arising from this process. on October 2, 2021 by guest. Protected copyright. 42 43

44 45 Print Name of Interpreter Signature Date 46 47 48 Relationship to Participant Language 49 50 The consent form was read to the participant. The person signing below attests that the 51 study as set out in this form was accurately explained to, and has had any questions answered. 52 53 54 Print Name of Witness Signature Date 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 Relationship to Participant 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Reporting checklist for protocol of a clinical trial. 4 5 6 Based on the SPIRIT guidelines. 7 8 9 Instructions to authors 10 11 Complete this checklist by entering the page numbers from your manuscript where readers will find each of the items listed below. 12 13 Your article may not currently address all the items on the checklist. Please modify your text to include the missing information. If you are 14 15 certain that an item does not apply, please write "n/a" and provide a short explanation. 16 For peer review only 17 Upload your completed checklist as an extra file when you submit to a journal. 18 19 20 In your methods section, say that you used the SPIRITreporting guidelines, and cite them as: 21 22 Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann H, Dickersin K, Berlin J, Doré C, 23 24 Parulekar W, Summerskill W, Groves T, Schulz K, Sox H, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard 25 26 protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207 27 28 Reporting Item Page Number 29 30 Administrative 31 32 information 33 http://bmjopen.bmj.com/ 34 Title #1 Descriptive title identifying the study design, population, 1 35 36 interventions, and, if applicable, trial acronym 37 38 Trial registration #2a Trial identifier and registry name. If not yet registered, name of 3 39 40 intended registry 41 42 Trial registration: data #2b All items from the World Health Organization Trial Registration Online supplemental material (Table on October 2, 2021 by guest. Protected copyright. 43 44 set Data Set 1) 45 46 Protocol version #3 Date and version identifier 3 47 48 Funding #4 Sources and types of financial, material, and other support 21 49 50 51 Roles and #5a Names, affiliations, and roles of protocol contributors 1, 22, Online supplemental material 52 responsibilities: (Table 2) 53 54 contributorship 55 56 Roles and #5b Name and contact information for the trial sponsor Online supplemental material (Table 57 58 responsibilities: 1) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from sponsor contact 1 2 information 3 4 Roles and #5c Role of study sponsor and funders, if any, in study design; 21 5 6 responsibilities: collection, management, analysis, and interpretation of data; 7 sponsor and funder writing of the report; and the decision to submit the report for 8 9 publication, including whether they will have ultimate authority 10 over any of these activities 11 12 13 Roles and #5d Composition, roles, and responsibilities of the coordinating Online supplemental material (Table 14 responsibilities: centre, steering committee, endpoint adjudication committee, data 2) 15 16 committees managementFor peerteam, and other reviewindividuals or groups overseeingonly the 17 trial, if applicable (see Item 21a for data monitoring committee) 18 19 20 Introduction 21 22 Background and #6a Description of research question and justification for undertaking 5-8 23 24 rationale the trial, including summary of relevant studies (published and 25 unpublished) examining benefits and harms for each intervention 26 27 28 Background and #6b Explanation for choice of comparators 7, 13 29 rationale: choice of 30 31 comparators 32 33 Objectives #7 Specific objectives or hypotheses 7-8 34 http://bmjopen.bmj.com/ 35 Trial design #8 Description of trial design including type of trial (eg, parallel 10 36 37 group, crossover, factorial, single group), allocation ratio, and 38 framework (eg, superiority, equivalence, non-inferiority, 39 40 exploratory) 41 on October 2, 2021 by guest. Protected copyright. 42 Methods: 43 44 Participants, 45 interventions, and 46 47 outcomes 48 49 Study setting #9 Description of study settings (eg, community clinic, academic 8, 10 50 51 hospital) and list of countries where data will be collected. 52 Reference to where list of study sites can be obtained 53 54 55 Eligibility criteria #10 Inclusion and exclusion criteria for participants. If applicable, 8-9 56 eligibility criteria for study centres and individuals who will 57 58 perform the interventions (eg, surgeons, psychotherapists) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 Interventions: #11a Interventions for each group with sufficient detail to allow 11-14 2 3 description replication, including how and when they will be administered 4 5 Interventions: #11b Criteria for discontinuing or modifying allocated interventions for 19; minimal risk 6 7 modifications a given trial participant (eg, drug dose change in response to 8 harms, participant request, or improving / worsening disease) 9 10 11 Interventions: #11c Strategies to improve adherence to intervention protocols, and 13 12 adherance any procedures for monitoring adherence (eg, drug tablet return; 13 14 laboratory tests) 15 16 Interventions: #11d RelevantFor concomitant peer care and review interventions that are only permitted or 9 17 concomitant care prohibited during the trial 18 19 20 Outcomes #12 Primary, secondary, and other outcomes, including the specific 14-17 21 measurement variable (eg, systolic blood pressure), analysis 22 23 metric (eg, change from baseline, final value, time to event), 24 method of aggregation (eg, median, proportion), and time point 25 26 for each outcome. Explanation of the clinical relevance of chosen 27 28 efficacy and harm outcomes is strongly recommended 29 30 Participant timeline #13 Time schedule of enrolment, interventions (including any run-ins 10-11 31 and washouts), assessments, and visits for participants. A 32 33 schematic diagram is highly recommended (see Figure) 34 http://bmjopen.bmj.com/ 35 Sample size #14 Estimated number of participants needed to achieve study 8 36 37 objectives and how it was determined, including clinical and 38 statistical assumptions supporting any sample size calculations 39 40 41 Recruitment #15 Strategies for achieving adequate participant enrolment to reach 8-9 on October 2, 2021 by guest. Protected copyright. 42 target sample size 43 44 45 Methods: 46 Assignment of 47 48 interventions (for 49 controlled trials) 50 51 52 Allocation: sequence #16a Method of generating the allocation sequence (eg, computer- 10 53 generation generated random numbers), and list of any factors for 54 55 stratification. To reduce predictability of a random sequence, 56 details of any planned restriction (eg, blocking) should be 57 58 provided in a separate document that is unavailable to those who 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from enrol participants or assign interventions 1 2 3 Allocation #16b Mechanism of implementing the allocation sequence (eg, central 10 4 concealment telephone; sequentially numbered, opaque, sealed envelopes), 5 6 mechanism describing any steps to conceal the sequence until interventions 7 are assigned 8 9 10 Allocation: #16c Who will generate the allocation sequence, who will enrol 10 11 implementation participants, and who will assign participants to interventions 12 13 14 Blinding (masking) #17a Who will be blinded after assignment to interventions (eg, trial 10 15 participants, care providers, outcome assessors, data analysts), 16 For peer review only 17 and how 18 19 Blinding (masking): #17b If blinded, circumstances under which unblinding is permissible, n/a; enough team members are 20 21 emergency and procedure for revealing a participant’s allocated intervention unblinded to be able to intervene if 22 unblinding during the trial necessary 23 24 Methods: Data 25 26 collection, 27 28 management, and 29 analysis 30 31 Data collection plan #18a Plans for assessment and collection of outcome, baseline, and 15 32 33 other trial data, including any related processes to promote data 34 http://bmjopen.bmj.com/ 35 quality (eg, duplicate measurements, training of assessors) and a 36 description of study instruments (eg, questionnaires, laboratory 37 38 tests) along with their reliability and validity, if known. Reference 39 to where data collection forms can be found, if not in the protocol 40 41

Data collection plan: #18b Plans to promote participant retention and complete follow-up, 9-11, 13 on October 2, 2021 by guest. Protected copyright. 42 43 retention including list of any outcome data to be collected for participants 44 45 who discontinue or deviate from intervention protocols 46 47 Data management #19 Plans for data entry, coding, security, and storage, including any 15, 19 48 related processes to promote data quality (eg, double data entry; 49 50 range checks for data values). Reference to where details of data 51 52 management procedures can be found, if not in the protocol 53 54 Statistics: outcomes #20a Statistical methods for analysing primary and secondary 17-19 55 outcomes. Reference to where other details of the statistical 56 57 analysis plan can be found, if not in the protocol 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 Statistics: additional #20b Methods for any additional analyses (eg, subgroup and adjusted 17-19 2 3 analyses analyses) 4 5 Statistics: analysis #20c Definition of analysis population relating to protocol non- 18 6 7 population and adherence (eg, as randomised analysis), and any statistical 8 missing data methods to handle missing data (eg, multiple imputation) 9 10 11 Methods: 12 Monitoring 13 14 Data monitoring: #21a Composition of data monitoring committee (DMC); summary of n/a: study team members will be 15 16 formal committee itsFor role and reportingpeer structure; review statement of whether only it is monitoring data 17 independent from the sponsor and competing interests; and 18 19 reference to where further details about its charter can be found, if 20 21 not in the protocol. Alternatively, an explanation of why a DMC 22 is not needed 23 24 Data monitoring: #21b Description of any interim analyses and stopping guidelines, n/a; present study does not have 25 26 interim analysis including who will have access to these interim results and make potentially serious outcomes 27 28 the final decision to terminate the trial 29 30 Harms #22 Plans for collecting, assessing, reporting, and managing solicited 16-17, 19 31 and spontaneously reported adverse events and other unintended 32 33 effects of trial interventions or trial conduct 34 http://bmjopen.bmj.com/ 35 Auditing #23 Frequency and procedures for auditing trial conduct, if any, and n/a; study team meets regularly to 36 37 whether the process will be independent from investigators and address and review operating 38 the sponsor procedures 39 40 41 Ethics and on October 2, 2021 by guest. Protected copyright. 42 dissemination 43 44 45 Research ethics #24 Plans for seeking research ethics committee / institutional review 19 46 approval board (REC / IRB) approval 47 48 49 Protocol amendments #25 Plans for communicating important protocol modifications (eg, 19 50 changes to eligibility criteria, outcomes, analyses) to relevant 51 52 parties (eg, investigators, REC / IRBs, trial participants, trial 53 registries, journals, regulators) 54 55 56 Consent or assent #26a Who will obtain informed consent or assent from potential trial 19 57 participants or authorised surrogates, and how (see Item 32) 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 Consent or assent: #26b Additional consent provisions for collection and use of participant n/a 2 3 ancillary studies data and biological specimens in ancillary studies, if applicable 4 5 Confidentiality #27 How personal information about potential and enrolled 19 6 7 participants will be collected, shared, and maintained in order to 8 protect confidentiality before, during, and after the trial 9 10 11 Declaration of #28 Financial and other competing interests for principal investigators 21 12 interests for the overall trial and each study site 13 14 Data access #29 Statement of who will have access to the final trial dataset, and 19 15 16 disclosureFor of peercontractual agreements review that limit such accessonly for 17 investigators 18 19 20 Ancillary and post #30 Provisions, if any, for ancillary and post-trial care, and for Online supplemental material 21 trial care compensation to those who suffer harm from trial participation (Model consent form) 22 23 24 Dissemination policy: #31a Plans for investigators and sponsor to communicate trial results to 19-20 25 trial results participants, healthcare professionals, the public, and other 26 27 relevant groups (eg, via publication, reporting in results 28 databases, or other data sharing arrangements), including any 29 30 publication restrictions 31 32 Dissemination policy: #31b Authorship eligibility guidelines and any intended use of 20 33 34 authorship professional writers http://bmjopen.bmj.com/ 35 36 Dissemination policy: #31c Plans, if any, for granting public access to the full protocol, n/a; based on institutional policies 37 38 reproducible research participant-level dataset, and statistical code will likely not be made available 39 publically, or without restrictions 40 41 due to clinical aspect of patient data, on October 2, 2021 by guest. Protected copyright. 42 but can be available upon request as 43 44 long as de-identified 45 46 Appendices 47 48 49 Informed consent #32 Model consent form and other related documentation given to Online supplemental material 50 materials participants and authorised surrogates (Model consent form) 51 52 53 Biological specimens #33 Plans for collection, laboratory evaluation, and storage of n/a 54 biological specimens for genetic or molecular analysis in the 55 56 current trial and for future use in ancillary studies, if applicable 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 51 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from None The SPIRIT checklist is distributed under the terms of the Creative Commons Attribution License CC-BY-ND 3.0. This checklist 1 2 can be completed online using https://www.goodreports.org/, a tool made by the EQUATOR Network in collaboration with Penelope.ai 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from

Remotely delivered environmental enrichment intervention for traumatic brain injury: A randomised controlled trial

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-039767.R1 review only Article Type: Protocol

Date Submitted by the 25-Aug-2020 Author:

Complete List of Authors: Belchev, Zorry; University of Toronto, Psychology; Rotman Research Institute, Boulos, Mary Ellene; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Rybkina, Julia; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Johns, Kadeen; Toronto Rehabilitation Institute, KITE Jeffay, Eliyas; Rotman Research Institute, ; Toronto Rehabilitation Institute, KITE Colella, Brenda; Toronto Rehabilitation Institute, KITE Ozubko, Jason; State University of New York College at Geneseo, Psychology Bray, Michael; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE

Di Genova, Nicholas; Toronto Rehabilitation Institute, KITE; McMaster http://bmjopen.bmj.com/ University, Computing and Software Levi, Adina; Rotman Research Institute, ; York University, Psychology Changoor, Alana; Toronto Rehabilitation Institute, KITE; McMaster University Faculty of Health Sciences, Global Health Program Worthington, Thomas; Toronto Rehabilitation Institute, KITE; York University, Psychology Gilboa, Asaf; University of Toronto, Psychology; Rotman Research Institute, Green, Robin; Toronto Rehabilitation Institute, KITE; University of on October 2, 2021 by guest. Protected copyright. Toronto, Psychiatry

Primary Subject Rehabilitation medicine Heading:

Secondary Subject Heading: Evidence based practice

REHABILITATION MEDICINE, Neurological injury < NEUROLOGY, Keywords: THERAPEUTICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 76

1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 2, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 76 BMJ Open

Running head: REMOTE ENRICHMENT IN TBI 1 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 Title: Remotely delivered environmental enrichment intervention for traumatic brain injury: A 7 randomised controlled trial 8 9 Authors: 1,2Belchev, Zorry, 3,4Boulos, Mary E., 3,4Rybkina, Julia, 4Johns, Kadeen, 1,2,4Jeffay, 10 Eliyas, 4Colella, Brenda, 5Ozubko, Jason, 3,4Bray, Michael J. C., 4,6Di Genova, Nicholas, 2,7Levi, 11 Adina, 4,8Changoor, Alana, 4,7Worthington, Thomas, 1,2,4Gilboa, Asaf*, 4,9Green, Robin E.* 12 *Co-senior authors 13 14 15 1Department of Psychology, University of Toronto, Toronto, ON, Canada 16 2Rotman Research InstituteFor at peer Baycrest, Toronto, review ON, Canada only 17 3Graduate Department of Rehabilitation Science, University of Toronto, Toronto, ON, Canada 18 4Toronto Rehabilitation Institute (KITE), Toronto, ON, Canada 19 5Department of Psychology, The State University of New York, Geneseo, NY, USA 20 6 21 Department of Computing and Software, McMaster University, Hamilton, ON, Canada 7 22 Department of Psychology, York University, Toronto, ON, Canada 23 8Global Health Program, Faculty of Health Sciences, McMaster University, Hamilton, ON, 24 Canada 25 9Department of Psychiatry, University of Toronto, ON, Canada 26 27 28 29 Corresponding Author Information: 30 Zorry Belchev 31 (t) 416-785-2500 x3354. (e) [email protected] 32 Rotman Research Institute at Baycrest 33 3460 Bathurst St., North York, Ontario, Canada M6A 2E1 34 http://bmjopen.bmj.com/ 35 Word Count (between Article Summary and Acknowledgments): 5527 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 76

REMOTE ENRICHMENT IN TBI 2 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 ABSTRACT 4 5 6 Introduction: Individuals with moderate-severe traumatic brain injury (m-sTBI) experience 7 8 progressive brain and behavioural declines in the chronic stages of injury. Longitudinal studies 9 10 found that a majority of m-sTBI patients exhibit significant hippocampal atrophy from 5-12 11 12 months post-injury, associated with decreased cognitive environmental enrichment (EE). 13 14 15 Encouragingly, engaging in EE has been shown to lead to neural improvements, suggesting it is 16 For peer review only 17 a promising avenue for offsetting hippocampal neurodegeneration in m-sTBI. Allocentric spatial 18 19 navigation (i.e., flexible, bird’s eye view approach), is a good candidate for EE in m-sTBI 20 21 22 because it is associated with hippocampal activation and reduced aging-related volume loss. 23 24 Efficacy of EE requires intensive daily training, prohibitive within most current health delivery 25 26 systems. The present protocol is a novel, remotely delivered and self-administered intervention 27 28 29 designed to harness principles from EE and allocentric spatial navigation to offset hippocampal 30 31 atrophy and potentially improve hippocampal functions such as navigation and memory for m- 32 33 sTBI patients. 34 http://bmjopen.bmj.com/ 35 Methods and Analysis: Eighty-four chronic m-sTBI participants are being recruited from an 36 37 38 urban rehabilitation hospital and randomised into a 16-week intervention (five hours/week; total: 39 40 80 hrs.) of either targeted spatial navigation or an active control group. The spatial navigation 41 on October 2, 2021 by guest. Protected copyright. 42 group engages in structured exploration of different cities using Google Street View that includes 43 44 45 daily navigation challenges. The active control group watches and answers subjective questions 46 47 about educational videos. Following a brief orientation, participants remotely self-administer the 48 49 intervention on their home computer. In addition to feasibility and compliance measures, clinical 50 51 52 and experimental cognitive measures as well as MRI scan data are collected pre- and post- 53 54 intervention to determine behavioural and neural efficacy. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI 3 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Ethics and Dissemination: Ethics approval has been obtained from ethics boards at the 4 5 6 University Health Network and University of Toronto. Findings will be presented at academic 7 8 conferences and submitted to peer-reviewed journals. 9 10 Trial registration: Version 1 (2 April 2020), ClinicalTrials.gov: NCT04331392 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 76

REMOTE ENRICHMENT IN TBI 4 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 ARTICLE SUMMARY 4 5 6 Strengths and limitations of this study 7 8 ● A remote, self-administered intervention will allow patients greater access to clinically 9 10 relevant resources regardless of physical and economical restrictions, and increase 11 12 current telerehabilitation offerings. 13 14 15 ● The inclusion of neuroimaging outcomes allow for the examination of structural 16 For peer review only 17 changes that may occur alongside potential cognitive improvements associated with 18 19 targeted behavioural training, increasing our understanding of the mechanisms of these 20 21 22 potential changes in humans. 23 24 ● The inclusion of an active control group is critical in determining whether targeted 25 26 rather than generalised training is effective in improving hippocampal-dependent 27 28 29 abilities, but introduces a conservative bias in observing these effects more than if it 30 31 only included a waitlisted control group. 32 33 ● Although the present protocol builds on the principles of successful environmental 34 http://bmjopen.bmj.com/ 35 enrichment observed in rodents in terms of targeted training and high dose, a potential 36 37 38 component that may mediate the benefit is the addition of vigorous physical exercise, 39 40 which will be a consideration for future studies. 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI 5 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 INTRODUCTION 4 5 6 Traumatic brain injury (TBI) is a significant global public health problem, with an 7 8 estimated worldwide incidence rate of 874-1005 cases per 100,000[1]. Contrary to typical 9 10 models of the recovery trajectory, recent longitudinal studies show that degeneration continues at 11 12 least up to 2 years post-injury[2–4]. These recent lines of evidence have signaled a shift from 13 14 15 viewing TBI as a single event, to treating it as a chronic neurodegenerative disorder[5,6], 16 For peer review only 17 necessitating a need for appropriate long-term treatments for patients past their acute phase of 18 19 recovery. 20 21 22 Neurodegeneration and cognitive impairment in chronic TBI 23 24 There is evidence that moderate-severe TBI (m-sTBI) results in chronic volumetric 25 26 decline in both white matter (WM) and gray matter (GM) through the first and up to at least the 27 28 29 second year post-injury. Structures affected include the fornix[7] corpus callosum[3] (CC), and 30 31 temporal, frontal, and occipital regions[2]. Notably, the hippocampus (HPC) tends to be 32 33 particularly vulnerable to chronic degeneration, where Green and colleagues[3] found over 70% 34 http://bmjopen.bmj.com/ 35 of patients showed significant declines (over 2 standard deviations away from controls) in the 36 37 38 HPC. In another study, specific degeneration was found in the HPC, in addition to sub-cortical 39 40 regions that included the thalamus, putamen, amygdala, and caudate[2]. The heightened 41 on October 2, 2021 by guest. Protected copyright. 42 vulnerability of the HPC has been attributed to its sensitivity to excitotoxicity[8], and Wallerian 43 44 45 degeneration through damage distal to the site of the injury[9–11]. 46 47 In addition to neural declines, patients with TBI also exhibit chronic cognitive deficits, 48 49 including in spatial abilities[12] and memory[13,14]. These types of cognitive deficits have been 50 51 52 linked to the underlying degeneration in the HPC, including memory[15]. Furthermore, these 53 54 cognitive deficits may generalise to daily functioning, as lower acute volumes in areas known to 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 76

REMOTE ENRICHMENT IN TBI 6 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 be associated with cognitive deficits in TBI (i.e., HPC, thalamus), predict poorer functional 4 5 6 outcome measured in the chronic stage[16]. 7 8 Impact of external factors on recovery 9 10 Tertiary factors can also negatively contribute to the continued degeneration in the 11 12 chronic stages of TBI in addition to or by compounding the persistent underlying 13 14 15 neuropathology[17,18]. As outlined by the negative neuroplasticity framework[19,20], three 16 For peer review only 17 factors can have a negative impact on neural recovery from a TBI, including: 1) reduced 18 19 schedules of activity following rehabilitation regimen in the acute periods; 2) noisy processing 20 21 22 from sensory deficits, and; 3) weakened neuromodulatory control due to neurotransmitter 23 24 dysfunction. These factors can contribute to negative learning through preference for low-level, 25 26 low-effort cognitive tasks, leading to negative neuroplasticity. Thus, the chronic period that 27 28 29 follows in-patient rehabilitative treatments is critical for ensuring continued cognitive and neural 30 31 stimulation, with therapeutic support during this period that can be scalable and does not 32 33 necessitate extensive therapist involvement. 34 http://bmjopen.bmj.com/ 35 Harnessing environmental enrichment to improve post-injury outcomes 36 37 38 The HPC is commonly impacted by TBI[2–4,16], yet also holds an innate affinity for 39 40 neurogenesis and neuroplasticity[21–23], highlighting it as a good candidate for targeted 41 on October 2, 2021 by guest. Protected copyright. 42 interventions. Evidence from animal studies show that environmental enrichment (EE) through 43 44 45 extensive maze training can support positive neuroplasticity in the HPC[24]. Support for this 46 47 intervention approach has also been shown in humans, particularly when focusing on allocentric 48 49 spatial navigation, involving flexible navigation from a bird’s eye view perspective[25,26]. For 50 51 52 example, an intensive 90 hours of training on a video game associated with allocentric 53 54 navigation resulted in increased HPC volume in those who generally use the opposite strategy 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI 7 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 (i.e., egocentric[27]). Another study showed that intensive virtual navigation training in healthy 4 5 6 older adults resulted in successfully offsetting expected age-related volume declines in the 7 8 HPC[28] and increased hippocampal neural density which was moderated by genotype[29]. 9 10 Informed by the efficacy of such interventions, here we designed a novel intervention 11 12 focused on three factors: 1) targeting the HPC through training on allocentric navigation; 2) 13 14 15 high-intensity and high-dose schedules, and; 3) scalability and convenience through remote 16 For peer review only 17 training online. Google Street View (GSV) was chosen as the navigation platform because it is 18 19 easily accessible from patients’ homes and does not require specialised software, allowing 20 21 22 intensive training of allocentric navigation with only a browser and internet. Based on current 23 24 experimental evidence, we created a website with set virtual environments (cities) consisting of 25 26 routes learning and associated navigation tasks such as vector mapping, distance judgments, 27 28 29 reverse and blocked routes and landmark mapping known to significantly engage hippocampal 30 31 function. The dose of the structured navigation training is 80 hours based on previous findings 32 33 that produced significant benefits[28,29]. Different levels of difficulty are available to adjust to 34 http://bmjopen.bmj.com/ 35 patients’ ability and maintain an appropriate challenge level. To ensure compliance, intrinsic and 36 37 38 extrinsic rewards are embedded into the intervention, and remote progress tracking allows for 39 40 immediate assistance. 41 on October 2, 2021 by guest. Protected copyright. 42 Study objectives and hypotheses 43 44 45 The present protocol is a component of a multi-arm study with three types of patient 46 47 populations (m-sTBI, multiple sclerosis, TBI patients living in remote areas). The present study 48 49 specifically examines the efficacy and feasibility of a novel, remotely-delivered and self- 50 51 52 administered intervention designed to offset HPC atrophy following m-sTBI. The primary 53 54 objective includes two sub-goals examining the intervention’s ability to: 1) behaviourally 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 76

REMOTE ENRICHMENT IN TBI 8 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 improve spatial abilities and memory, and; 2) reduce chronic HPC neurodegeneration. By 4 5 6 comparing the navigation intervention to an active control intervention that provides generalised 7 8 EE, we predict that the navigation intervention will lead to more HPC-specific neural and 9 10 behavioural improvements. The secondary objective takes an exploratory approach to assess the 11 12 feasibility of this intervention in this population. For a broad overview of the trial registration 13 14 15 data set, please refer to Supplementary Table 1. 16 For peer review only 17 METHODS 18 19 Participants 20 21 22 M-sTBI patients from Toronto Rehabilitation Institute’s Acquired Brain Injury Inpatient 23 24 Unit, Outpatient clinics, and Day Hospital program who are under seven months post-injury are 25 26 in the process of being recruited, with a projected recruited sample size of N = 84. This sample 27 28 29 size accounts for an estimated attrition rate of just under 20%, with an expected resultant sample 30 31 size of N = 70 (35 per group). When factoring in attrition, this target sample size will achieve 32 33 0.80 power to detect medium-large effects based on a power analysis for a linear regression with 34 http://bmjopen.bmj.com/ 35 eight predictors (using G*Power[30]). Power will be further maximised by employing dimension 36 37 38 reduction methods (i.e., principal component analysis) prior to conducting the linear regression 39 40 analyses, with the projected number of resultant predictors not exceeding eight. 41 on October 2, 2021 by guest. Protected copyright. 42 Inclusion criteria include: 1) acute care diagnosis of m-sTBI; 2) PTA of 24 hours or more 43 44 45 and/or lowest GCS <13; 3) positive CT or MRI; 4) between 18 to 55 years of age; 5) fluency in 46 47 English; 6) competency to provide informed consent or availability of a legal substitute decision 48 49 maker; 7) basic computer skills (use of internet/email, mouse and arrow keys); 8) functional use 50 51 52 of at least one upper extremity for computer use, and; 9) resident of Greater Toronto Area (to 53 54 facilitate access to the MRI). The age cut-off excluded patients over 55 to prevent potential age- 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI 9 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 related confounds in brain volume and cognitive changes, as research has shown that decline 4 5 6 begins to accelerate in the fifth to sixth decade of life[31]. Exclusion criteria include: 1) 7 8 neurological disorder other than TBI (e.g., dementia, stroke); 2) diagnosis of a 9 10 neurodevelopmental disorder; 3) TBI sustained before age 18; 4) systemic comorbidities (e.g., 11 12 lupus, diabetes); 5) current diagnosis of aphasia, and; 6) presence of metal inside the body (e.g., 13 14 15 surgical clips, pacemaker) leading to ineligibility for an MRI. It is noted that although exclusion 16 For peer review only 17 on the basis of a diagnosis of aphasia is necessary for establishing proof of principle, future 18 19 development should emphasise the incorporation of aphasia-friendly materials in order to benefit 20 21 22 as many patients as possible. 23 24 Inclusion criteria pertaining to the participant’s medical history are assessed using a chart 25 26 review. During recruitment, patients are informed that they do not need to discontinue ongoing 27 28 29 rehabilitative activities to participate in the study. Basic computer skills are evaluated at the pre- 30 31 intervention assessment. Participants are compensated for their participation by receiving 32 33 $75CAD following the completion of each of the pre- and post-intervention assessments, and 34 http://bmjopen.bmj.com/ 35 $75CAD in electronic gift cards (i.e., Amazon) for each month of intervention completion. To 36 37 38 maximise retention and compliance to intervention dose, participants also have the opportunity 39 40 to receive an additional $40CAD in coffee cards ($2.50 for each completed week). A 41 on October 2, 2021 by guest. Protected copyright. 42 consideration regarding compensation is that though it is a necessary component of research 43 44 45 studies, its inclusion may impact the assessment of the feasibility of implementing the 46 47 intervention clinically, in terms of both uptake and compliance. This is partially addressed by a 48 49 debriefing question posed to participants in a post-intervention semi-structured interview, which 50 51 52 asks whether they would have completed the intervention without compensation (for more 53 54 detailed information, refer to the outcome measures and Supplementary Table 2). Based on the 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 10 3 hourly rate (4.25CAD), it is unlikely to provide significant financial incentive. Furthermore, once 4 5 6 the efficacy of the intervention is validated, this would provide an innate incentive for patients to 7 8 complete it as part of their clinical rehabilitation and recovery. 9 10 Patient and Public Involvement 11 12 Patients were not involved in the initial design and development of the research questions 13 14 15 and outcome measures. Once the intervention was developed, pilot patients were recruited to 16 For peer review only 17 complete three to five weeks of the designed intervention to gauge the feasibility of the format 18 19 and intensity of remote training; the patients were able to complete the training as designed and 20 21 22 showed improvements on the targeted training tasks. Patients in the present study will be asked 23 24 to assess the burden of the intervention through the weekly administration of the How Much Is 25 26 Too Much Scale[32]. As part of a post-intervention semi-structured interview they will also be 27 28 29 asked to identify any facilitators and barriers they encountered to completing the intervention, as 30 31 well as the average amount of time they required to participate in the intervention. The public 32 33 was not involved in the design of the study, but a number of public organizations will be engaged 34 http://bmjopen.bmj.com/ 35 for recruitment aid (e.g., March of Dimes, Community Brain Injury Services). Study contacts at 36 37 38 each organization will be provided with a recruitment flyer for circulation among their case 39 40 managers, and in communication with their members (i.e., monthly newsletters). 41 on October 2, 2021 by guest. Protected copyright. 42 Study Design 43 44 45 The present study is a randomised, controlled, patient and (partially) observer blinded, 46 47 parallel group, two arm, superiority trial with a 1:1 allocation. Participants are randomly assigned 48 49 to either the experimental targeted navigation intervention or to active control training 50 51 52 (educational videos), and are blinded to their assigned experimental vs. active control condition. 53 54 Randomisation is conducted using the rand() function in Microsoft Excel by the study 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 11 3 coordinator prior to study commencement. A central recruiter from the institutional recruitment 4 5 6 office who is not part of the study team is employed, who engages in initial contact and primary 7 8 screening. The study coordinator then conducts secondary screening and formal enrollment by 9 10 assigning participants their study identity numbers, which are not directly linked to group 11 12 allocation. The study team member conducting the in-person assessments, as well as the MRI 13 14 15 technologist, are blinded to group assignments. The experimenter conducting the remote 16 For peer review only 17 assessments and training is not blind to group assignments, as they need to train the participant 18 19 on the task, but potential bias is minimised by the absence of nonverbal cues over the phone, and 20 21 22 close adherence to standardised scripts. Participants complete their assigned intervention online, 23 24 using their computer at home. In the event that a participant does not have access to a computer 25 26 or internet connection, they are lent to them at no cost for the duration of the study. 27 28 29 Cognitive assessments are conducted at pre-intervention (week 0) and post-intervention 30 31 (week 17) by the study team and are each split over two days (for a CONSORT study flow 32 33 diagram, see Figure 1). Participants are scheduled to complete pre-intervention assessment at 34 http://bmjopen.bmj.com/ 35 approximately seven months post-injury, in order to target a critical recovery period when 36 37 38 chronic degeneration is known to occur[2–4]. Participants who are recruited at the acute stage 39 40 post-injury are put on a waitlist until they reach seven months post-injury. Pre-intervention 41 on October 2, 2021 by guest. Protected copyright. 42 assessment occurs one week prior to beginning the intervention, in-person at the University of 43 44 45 Toronto Neuroimaging Facility, and over the phone. At the end of the pre-intervention 46 47 assessments, participants receive an orientation to their assigned intervention by completing a 48 49 sample level on the respective intervention’s website, guided by the experimenter over the 50 51 52 phone. Participants assigned to the navigation intervention are provided with instructions on how 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 12 3 to develop their allocentric navigation strategy, conducive to flexible navigation and linked to 4 5 6 HPC activation[33,34]. 7 8 Reminder emails are sent out immediately following the orientation, and on day 1 of the 9 10 intervention in order to support participants when they are beginning the intervention. For the 11 12 remainder of the 16-week intervention, participants receive reminder emails if they miss three 13 14 15 days of training, and a phone call if they miss an entire week of training, in order to follow-up 16 For peer review only 17 and work through any potential barriers to participation. If required, daily text-message or email 18 19 reminders are implemented. A month before the end of the intervention period, the post- 20 21 22 intervention assessments are scheduled to ensure that it is conducted a maximum of one to two 23 24 weeks following intervention completion. 25 26 Targeted navigation intervention 27 28 29 The targeted navigation intervention involves virtual navigation training with a focus on 30 31 allocentric navigation, which is highly associated with the HPC[35,36]). The dose and intensity 32 33 match the design of a previous study with successful outcomes[28,29], with a modified format: 34 http://bmjopen.bmj.com/ 35 approximately one hour a day, five days a week, for 16 weeks on the designated website hosted 36 37 38 within the University Health Network’s (UHN) secure servers. Each week, participants learn a 39 40 section of a new city through basic to more challenging navigation tasks, with the goal of being 41 on October 2, 2021 by guest. Protected copyright. 42 able to independently navigate the assigned section by the end of the week. During task 43 44 45 development, cities were selected based on availability of GSV, presence of English street 46 47 names, sufficient size (i.e., a city centre at least 1 square kilometre), and availability of notable 48 49 landmarks. Participants are asked to complete tasks in new cities with increasingly challenging 50 51 52 layouts each week. Prior to starting the intervention, participants are administered a survey of 53 54 cities visited to ensure all cities are novel to participants. If a participant has visited a test city, a 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 13 3 replacement city is assigned. The challenge level of the tasks within each week vary based on the 4 5 6 selected level, ranging from Level 1 to 4, which differ in number of streets, turns, and landmarks 7 8 (see below) . All participants are initially placed in Level 1, and levels for subsequent weeks are 9 10 based on performance of at least 80% on all of the main task measures during the previous week. 11 12 If participants are performing less than 60% on any of the main task measures in subsequent 13 14 15 weeks, they will be placed in a lower level the following week. If participants are performing 16 For peer review only 17 between 60-79% on any of the main task measures, they will remain in the same level they were 18 19 assigned the previous week. 20 21 22 Inspired by the format of the study maps used in another study[37], each week of training 23 24 begins with studying a map stripped of all labelling except for pre-selected landmarks and street 25 26 names. Based on the challenge level, an initial three landmarks and 8-10 street names were 27 28 29 selected for Level 1 to 3, and an initial five landmarks and 11-13 street names were selected for 30 31 Level 4. Throughout the week, participants learn additional landmarks and street names, where 32 33 by the end of the week they will have learned five landmarks and 11-13 street names for Level 1 34 http://bmjopen.bmj.com/ 35 and 2, seven landmarks and 14-16 street names for Level 3, and nine landmarks and 17-20 street 36 37 38 names selected for Level 4. 39 40 Learning is scaffolded using two types of activities that increase in difficulty throughout 41 on October 2, 2021 by guest. Protected copyright. 42 the week. The first activity is navigation, which requires participants to navigate routes of 43 44 45 increasing difficulty, including: 1) passive routes, where participants are shown videos of route 46 47 navigation in GSV between each of the new landmarks; 2) active routes, which require them to 48 49 independently navigate the same routes shown in the videos; 3) reverse routes, which require 50 51 52 them to navigate to and from landmarks in the opposite direction from what was learned in the 53 54 videos; 4) alternate/new routes, which involves finding routes to learned landmarks or 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 14 3 intersections that had not been previously paired, and; 5) blocked routes, where participants are 4 5 6 instructed to find detours to landmarks or intersections when certain streets are identified as 7 8 inaccessible. When navigating each route, participants are provided a dual-map view earlier in 9 10 the week, with a map inset on one half of the screen, and GSV on the other half. Later in the 11 12 week, participants are required to navigate solely using GSV. Dual-maps and GSV are embedded 13 14 15 in a new page within the website using scripts incorporating Google Maps javascript API, which 16 For peer review only 17 collects participant path data. 18 19 The second activity used to scaffold and to test learning involves a set of end-of-day 20 21 22 multiple-choice challenges based on information learned during the day and throughout the 23 24 week. Participants are asked three types of spatial mapping questions previously used to test both 25 26 egocentric and allocentric spatial knowledge[38–41], including: 1) landmark sequencing (e.g., 27 28 29 You’re walking along X St. from Y St. to Z St. Which landmark do you most closely pass?); 2) 30 31 distance judgment (e.g., Which is closer to X?), and; 3) vector mapping (e.g., Facing X St. from 32 33 Y, which degree represents the direction of Z?). Participants also complete a map placement 34 http://bmjopen.bmj.com/ 35 task, which involves presenting two reproductions of the study map stripped of all information; 36 37 38 letters and numbers representing landmarks and streets, respectively, need to be matched to a list 39 40 of learned landmark and street names. 41 on October 2, 2021 by guest. Protected copyright. 42 To increase compliance and engagement, in addition to earning potential coffee cards, 43 44 45 auditory and written rewards are provided throughout training. Auditory rewards are presented in 46 47 the form of short audio clips about each new landmark, with information about the landmark that 48 49 is part of a greater fictional narrative created for each city. Written rewards are in the form of 50 51 52 eight different encouraging pop-up messages appearing randomly throughout the week (e.g., 53 54 “Good work, keep it up!”). Placement of written and coffee card rewards are based on four 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 15 3 randomised schedules, with a maximum of four combined rewards, at approximately 25%, 50%, 4 5 6 75%, and 100% of the way into the day. The four schedules were additionally randomised to 7 8 each be the set reward schedules of four different weeks. 9 10 Active control training 11 12 Participants randomly assigned to an active control counterpart to the experimental 13 14 15 intervention complete a 16-week educational video intervention at the same intensity as the 16 For peer review only 17 navigation training, also on a designated website hosted on the secure UHN server. Training 18 19 involves watching videos on educational topics (i.e., TED Talks), to control for placebo effects 20 21 22 and for the effects of generalised environmental enrichment of the same dose as the targeted 23 24 navigation training. For each day of training, participants are asked to select one of two possible 25 26 videos, watching a total of three videos. Videos were selected by two raters, basing their 27 28 29 decisions on the educational and engagement level. The videos were further screened for coarse 30 31 language, sexual content, and highly political, religious or polarising topics. Any videos 32 33 involving topics revolving around health, which could be regarded as providing medical advice, 34 http://bmjopen.bmj.com/ 35 were also excluded (refer to Supplementary Table 3 for the final list of videos). Compliance is 36 37 38 indexed by the amount of time patients spend on each of the videos. As an indirect measure, this 39 40 is acknowledged as a potential limitation, but allows some insight into degree of compliance. To 41 on October 2, 2021 by guest. Protected copyright. 42 encourage maximal attention to the videos, at the end of each video, participants rate five aspects 43 44 45 of the content (relevance, interest, comprehensibility, complexity, informative), and speaker 46 47 (persuasiveness, quality of delivery, facial expression, convincingness, captivation), on a scale of 48 49 1 (lowest) to 5 (highest). This rating task was chosen because it does not have a strong memory 50 51 52 component associated with it and thus ensures that the task is not targeting memory functioning. 53 54 As an innate characteristic of self-administered therapy, and generalised questions, attention is 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 16 3 not able to be measured directly, and is acknowledged as a potential limitation. Additionally, as 4 5 6 with navigation participants, they are given written rewards of encouragement with the same 7 8 randomised placement as described above. 9 10 Outcome measures 11 12 Brain structural changes using Magnetic Resonance Imaging 13 14 15 A Siemens Prisma 3 Tesla scanner with a 32 channel head coil is used for imaging 16 For peer review only 17 acquisition. The primary imaging measures include total HPC volumes, and HPC sub-structures. 18 19 The secondary imaging measures include the integrity of white matter tracts involving the HPC 20 21 22 (i.e., fimbria-fornix pathway). 23 24 Cognitive changes: Experimental measures 25 26 The primary cognitive outcome measures include near-, medium-, and far-transfer 27 28 29 measures. Near-transfer outcome measures (navigation intervention only) are performance 30 31 outcomes in a city on which participants were not trained following the intervention. Medium- 32 33 transfer measures are used to assess changes to spatial abilities that were not trained: 1) 34 http://bmjopen.bmj.com/ 35 Cognitive Map Formation Test (CMFT; earlier version described in [42]); 2) Different Approach 36 37 38 Task[43], and; 3) Path Integration Task[44]. Far-transfer measures include memory tasks 39 40 sensitive to HPC integrity to assess generalizability of training to HPC-dependent abilities that 41 on October 2, 2021 by guest. Protected copyright. 42 were not directly trained: 1) Memory Image Completion Task[45,46] (MIC), and; 2) Mnemonic 43 44 45 Similarity Test[47] (MST). Additional secondary outcome measures include subjective changes 46 47 to navigation and memory in daily life with the following self-report measures; 1) Santa Barbara 48 49 Sense of Direction Scale[48] (SBSOD); 2) Navigational Strategies Questionnaire[49] (NSQ), 50 51 52 and; 3) Everyday Memory Questionnaire[50] (EMQ). Alternate forms of the primary tasks are 53 54 used (i.e., MST, MIC, CMFT, Different Approach Task, Path Integration Task), with the specific 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 17 3 form used for the pre- and post-intervention assessments counterbalanced across participants. To 4 5 6 maintain consistency in administration, data collection, and data entry, experimenters will 7 8 undergo matched training and utilise scripts and detailed instructions. Coding of the key 9 10 components of the measures will be entered and checked by multiple experimenters. 11 12 Cognition: Clinical measures 13 14 15 A comprehensive neuropsychological assessment battery validated for use with 16 For peer review only 17 individuals with TBI will be administered by a trained neuropsychologist blind to group 18 19 allocation, to characterise the participants at baseline, and determine changes to performance on 20 21 22 traditional clinical measures following the intervention. The tests administered include: 1) the 23 24 Wechsler Test of Adult Reading[51] (for characterisation only); 2) Digit Span forwards and 25 26 backwards[52]; Visual Spatial Span (forwards and backwards); 4) the Rey Auditory Verbal 27 28 29 Learning Test[53] (RAVLT); 5) the Rey Visual Design Learning Test[54] (RVDLT); 6) the 30 31 Sustained Attention to Response Test[55] (SART); the Symbol Digit Modalities Test[56], and; 32 33 7) select sub-tests of the NIH toolbox[57], including the picture sequence memory test, flanker 34 http://bmjopen.bmj.com/ 35 inhibitory control and attention test, dimensional change card sort test, and pattern comparison 36 37 38 processing speed test. An alternate form of the picture sequence memory test is used for the post- 39 40 intervention assessment. As a broader index of functional outcome, the Glasgow Outcome Scale 41 on October 2, 2021 by guest. Protected copyright. 42 Extended[58] will be administered pre- and post-intervention. In addition to the clinical 43 44 45 cognitive measures outlined above, mood assessments will also be employed, including the Beck 46 47 Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI), as part of the clinical 48 49 neuropsychological feedback provided to participants post-intervention[59,60]. Feedback is 50 51 52 provided via phone call by the neuropsychologist and one of the lead scientists (RG), to the 53 54 participant and their significant other or caregiver. Information from their clinical interview, 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 18 3 performance across the clinical measures, and medical chart is integrated. Feedback includes: 1) 4 5 6 a review of the purpose and expectations of the assessment; 2) a review of strengths and 7 8 weaknesses across cognitive domains that have been observed and connect them (if applicable) 9 10 to clinical complaints or symptoms; 3) a discussion regarding personal goals and how best to use 11 12 identified strengths to offset their weaknesses, and; 4) further referrals to medical professionals, 13 14 15 if applicable. 16 For peer review only 17 Training-related outcome measures 18 19 To assess improvements in navigation-related, within-task intervention components, the 20 21 22 following measures are collected for navigation training participants only: 1) spatial learning 23 24 ability based on end-of-day questions; 2) overall spatial ability improvement based on the 25 26 difference in performance of end-of-week end-of-day questions, between earlier to later weeks of 27 28 29 training; 3) independent navigation ability improvement on GSV-only reverse, alternate, and 30 31 blocked routes, based on differences in performance between earlier to later weeks of training, 32 33 and; 4) cognitive map formation ability, based on differences in end-of-week performance 34 http://bmjopen.bmj.com/ 35 between earlier and later weeks of training. Because the complexity of the cities increases 36 37 38 throughout the 16 weeks of training, and participants may switch challenge levels, this is not a 39 40 direct comparison of pre- and post-intervention ability. Therefore, performance is also compared 41 on October 2, 2021 by guest. Protected copyright. 42 between the first week of training, and an additional week following the completion of the 43 44 45 intervention, based on a novel city of similar complexity as the first city. 46 47 Assessments of feasibility 48 49 General feasibility of the intervention will be determined by the recruitment rate, 50 51 52 retention rate (including factors influencing retention), and compliance rates, based on objective 53 54 rates and subjectively through daily, weekly, and bi-weekly self-reported questionnaires. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 19 3 Recruitment rate will be determined by dividing the number of participants consented by the 4 5 6 number of eligible participants approached, retention rate will be determined by dividing the 7 8 number of consented participants at baseline by the number of consented participants retained at 9 10 follow-up, and compliance rate will be determined by calculating the percentage of participants 11 12 adhering to at least 80% of the training protocol, as well as by calculating the average of each 13 14 15 individual participant’s percentage of completion of each of the daily tasks across the entire 16 For peer review only 17 duration of the intervention. Retention and compliance rates close to 100% are desired, but 70% 18 19 or greater would be considered successfully high, based on previous studies assessing feasibility 20 21 22 of self-administered computerised interventions in this type of population[61–63]. The degree of 23 24 burden to the participants in completing the intervention will be assessed by The How Much is 25 26 Too Much Scale[32], administered each week to measure physical, mental, and mood symptom 27 28 29 onset following intervention participation, incorporated on the intervention website at the end of 30 31 the week’s tasks. Participants placed in the targeted navigation intervention group also complete 32 33 a semi-structured interview following the intervention for a qualitative assessment of their 34 http://bmjopen.bmj.com/ 35 experiences to inform the feasibility of the method of delivery and content of the intervention 36 37 38 (please see Supplementary Table 2 for the full set of questions). Responses are collected over the 39 40 phone by the experimenter who conducts the remote assessments, following all of the outcome 41 on October 2, 2021 by guest. Protected copyright. 42 measures. 43 44 45 Control variables 46 47 Demographic information, injury history, and hours of therapy for all participants are 48 49 collected using a secure, online survey prior to the pre-intervention assessment. At the pre- 50 51 52 intervention assessment, a personal interview is conducted to validate the contents of the survey 53 54 and gather additional information. In addition to inclusion for clinical feedback, BAI and BDI 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 20 3 scores are also considered as control variables[59,60]. Participants’ current level of physical 4 5 6 activity are assessed using the International Physical Activity Questionnaire - Short Form[64] 7 8 (IPAQ). 9 10 PLANNED STATISTICAL ANALYSES 11 12 Primary objective: Efficacy 13 14 15 To address the first sub-goal of the primary objective of determining whether our 16 For peer review only 17 intervention can improve cognitive domains related to the HPC, descriptive and inferential 18 19 statistics will be employed to examine group-level changes in the following cognitive outcomes 20 21 22 (experimental and clinical): far-transfer tasks associated with executive functioning (Digit Span, 23 24 Visual Spatial Span, SART, Symbol Digit Modalities Test, flanker inhibitory control and 25 26 attention test, dimensional change card sort test, and pattern comparison processing speed test), 27 28 29 far-transfer tasks associated with memory (MIC, MST, RAVLT, RVDLT, picture sequence 30 31 memory test), medium-transfer associated with spatial abilities (CMFT, Different Approach 32 33 Task, Path Integration Task); near-transfer of navigating using GSV, and subjective measures 34 http://bmjopen.bmj.com/ 35 (SBSOD, NSQ, EMQ). A principal component analysis will be conducted for dimension 36 37 38 reduction of these measures, and the resultant components will be used as predictors in a series 39 40 of between-group (targeted navigation and active control) analyses, which will be used to 41 on October 2, 2021 by guest. Protected copyright. 42 estimate the average causal treatment effect. Secondary control measures will then be introduced 43 44 45 individually to test for interactions that, if present, indicate that the corresponding variable acts 46 47 as a moderator of the treatment effect, including depression (BDI-II), anxiety (BAI), age, sex, 48 49 injury severity (i.e., GCS), hours of therapy, and physical activity (IPAQ). If so, specific effects 50 51 52 will be estimated. Within the targeted navigation group, changes to near-transfer outcomes will 53 54 be assessed using single-group analyses on the training-related outcome measures. The analyses 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 21 3 will be carried out with mixed models using information available from all participants, 4 5 6 including those with partially missing data (combining mixed models with multiple imputation 7 8 for longitudinal data) to reduce potential bias due to attrition. Analyses will be carried out “as 9 10 randomised” (intent-to-treat analyses) as well as “per protocol” taking the degree of compliance 11 12 into account. We anticipate group effects and group by time interactions, with improvements in 13 14 15 the navigation group at post-intervention (vs. control). For navigation participants, we also 16 For peer review only 17 anticipate improvements on the training-related outcome measures. 18 19 To test our second sub-goal of determining the efficacy of the intervention to reduce HPC 20 21 22 degeneration, the same analyses described above for the cognitive measures will be undertaken 23 24 for our imaging outcomes. We expect specific HPC degeneration in controls and stable or 25 26 increased volumes in the navigation group. Additional HPC sub-field analyses will be completed 27 28 29 based on manual segmentation of the T2 volumes, where data analysts will be blinded to the 30 31 allocation of the participant. We expect the dentate gyrus and CA1 sub-regions to most strongly 32 33 express degeneration and preservation trajectories due to roles in allocentric navigation and 34 http://bmjopen.bmj.com/ 35 neurogenesis. For DTI, we expect an offset of previously reported fornix degeneration following 36 37 38 navigation training[7]. Cingulum integrity could also be expected to be modulated with 39 40 improved HPC function and/or structure. 41 on October 2, 2021 by guest. Protected copyright. 42 Secondary objective: Feasibility 43 44 45 This secondary objective will be achieved by assessing recruitment and retention in the 46 47 study, by measuring compliance of participants in the completion of the interventions and the 48 49 completion of all behavioural outcome measures of the study, and by assessing scores on the 50 51 52 How Much is Too Much Scale. A semi-structured interview will help identify barriers to 53 54 completion and to elicit suggestions for improvement. Descriptive statistics will be used to 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 22 3 summarise the outcomes of the feasibility component of the study. Recorded responses to the 4 5 6 questions from the semi-structured interviews will be transcribed and manual thematic 7 8 analysis[65] will be undertaken by two independent reviewers to identify themes of barriers and 9 10 facilitation to participation, after which a qualitative metasummary will be prepared. 11 12 ETHICS AND DISSEMINATION 13 14 15 This study has been approved by the University Health Network Research Ethics Board 16 For peer review only 17 and the Research Oversight and Compliance Office at the University of Toronto. This study will 18 19 be conducted in accordance with the Declaration of Helsinki and the Tri-Council Policy 20 21 22 Statement: Ethical Conduct for Research Involving Humans, 2nd edition[66]. The present study 23 24 began on October 20, 2018 and recruitment is ongoing. Any modifications to the present 25 26 protocol will be submitted as formal amendments to the original ethics application and reviewed 27 28 29 by the above ethics boards prior to their implementation. All participants will be recruited 30 31 through an informed consent protocol in-person and by telephone (please see online 32 33 supplemental material for a model consent form). At the time of consent, participants are assured 34 http://bmjopen.bmj.com/ 35 that withdrawing from the study will not affect the care they receive at Toronto Rehabilitation 36 37 38 Institute. Participants are informed that the study involves minimal risks (i.e., fatigue from 39 40 assessments or intervention, claustrophobia during MRI). Participants may leave the study at any 41 on October 2, 2021 by guest. Protected copyright. 42 time. The protocol follows the guidelines prescribed by the Standard Protocol Items: 43 44 45 Recommendations for Interventional Trials Statement[67]. All collected physical data will be 46 47 stored securely in locked cabinets, and electronic data will be stored on a secure server at 48 49 Toronto Rehabilitation Institute. Only the direct study team will have access to identifying 50 51 52 information, which will be kept confidential, and to the final dataset. Results summarising the 53 54 anonymised data will be presented at academic and clinical conferences and findings will be 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 23 3 submitted to peer-reviewed journals. Authorship for publications will be determined based on the 4 5 6 uniform requirements for manuscripts submitted to biomedical journals[68]. Key findings will be 7 8 shared directly with participantss who have participated in the study by email, summarising the 9 10 broad results in a simplified and accessible format, and will be made available to the public 11 12 through media releases shared through the Marketing and Communications departments at 13 14 15 Toronto Rehabilitation Institute and the Rotman Research Institute at Baycrest. 16 For peer review only 17 SIGNIFICANCE AND IMPACT 18 19 The strength and novelty of the present study is the unique design of an intervention that 20 21 22 can be completed by participants in their own homes using widely available software, which can 23 24 therefore be delivered with minimal resources, anywhere in the world. This enhances the 25 26 scalability and reach of the intervention, allowing the study to be replicated and the intervention 27 28 29 to be available to large samples and other patient populations with similar neuropathology. 30 31 Furthermore, using the principles of EE, the intervention is designed to be continuously novel 32 33 and challenging, allowing participants to remain engaged while stimulating the HPC through 34 http://bmjopen.bmj.com/ 35 tasks known to be hippocampal-dependent. Additionally, the study employs an active control to 36 37 38 allow more robust conclusions to be made regarding the effectiveness of a targeted navigation 39 40 intervention for m-s TBI, compared to generalised EE. Finally, the online setting of the 41 on October 2, 2021 by guest. Protected copyright. 42 intervention allows for real-time data collection to monitor compliance and performance while 43 44 45 maintaining accurate records. 46 47 Importantly, the proposed research aims to develop infrastructure for ongoing 48 49 neurorehabilitation in remote communities, and for individuals who may face other barriers to 50 51 52 obtaining necessary resources (e.g., reduced mobility, or financial burden). The self-administered 53 54 feasibility questionnaire as well as the post-intervention interview will help to ascertain barriers 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 24 3 and facilitators to retention and compliance for computerised cognitive tasks for individuals with 4 5 6 m-sTBI, to ultimately expand the availability of treatment options for individuals in this 7 8 population. 9 10 ACKNOWLEDGMENTS 11 12 We would like to thank all of the volunteers, research assistants and undergraduate 13 14 15 project students who graciously offered their time to assist in the development of the 16 For peer review only 17 intervention: Taha Arshad, Marta Bogacki, Priyanka Prince, Sonia Persaud, Michelle Gomez, 18 19 Robert Dydynsky, Alexander Drohobycky, Mikael Salnikov, Reid Syrydiuk, Ginelle Feliciano, 20 21 22 Roy Kuo, Maleeha Khan, Gina D'Souza, Mubina Butt, Samreen Aziz, Madison Fraser. Finally, 23 24 we would also like to acknowledge our recruitment contacts and partners who are central in 25 26 strengthening our recruitment reach in order to assess the feasibility and efficacy of this 27 28 29 intervention in patients: Dr. Matthew Burke (Sunnybrook Health Sciences Center), Dr. Karl F. 30 31 Gunnarsson (West Park Healthcare Centre), Kamilah Francis and Crystal McCollum (March of 32 33 Dimes Canada), and Michelle Pangilinan (Community Brain Injury Services). 34 http://bmjopen.bmj.com/ 35 COMPETING INTERESTS 36 37 38 The authors declare no competing interests related to this study. 39 40 FUNDING 41 on October 2, 2021 by guest. Protected copyright. 42 This work is supported and funded by the Ontario Neurotrauma Foundation (ONF; 2017- 43 44 45 ABI-INFRA-1035), the Canadian Centre for Aging & Brain Health Innovation (CABHI), the 46 47 Canadian Traumatic Brain Injury Research Consortium (CTRC), the Branch Out Neurological 48 49 Foundation, and the Canada Research Chairs (950-230647). None of the funding sources had any 50 51 52 role in the design of the protocol nor will be involved in its execution, analyses, data 53 54 interpretation, or dissemination of results. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 25 3 AUTHOR CONTRIBUTIONS 4 5 6 AG and REG conceived the original idea for the intervention, with BC as study manager. 7 8 AG and REG are also supervising the study, are helping maintain recruitment avenues, and 9 10 contributed to the final manuscript. ZB developed the materials for the intervention with 11 12 assistance and supervision by AG and REG, and with the aid of AL and AC. ZB, MEB and JR 13 14 15 all contributed to the implementation of the intervention on the training website, with JO 16 For peer review only 17 completing the initial methodology for GSV and overseeing ND as programmer, and with 18 19 assistance from TW and AL. MJCB and MEB developed the semi-structured interview that will 20 21 22 be administered to participants following completion of the study. KJ oversees the recruitment 23 24 and screening of patients, with help from EJ, JR, MEB, and ZB, as well as all other 25 26 administrative aspects of the study. ZB, JR, and MEB oversee data collection and training 27 28 29 participants on the intervention, with EJ completing the administration of neuropsychological 30 31 assessments and reports, and TW assisting in data collection and training. ZB, MEB, and JR 32 33 wrote the manuscript with consultation from AG and REG. (Please also refer to Supplementary 34 http://bmjopen.bmj.com/ 35 Table 4 for an overview of roles and responsibilities.) 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 26 3 REFERENCES 4 5 6 1 World Health Organization. World Health Statistics 2015. 7 8 2015.https://www.who.int/gho/publications/world_health_statistics/2015/en/ (accessed 22 9 10 Apr 2020). 11 12 2 Cole JH, Jolly A, de Simoni S, et al. Spatial patterns of progressive brain volume loss 13 14 15 after moderate-severe traumatic brain injury. Brain 2018;141:822–36. 16 For peer review only 17 doi:10.1093/brain/awx354 18 19 3 Green REA, Colella B, Maller JJ, et al. Scale and pattern of atrophy in the chronic stages 20 21 22 of moderate-severe TBI. Front Hum Neurosci 2014;8:67. doi:10.3389/fnhum.2014.00067 23 24 4 Ng K, Mikulis DJ, Glazer J, et al. Magnetic Resonance Imaging Evidence of Progression 25 26 of Subacute Brain Atrophy in Moderate to Severe Traumatic Brain Injury. Arch Phys Med 27 28 29 Rehabil 2008;89:S35–44. doi:10.1016/j.apmr.2008.07.006 30 31 5 Green REA. Editorial: Brain Injury as a Neurodegenerative Disorder. Front Hum 32 33 Neurosci 2016;9:615. doi:10.3389/fnhum.2015.00615 34 http://bmjopen.bmj.com/ 35 6 Masel BE, DeWitt DS. Traumatic brain injury: A disease process, not an event. J. 36 37 38 Neurotrauma. 2010;27:1529–40. doi:10.1089/neu.2010.1358 39 40 7 Adnan A, Crawley A, Mikulis D, et al. Moderate–severe traumatic brain injury causes 41 on October 2, 2021 by guest. Protected copyright. 42 delayed loss of white matter integrity: Evidence of fornix deterioration in the chronic 43 44 45 stage of injury. Brain Inj 2013;27:1415–22. doi:10.3109/02699052.2013.823659 46 47 8 Mccarthy MM. Stretching the truth Why hippocampal neurons are so vulnerable following 48 49 traumatic brain injury. Published Online First: 2003. doi:10.1016/j.expneurol.2003.08.020 50 51 52 9 Mckee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin 53 54 Neurol 2015;127:45–66. doi:10.1016/B978-0-444-52892-6.00004-0 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 76 BMJ Open

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REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 29 3 stage of Alzheimer’s disease: Insights from imaging and behavioral studies. Ageing Res. 4 5 6 Rev. 2013;12:201–13. doi:10.1016/j.arr.2012.04.007 7 8 27 West GL, Konishi K, Bohbot VD. Video Games and Hippocampus-Dependent Learning. 9 10 Curr Dir Psychol Sci 2017;26. doi:10.1177/0963721416687342 11 12 28 Lövdén M, Schaefer S, Noack H, et al. Spatial navigation training protects the 13 14 15 hippocampus against age-related changes during early and late adulthood. Neurobiol 16 For peer review only 17 Aging 2012;33:620.e9-620.e22. doi:10.1016/J.NEUROBIOLAGING.2011.02.013 18 19 29 Lövdén M, Schaefer S, Noack H, et al. Performance-related increases in hippocampal N- 20 21 22 acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val 23 24 homozygotes. Cereb Cortex 2011;21:1435–42. doi:10.1093/cercor/bhq230 25 26 30 Faul F, Erdfelder E, Buchner A, et al. Statistical power analyses using G*Power 3.1: Tests 27 28 29 for correlation and regression analyses. Behav Res Methods 2009;41:1149–60. 30 31 doi:10.3758/BRM.41.4.1149 32 33 31 Raz N, Ghisletta P, Rodrigue KM, et al. Trajectories of brain aging in middle-aged and 34 http://bmjopen.bmj.com/ 35 older adults: Regional and individual differences. Neuroimage 2010;51:501–11. 36 37 38 doi:10.1016/j.neuroimage.2010.03.020 39 40 32 Tomaszczyk JC, Sharma B, Chan AA, et al. Measuring cognitive assessment and 41 on October 2, 2021 by guest. Protected copyright. 42 intervention burden in patients with acquired brain injury: Development of the ‘how Much 43 44 45 Is Too Much?’ questionnaire. J Rehabil Med 2018;50:519–26. doi:10.2340/16501977- 46 47 2344 48 49 33 Iaria G, Petrides M, Dagher A, et al. Cognitive strategies dependent on the hippocampus 50 51 52 and caudate nucleus in human navigation: Variability and change with practice. J 53 54 Neurosci 2003;23:5945–52. doi:10.1523/jneurosci.23-13-05945.2003 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 30 3 34 Ohnishi T, Matsuda H, Hirakata M, et al. Navigation ability dependent neural activation 4 5 6 in the human brain: An fMRI study. Neurosci Res 2006;55:361–9. 7 8 doi:10.1016/J.NEURES.2006.04.009 9 10 35 O’Keefe J, Dostrovsky J. The hippocampus as spatial map: Preliminary evidence from 11 12 unit activity in the freely-moving rat. Brain Res 1971;34:171–5. 13 14 15 36 Bohbot VD, Lerch J, Thorndycraft B, et al. Gray Matter Differences Correlate with 16 For peer review only 17 Spontaneous Strategies in a Human Virtual Navigation Task. Published Online First: 18 19 2007. doi:10.1523/JNEUROSCI.1763-07.2007 20 21 22 37 Howard LR, Javadi AH, Yu Y, et al. The Hippocampus and Entorhinal Cortex Encode the 23 24 Path and Euclidean Distances to Goals during Navigation. Curr Biol 2014;24:1331–40. 25 26 doi:10.1016/J.CUB.2014.05.001 27 28 29 38 Hirshhorn M, Grady C, Rosenbaum RS, et al. The hippocampus is involved in mental 30 31 navigation for a recently learned, but not a highly familiar environment: A longitudinal 32 33 fMRI study. Hippocampus 2012;22:842–52. doi:10.1002/hipo.20944 34 http://bmjopen.bmj.com/ 35 39 Rosenbaum RS, Ziegler M, Winocur G, et al. ‘I have often walked down this street 36 37 38 before’: fMRI studies on the hippocampus and other structures during mental navigation 39 40 of an old environment. Hippocampus 2004;14:826–35. doi:10.1002/hipo.10218 41 on October 2, 2021 by guest. Protected copyright. 42 40 Rosenbaum RS, Cassidy BN, Herdman KA. Patterns of preserved and impaired spatial 43 44 45 memory in a case of developmental amnesia. Front Hum Neurosci 2015;9:196. 46 47 doi:10.3389/fnhum.2015.00196 48 49 41 Waller D, Hodgson E. Transient and enduring spatial representations under disorientation 50 51 52 and self-rotation. J Exp Psychol Learn Mem Cogn 2006;32:867–82. doi:10.1037/0278- 53 54 7393.32.4.867 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 31 3 42 Corrow JC, Corrow SL, Lee E, et al. Getting lost: Topographic skills in acquired and 4 5 6 developmental prosopagnosia. Cortex 2016;76:89–103. 7 8 doi:10.1016/J.CORTEX.2016.01.003 9 10 43 Wiener JM, Carroll D, Moeller S, et al. A novel virtual-reality-based route-learning test 11 12 suite: Assessing the effects of cognitive aging on navigation. Behav Res Methods 2019;:1– 13 14 15 11. doi:10.3758/s13428-019-01264-8 16 For peer review only 17 44 Persson J, Herlitz A, Engman J, et al. Remembering our origin: Gender differences in 18 19 spatial memory are reflected in gender differences in hippocampal lateralization. Behav 20 21 22 Brain Res 2013;256:219–28. doi:10.1016/j.bbr.2013.07.050 23 24 45 Vieweg P, Stangl M, Howard LR, et al. Changes in pattern completion – A key 25 26 mechanism to explain age-related recognition memory deficits? Cortex 2015;64:343–51. 27 28 29 doi:10.1016/J.CORTEX.2014.12.007 30 31 46 Vieweg P, Riemer M, Berron D, et al. Memory Image Completion: Establishing a task to 32 33 behaviorally assess pattern completion in humans. Hippocampus 2018;:1–18. 34 http://bmjopen.bmj.com/ 35 doi:10.1002/hipo.23030 36 37 38 47 Stark SM, Yassa MA, Lacy JW, et al. A task to assess behavioral pattern separation (BPS) 39 40 in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia 41 on October 2, 2021 by guest. Protected copyright. 42 2013;51:2442–9. doi:10.1016/J.NEUROPSYCHOLOGIA.2012.12.014 43 44 45 48 Hegarty M, Richardson AE, Montello DR, et al. Development of a self-report measure of 46 47 environmental spatial ability. Intelligence 2002;30:425–47. doi:10.1016/S0160- 48 49 2896(02)00116-2 50 51 52 49 Brunec IK, Bellana B, Ozubko JD, et al. Multiple Scales of Representation along the 53 54 Hippocampal Anteroposterior Axis in Humans. Curr Biol 2018;28:2129-2135.e6. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 32 3 doi:10.1016/J.CUB.2018.05.016 4 5 6 50 Sunderland A, Harris JE, Baddeley AD. Do laboratory tests predict everyday memory? A 7 8 neuropsychological study. J Verbal Learning Verbal Behav 1983;22:341–57. 9 10 doi:10.1016/S0022-5371(83)90229-3 11 12 51 Wechsler D. Wechsler Test of Adult Reading (WTAR). San Antonio, TX: : The 13 14 15 Psychological Corporation 2001. 16 For peer review only 17 52 Wechsler D. Manual for the Wechsler Adult Intelligence Scale - Revised. 1981. 18 19 doi:Thesis_references-Converted #317 20 21 22 53 Rey A. L’examen Clinique en Psychologie. 2e ed. Paris: : Presses universitaires de France 23 24 1964. doi:10.1176/appi.psychotherapy.1959.13.4.989 25 26 54 Rey A. L’examen Clinique en Psychologie. 1. éd. Paris: : Presses universitaires de France 27 28 29 1958. doi:10.1176/appi.psychotherapy.1959.13.4.989 30 31 55 Robertson IH, Manly T, Andrade J, et al. ‘Oops!’: Performance correlates of everyday 32 33 attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 34 http://bmjopen.bmj.com/ 35 1997;35:747–58. doi:10.1016/S0028-3932(97)00015-8 36 37 38 56 Smith A. Symbol Digits Modalities Test. Los Angeles: : Western Psychological Sciences 39 40 1982. 41 on October 2, 2021 by guest. Protected copyright. 42 57 Gershon RC, Cella D, Fox NA, et al. Assessment of neurological and behavioural 43 44 45 function: the NIH Toolbox. Lancet Neurol. 2010;9:138–9. doi:10.1016/S1474- 46 47 4422(09)70335-7 48 49 58 Wilson JTL, Pettigrew LEL, Teasdale GM. Structured interviews for the glasgow outcome 50 51 52 scale and the extended glasgow outcome scale: Guidelines for their use. J. Neurotrauma. 53 54 1998;15:573–80. doi:10.1089/neu.1998.15.573 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 33 3 59 Beck AT, Epstein N, Brown G, et al. An Inventory for Measuring Clinical Anxiety: 4 5 6 Psychometric Properties. J Consult Clin Psychol 1988;56:893–7. doi:10.1037/0022- 7 8 006X.56.6.893 9 10 60 Beck AT, Steer RA, Brown GK. Manual for the Beck depression inventory-II. San 11 12 Antonio, TX Psychol Corp 1996;:1–82. 13 14 15 61 Lebowitz MS, Dams-O K, Cantor JB. Feasibility of computerized brain plasticity-based 16 For peer review only 17 cognitive training after traumatic brain injury. 2012;49. doi:10.1682/JRRD/2011.07.0133 18 19 62 O’Neil-Pirozzi TM, Hsu H. Feasibility and benefits of computerized cognitive exercise to 20 21 22 adults with chronic moderate-to-severe cognitive impairments following an acquired brain 23 24 injury: A pilot study. Brain Inj 2016;30:1617–25. doi:10.1080/02699052.2016.1199906 25 26 63 Sharma B, Tomaszczyk JC, Dawson D, et al. Feasibility of online self-administered 27 28 29 cognitive training in moderate–severe brain injury. Disabil Rehabil 2017;39:1380–90. 30 31 doi:10.1080/09638288.2016.1195453 32 33 64 Craig CL, Marshall AL, Sjöström M, et al. International physical activity questionnaire: 34 http://bmjopen.bmj.com/ 35 12-Country reliability and validity. Med Sci Sports Exerc Published Online First: 2003. 36 37 38 doi:10.1249/01.MSS.0000078924.61453.FB 39 40 65 Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol 2006;3:77– 41 on October 2, 2021 by guest. Protected copyright. 42 101. doi:10.1191/1478088706qp063oa 43 44 45 66 Canadian Institute of Health Research, Natural Sciences and Engineering Research 46 47 Council of Canada SS and HRC. Tri-Council Policy Statement: Ethical Conduct for 48 49 Research Involving Humans. 2018. 50 51 52 67 Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: Defining standard 53 54 protocol items for clinical trials. Ann. Intern. Med. 2013;158:200–7. doi:10.7326/0003- 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 76

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 34 3 4819-158-3-201302050-00583 4 5 6 68 International Committee of Medical Journal Editors. Uniform Requirements for 7 8 Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 9 10 Publication. 2010. www.ICMJE.org (accessed 22 Apr 2020). 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 76 BMJ Open

REMOTE ENRICHMENT IN TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 35 3 Figure 1 4 5 6 CONSORT study flow diagram of the present protocol 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 Figure 1. CONSORT study flow diagram of the present protocol on October 2, 2021 by guest. Protected copyright. 43 200x219mm (300 x 300 DPI) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 1 4 5 6 7 Trial registration data for the study protocol based on World Health Organization Trial 8 Registration Data Set guidelines 9 10 11 12 Data category Information 13 Primary registry and trial identifying number ClinicalTrials.gov: NCT04331392 14 Date of registration in primary registry 2 April, 2020 15 Source(s) of monetary or material support Ontario Neurotrauma Foundation (ONF); 16 For peer review only 17 Canadian Centre for Aging & Brain Health 18 Innovation (CABHI); Canadian Traumatic 19 Brain Injury Research Consortium (CTRC); 20 Branch Out Neurological Foundation 21 Primary sponsor ONF; CABHI 22 Name and Contact Information for Primary Judy Gargaro, ABI Program Director, ONF - 23 24 sponsors [email protected] 25 James Mayer, Portfolio Manager, CABHI - 26 [email protected] 27 Secondary sponsor(s) CTRC; Branch Out Neurological Foundation 28 Contact for public queries REG, AG, ZB, MB, JR 29 30 Contact for scientific queries REG, AG, ZB, MB, JR 31 Public title Remotely Delivered Environmental 32 Enrichment Intervention for Traumatic Brain 33 Injury: A Randomized Controlled Trial 34 Scientific title Remotely Delivered Environmental http://bmjopen.bmj.com/ 35 Enrichment Intervention for Traumatic Brain 36 Injury: A Randomized Controlled Trial 37 38 Countries of recruitment Canada 39 Health condition(s) or problem(s) studied Traumatic brain injury 40 Intervention(s) Experimental: Spatial navigation intervention 41 Active Comparator: Educational Videos on October 2, 2021 by guest. Protected copyright. 42 Key inclusion and exclusion criteria Inclusion: 1) acute care diagnosis of m-sTBI; 43 44 2) PTA of 24 hours or more and/or lowest 45 GCS <13; 3) positive CT or MRI; 4) between 46 18 to 55 years of age; 5) fluency in English; 47 6) competency to provide informed consent or 48 availability of a legal decision maker; 7) basic 49 computer skills (use of internet/email, mouse 50 and arrow keys); 8) functional use of at least 51 52 one upper extremity for computer use, and; 9) 53 resident of Greater Toronto Area (to facilitate 54 access to the MRI) 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Exclusion: 1) neurological disorder other than 4 TBI (e.g., dementia, stroke); 2) diagnosis of a 5 6 neurodevelopmental disorder; 3) TBI 7 sustained before age 18; 4) systemic 8 comorbidities (e.g., lupus, diabetes); 5) 9 current diagnosis of aphasia, and; 6) presence 10 of metal inside the body (e.g., surgical clips, 11 pacemaker) leading to ineligibility for an MRI 12 13 Study type Interventional (Clinical Trial), Randomized 14 Parallel Assignment Masking (Participant, 15 Investigator, Outcomes Assessor) 16 For peer reviewPrimary purpose: only Treatment 17 Date of first enrolment 9 January, 2019 18 Target sample size 70 19 20 Recruitment status Recruiting 21 Primary outcome(s) Brain structural changes; cognitive changes 22 (memory: pattern separation, pattern 23 completion; near- and medium-transfer spatial 24 abilities; self-reported spatial abilities) 25 Key secondary outcome(s) Feasibility (recruitment, retention, 26 27 compliance, self-reported barriers) 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 2 4 5 6 Post-intervention semi-structured interview questions for navigation participants 7 8 9 10 Category Questions 11 First 1. Tell me about your experience with these tasks (i.e."I would 12 impressions like to get your initial thoughts on this intervention on the 13 whole, what was your general impression?”) 14 15 2. What was it like to interact with the program? 16 For peer Probe: The review website, the internet, only the computer? How did your 17 experience with the intervention change over the course of the 18 study?(e.g., was it easier to use over time?) 19 3. What was your impression of the pre- and post-intervention 20 21 assessments? I am referring to the neuropsychological 22 assessment on the phone and cognitive assessments on the 23 computer. (e.g., being on the phone for 2 hours, completing 24 tests without a paper, looking at screen for 2 hours, difficulty 25 level, enough breaks) 26 Targets for 4. What did you enjoy the most about this intervention? 27 Optimization/ 28  Probe: What about the tasks did you find the most engaging? 29 Enhancement  On convenience: What was it like to participate in a therapy 30 program online? 31 5. What did you enjoy the least? 32  Probe: How did you find using the computer? The internet? 33

The computer program? Intensity of intervention? http://bmjopen.bmj.com/ 34 35 Barriers to 6. For the most part, did you manage to complete the tasks as 36 Compliance assigned? 37  Probe: How long did you spend on the intervention each day? 38 (on average) 39  Did you find the demands of the intervention reasonable? What 40 41 could have helped you better stick to this schedule? 42  Did you encounter difficulties focusing on the tasks? Did you on October 2, 2021 by guest. Protected copyright. 43 find your mind wandering? 44 7. Did you run into anything which made it difficult to 45 participate? 46 47  Probe: Did you encounter any technological issues? 48  Probe: How did this affect your participation? Would more 49 technical support have been useful to you? In what way? 50  What, if anything, could have made you want to quit the 51 intervention? 52 8. What, if anything, would change about the intervention? 53 54 Barriers to 9. Do you think you would continue with the training going 55 Retention forward? Why or why not? 56 10. How did the monetary rewards affect your participation? 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3  Probe: Would you complete this intervention without any 4 5 monetary rewards? 6 Impact of 11. How has this program helped you? 7 Intervention  Probe: Was there anything that helped in a way you did not 8 expect? Did you find a change in how enriching/stimulating 9 your daily environment was during the program? 10 12. Have you noticed any changes in your functioning after the 11 12 intervention? (e.g., memory, learning, attention, navigation 13 abilities) 14  Probe: Any changes to cognition? Any changes to your mood? 15 Daily functioning? 16 For 13.peer Do you think review this is a suitable only intervention for individuals with 17 brain injuries? 18 19  Probe: How did your brain injury impact your participation? 20 How can we improve it for people with brain injury?(e.g., 21 amount of time on the screen, level of difficulty of 22 intervention, multitasking, pace) 23 Further 14. Overall, how satisfied were you with this intervention? 24 Suggestions 25 15. Would you recommend this to a friend in a similar situation? 26 16. (Thank participant, affirm importance of their input) Do you 27 have any other suggestions which would make this program 28 more enjoyable or a better fit for you? 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 3 4 5 6 7 List of TED Talks selected for the active control intervention 8 9 10 Title Speaker 11 12 The world needs all kinds of minds Temple Grandin 13 The best stats you've ever seen Hans Rosling 14 The enchanting music of sign language Christine Sun Kim 15 Using design to make ideas new Milton Glaser 16 Taking imaginationFor seriousl ypeer review onlyJanet Echelman 17 18 Want to be happier? Stay in the moment Matt Killingsworth 19 The art of choosing Sheena Iyengar 20 Let's turn the high seas into the world's largest nature reserve Enric Sala 21 The joy of lexicology Erin McKean 22 23 Folding way-new origami Robert Lang 24 Your words may predict your future mental health Mariano Sigman 25 The rise of human-computer cooperation Shyam Sankar 26 How stats fool juries Peter Donnelly 27 Lead like the great conductors Itay Talgam 28 29 How architecture helped music evolve David Byrne 30 How poachers became caretakers John Kasaona 31 Why good leaders make you feel safe Simon Sinek 32 The levitating superconductor Boaz Almog 33

The birth of a word Deb Roy http://bmjopen.bmj.com/ 34 35 Your body language shapes who you are Amy Cuddy 36 The beautiful math of coral Margaret Wertheim 37 Your brain is more than a bag of chemicals David Anderson 38 A universal translator for surgeons Steven Schwaitzberg 39 40 Thorium, an alternative nuclear fuel Kirk Sorensen 41 What makes us feel good about our work? Dan Ariely 42 Let's use video to reinvent education Sal Khan on October 2, 2021 by guest. Protected copyright. 43 44 Natural pest control ... using bugs! Shimon Steinberg 45 A performance of "Mathemagic" Arthur Benjamin 46 Life in the "digital now" Abha Dawesar 47 Imaging at a trillion frames per second Ramesh Raskar 48 49 Your elusive creative genius Elizabeth Gilbert 50 Retrofitting suburbia Ellen Dunham-Jones 51 52 Stanford University Commencement 2005 Steve Jobs 53 The mysterious workings of the adolescent brain Sarah-Jayne Blakemore 54 The shareable future of cities Alex Steffen 55 56 How to learn? From mistakes Diana Laufenberg 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 How I discovered DNA James Watson 4 5 Music and emotion through time Michael Tilson Thomas 6 The surprising science of happiness Nancy Etcoff 7 What we learned from 5 million books Erez Lieberman Aiden, 8 9 Jean-Baptiste Michel 10 Pool medical patents, save lives Ellen 't Hoen 11 Different ways of knowing Daniel Tammet 12 13 How I fell in love with a fish Dan Barber 14 Robots with "soul" Guy Hoffman 15 Healthier men, one moustache at a time Adam Garone 16 For peer review only 17 Everyday inventions Saul Griffith 18 What makes a good life? Lessons from the longest study on Robert Waldinger 19 happiness 20 Visualizing the wonder of a living cell David Bolinsky 21 22 A light switch for neurons Ed Boyden 23 Symmetry, reality's riddle Marcus du Sautoy 24 Are you a giver or a taker? Adam Grant 25 Actually, the world isn't flat Pankaj Ghemawat 26 27 How state budgets are breaking US schools Bill Gates 28 Dance vs. PowerPoint, a modest proposal John Bohannon, Black 29 Label Movement 30 Time-lapse proof of extreme ice loss James Balog 31 32 String theory Brian Greene 33 The weird, wonderful world of bioluminescence Edith Widder 34 A leap from the edge of space Steve Truglia http://bmjopen.bmj.com/ 35 The magic ingredient that brings Pixar movies to life Danielle Feinberg 36 Questioning the universe Stephen Hawking 37 38 The power of introverts Susan Cain 39 Stroke of insight Jill Bolte Taylor 40 A future beyond traffic gridlock Bill Ford 41

Building the Seed Cathedral Thomas Heatherwick on October 2, 2021 by guest. Protected copyright. 42 43 Every city needs healthy honey bees Noah Wilson-Rich 44 A shark-deterrent wetsuit (and it's not what you think) Hamish Jolly 45 Mosquitos, malaria and education Bill Gates 46 47 In the Internet age, dance evolves … The LXD 48 A Rosetta Stone for the Indus script Rajesh Rao 49 Why some of us don't have one true calling Emilie Wapnick 50 51 How to speak so that people want to listen Julian Treasure 52 Why you should talk to strangers Kio Stark 53 54 The beauty of data visualization David McCandless 55 On exploring the oceans Robert Ballard 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Shedding light on dark matter Patricia Burchat 4 5 The ancient ingenuity of water harvesting Anupam Mishra 6 How I teach kids to love science Cesar Harada 7 How human noise affects ocean habitats Kate Stafford 8 9 How bacteria "talk" Bonnie Bassler 10 How Benjamin Button got his face Ed Ulbrich 11 12 On spaghetti sauce Malcolm Gladwell 13 The 3 A's of awesome Neil Pasricha 14 The game layer on top of the world Seth Priebatsch 15 16 Psychedelic scienceFor peer review onlyFabian Oefner 17 A new ecosystem for electric cars Shai Agassi 18 Four principles for the open world Don Tapscott 19 20 The sound the universe makes Janna Levin 21 My dream of a flying car Paul Moller 22 23 The best kindergarten you've ever seen Takaharu Tezuka 24 When you reply to spam email James Veitch 25 26 Brain magic Keith Barry 27 Creative houses from reclaimed stuff Dan Phillips 28 Why a good book is a secret door Mac Barnett 29 30 The museum of you Jake Barton 31 The math behind basketball's wildest moves Rajiv Maheswaran 32 Why the secret to success is setting the right goals John Doerr 33 34 How to manage for collective creativity Linda Hill http://bmjopen.bmj.com/ 35 Watson, Jeopardy and me, the obsolete know-it-all Ken Jennings 36 My obsession with objects and the stories they tell Adam Savage 37 38 The business benefits of doing good Wendy Woods 39 Inside an Antarctic time machine Lee Hotz 40 41 Silk, the ancient material of the future Fiorenzo Omenetto 42 Thoughts on humanity, fame and love Shah Rukh Khan on October 2, 2021 by guest. Protected copyright. 43 How adaptive clothing empowers people with disabilities Mindy Scheier 44 45 Art that looks back at you Golan Levin 46 The unexpected benefit of celebrating failure Astro Teller 47 Why I live in mortal dread of public speaking Megan Washington 48 49 Why sneakers are a great investment Josh Luber 50 My solar-powered adventure Bertrand Piccard 51 52 The power of time off Stefan Sagmeister 53 To the South Pole and back — the hardest 105 days of my life Ben Saunders 54 Why we laugh Sophie Scott 55 56 How to design a library that makes kids want to read Michael Bierut 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Excuse me, may I rent your car? Robin Chase 4 5 The DIY orchestra of the future Ge Wang 6 The birth of virtual reality as an art form Chris Milk 7 How a driverless car sees the road Chris Urmson 8 9 Science is for everyone, kids included Beau Lotto, Amy O'Toole 10 Why we should build wooden skyscrapers Michael Green 11 12 A practical way to help the homeless find work and safety Richard J. Berry 13 4 lessons in creativity Julie Burstein 14 Unleash your creativity in a Fab Lab Neil Gershenfeld 15 16 A map of the brainFor peer review onlyAllan Jones 17 Don't fear intelligent machines. Work with them Garry Kasparov 18 Why you should love statistics Alan Smith 19 20 Adventures of an interplanetary architect Xavier De Kestelier 21 Why I fell in love with monster prime numbers Adam Spencer 22 23 The visual magic of comics Scott McCloud 24 Every piece of art you've ever wanted to see — up close and Amit Sood 25 searchable 26 How better tech could protect us from distraction Tristan Harris 27 28 Ancient wonders captured in 3D Ben Kacyra 29 A smog vacuum cleaner and other magical city designs Daan Roosegaarde 30 How to find a wonderful idea OK Go 31 32 Gorgeous portraits of the world's vanishing people Jimmy Nelson 33 Art with wire, sugar, chocolate and string Vik Muniz 34 http://bmjopen.bmj.com/ 35 A primer on 3D printing Lisa Harouni 36 Smart failure for a fast-changing world Eddie Obeng 37 The passing of time, caught in a single photo Stephen Wilkes 38 39 An honest look at the personal finance crisis Elizabeth White 40 The mad scientist of music Mark Applebaum 41 42 The voice of the natural world Bernie Krause on October 2, 2021 by guest. Protected copyright. 43 A multimedia theatrical adventure Natasha Tsakos 44 How to build with clay ... and community Diébédo Francis Kéré 45 46 3 reasons why we can win the fight against poverty Andrew Youn 47 How I became 100 artists Shea Hembrey 48 49 My journey in design John Maeda 50 How I teach kids to love science Cesar Harada 51 The thrilling potential for off-grid solar energy Amar Inamdar 52 53 4 larger-than-life lessons from soap operas Kate Adams 54 How many lives can you live? Sarah Kay 55 Rhythm is everything, everywhere Sivamani 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Optical illusions show how we see Beau Lotto 4 5 7 principles for building better cities Peter Calthorpe 6 The debut of the British Paraorchestra Charles Hazlewood, British 7 Paraorchestra 8 The shared experience of absurdity Charlie Todd 9 10 Discover the physical side of the internet Andrew Blum 11 A plea for bees Dennis van Engelsdorp 12 13 The astounding athletic power of quadcopters Raffaello D'Andrea 14 How we can turn the cold of outer space into a renewable resource Aaswath Raman 15 The painter and the pendulum Tom Shannon, John 16 For peer review onlyHockenberry 17 18 A forgotten Space Age technology could change how we grow Lisa Dyson 19 food 20 Asking for help is a strength, not a weakness Michele L. Sullivan 21 Ingenious homes in unexpected places Iwan Baan 22 Robots that fly ... and cooperate Vijay Kumar 23 24 Success stories from Kenya's first makerspace Kamau Gachigi 25 See invisible motion, hear silent sounds Michael Rubinstein 26 Two nerdy obsessions meet — and it's magic David Kwong 27 Turning dunes into architecture Magnus Larsson 28 29 Demo: A needle-free vaccine patch that's safer and way cheaper Mark Kendall 30 Using biology to rethink the energy challenge Juan Enriquez 31 Hack a banana, make a keyboard! Jay Silver 32 33 Fashion has a pollution problem — can biology fix it? Natsai Audrey Chieza 34 The art of puzzles Scott Kim http://bmjopen.bmj.com/ 35 36 How we found the worst place to park in New York City — using Ben Wellington 37 big data 38 The hidden influence of social networks Nicholas Christakis 39 Memes and "temes" Susan Blackmore 40 41 An ode to envy Parul Sehgal 42 Can clouds buy us more time to solve climate change? Kate Marvel on October 2, 2021 by guest. Protected copyright. 43 How college loans exploit students for profit Sajay Samuel 44 45 Electrical experiments with plants that count and communicate Greg Gage 46 Let my dataset change your mindset Hans Rosling 47 48 It's time to question bio-engineering Paul Root Wolpe 49 My green school dream John Hardy 50 How to turn a group of strangers into a team Amy Edmondson 51 52 How to build your creative confidence David Kelley 53 10 ways to have a better conversation Celeste Headlee 54 How to escape education's death valley Ken Robinson 55 56 A reality check on renewables David MacKay 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 How I use sonar to navigate the world Daniel Kish 4 5 The warmth and wisdom of mud buildings Anna Heringer 6 Pirates, nurses and other rebel designers Alice Rawsthorn 7 Synthetic voices, as unique as fingerprints Rupal Patel 8 9 How we wrecked the ocean Jeremy Jackson 10 The intriguing sound of marine mammals Peter Tyack 11 12 Dragonflies that fly across oceans Charles Anderson 13 The first secret of design is ... Noticing Tony Fadell 14 Embrace the near win Sarah Lewis 15 How to make filthy water drinkable Michael Pritchard 16 For peer review only 17 Victims of the city Mark Raymond 18 My subversive (garden) plot Roger Doiron 19 20 Learning from leadership's missing manual Fields Wicker-Miurin 21 Math class needs a makeover Dan Meyer 22 Older people are happier Laura Carstensen 23 24 A thought experiment on the intelligence of crows Joshua Klein 25 How trees talk to each other Suzanne Simard 26 Organic design, inspired by nature Ross Lovegrove 27 28 The art of creating awe Rob Legato 29 Between music and medicine Robert Gupta 30 31 Meet the dazzling flying machines of the future Raffaello D'Andrea 32 How to air-condition outdoor spaces Wolfgang Kessling 33 34 How not to be ignorant about the world Hans and Ola Rosling http://bmjopen.bmj.com/ 35 The wonderful and terrifying implications of computers that can Jeremy Howard 36 learn 37 Optical illusions show how we see Beau Lotto 38 39 Intricate beauty by design Marian Bantjes 40 Be an opportunity maker Kare Anderson 41

The world is one big dataset. Now, how to photograph it … Dan Berkenstock on October 2, 2021 by guest. Protected copyright. 42 43 Wiring an interactive ocean John Delaney 44 How public spaces make cities work Amanda Burden 45 46 Why great architecture should tell a story Ole Scheeren 47 Open science now! Michael Nielsen 48 The beautiful math behind the world's ugliest music Scott Rickard 49 50 Embrace the remix Kirby Ferguson 51 Listening to global voices Ethan Zuckerman 52 The mysterious lives of giant trees Richard Preston 53 54 How loss helped one artist find beauty in imperfection Alyssa Monks 55 New York - before the City Eric Sanderson 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 For argument's sake Daniel H. Cohen 4 5 Cooking as alchemy Homaro Cantu, Ben Roche 6 The secret structure of great talks Nancy Duarte 7 The future of lying Jeff Hancock 8 9 The anthropology of mobile phones Jan Chipchase 10 Let's save the last pristine continent Robert Swan 11 12 Why architects need to use their ears Julian Treasure 13 Why we will rely on robots Rodney Brooks 14 Discovering ancient climates in oceans and ice Rob Dunbar 15 16 Paper beats plastic?For How to peerrethink environmental review folklore onlyLeyla Acaroglu 17 Why bees are disappearing Marla Spivak 18 The science of scent Luca Turin 19 20 Play with smart materials Catarina Mota 21 Let's bridge the digital divide! Aleph Molinari 22 23 The science of cells that never get old Elizabeth Blackburn 24 A free digital library Brewster Kahle 25 Nature is everywhere — we just need to learn to see it Emma Marris 26 27 How Arduino is open-sourcing imagination Massimo Banzi 28 Why design should include everyone Sinéad Burke 29 The discoveries awaiting us in the ocean's twilight zone Heidi M. Sosik 30 31 A new ecosystem for electric cars Shai Agassi 32 The new power of collaboration Howard Rheingold 33 34 The magnificence of spider silk Cheryl Hayashi http://bmjopen.bmj.com/ 35 What a bike ride can teach you Shimon Schocken 36 Global population growth, box by box Hans Rosling 37 38 How the "ghost map" helped end a killer disease Steven Johnson 39 The birth of Wikipedia Jimmy Wales 40 Plug into your hard-wired happiness Srikumar Rao 41 42 The search for "aha!" moments Matt Goldman on October 2, 2021 by guest. Protected copyright. 43 A robot that runs and swims like a salamander Auke Ijspeert 44 45 Crop insurance, an idea worth seeding Rose Goslinga 46 Why jobs of the future won't feel like work David Lee 47 The surprising science of happiness Dan Gilbert 48 49 The case for optimism Larry Brilliant 50 Technology crafts for the digitally underserved Vinay Venkatraman 51 The secret to great opportunities? The person you haven't met yet Tanya Menon 52 53 A new weapon in the fight against superbugs David Brenner 54 Let's clean up the space junk orbiting Earth Natalie Panek 55 56 The science of sync Steven Strogatz 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Tagging tuna in the deep ocean Barbara Block 4 5 Lifesaving scientific tools made of paper Manu Prakash 6 Scientists must be free to learn, to speak and to challenge Kirsty Duncan 7 8 A printable, flexible, organic solar cell Hannah Bürckstümmer 9 The linguistic genius of babies Patricia Kuhl 10 The next 5,000 days of the web Kevin Kelly 11 12 The sticky wonder of gecko feet Robert Full 13 Glow-in-the-dark sharks and other stunning sea creatures David Gruber 14 15 Demo: A needle-free vaccine patch that's safer and way cheaper Mark Kendall 16 Reviving New York'sFor rivers peer— with oysters! review onlyKate Orff 17 Biohacking — you can do it, too Ellen Jorgensen 18 19 Robots inspired by cockroach ingenuity Robert Full 20 The riddle of experience vs. memory Daniel Kahneman 21 22 My $500 house in Detroit — and the neighbors who helped me Drew Philp 23 rebuild it 24 Great piano performances, recreated John Q. Walker 25 Special Olympics let me be myself — a champion Matthew Williams 26 27 Revealing the lost codex of Archimedes William Noel 28 Let the environment guide our development Johan Rockstrom 29 30 Connected, but alone? Sherry Turkle 31 How adaptive clothing empowers people with disabilities Mindy Scheier 32 What happens when an NGO admits failure David Damberger 33 34 3 new ways to kill mosquitoes Bart Knols http://bmjopen.bmj.com/ 35 How to build an information time machine Frederic Kaplan 36 My wish: Protect our oceans Sylvia Earle 37 38 What are animals thinking and feeling? Carl Safina 39 6 ways to save the internet Roger McNamee 40 41 Make data more human Jer Thorp 42 Teachers need real feedback Bill Gates on October 2, 2021 by guest. Protected copyright. 43 Using nature to grow batteries Angela Belcher 44 45 A powerful idea about ideas Alan Kay 46 The thinking behind 50x15 Hector Ruiz 47 Sculpted space, within and without Antony Gormley 48 49 An art made of trust, vulnerability and connection Marina Abramović 50 What makes something go viral? Dao Nguyen 51 52 Why the best hire might not have the perfect resume Regina Hartley 53 A solar energy system that tracks the sun Bill Gross 54 What do babies Think? Alison Gopnik 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Extreme swimming with the world's most dangerous jellyfish Diana Nyad 4 5 A forgotten ancient grain that could help Africa prosper Pierre Thiam 6 How artists can (finally) get paid in the digital age Jack Conte 7 To eliminate waste, we need to rediscover thrift Andrew Dent 8 9 The way we think about charity is dead wrong Dan Pallotta 10 Kids can teach themselves Sugata Mitra 11 12 How we're using drones to deliver blood and save lives Keller Rinaudo 13 A choreographer's creative process in real time Wayne McGregor 14 Buildings that blend nature and city Jeanne Gang 15 16 Learning from the Forgecko's tail peer review onlyRobert Full 17 What we're learning from online education Daphne Koller 18 Robots will invade our lives Rodney Brooks 19 20 Everyday moments, caught in time Billy Collins 21 Software (as) art Golan Levin 22 23 How to gain control of your free time Laura Vanderkam 24 The coolest animal you know nothing about ... and how we can Patrícia Medici 25 save it 26 Hooked by an octopus Mike deGruy 27 28 My wish: Build the Encyclopedia of Life E.O. Wilson 29 This is your brain on communication Uri Hasson 30 Fly with the Jetman Yves Rossy 31 32 What a driverless world could look like Wanis Kabbaj 33 This virtual lab will revolutionize science class Michael Bodekaer 34 http://bmjopen.bmj.com/ 35 The era of open innovation Charles Leadbeater 36 Animate characters by evolving them Torsten Reil 37 A virtual choir 2,000 voices strong Eric Whitacre 38 39 How record collectors find lost music and preserve our cultural Alexis Charpentier 40 heritage 41 Don't misrepresent Africa Leslie Dodson on October 2, 2021 by guest. Protected copyright. 42 How an old loop of railroads is changing the face of a city Ryan Gravel 43 44 Organic algorithms in architecture Greg Lynn 45 Flow, the secret to happiness Mihaly Csikszentmihalyi 46 How to engineer a viral music video Adam Sadowsky 47 48 Why wildfires have gotten worse — and what we can do about it Paul Hessburg 49 Inside the secret shipping industry Rose George 50 51 How to get better at the things you care about Eduardo Briceño 52 Hedonistic sustainability Bjarke Ingels 53 To create for the ages, let's combine art and engineering Bran Ferren 54 55 For survivors of Ebola, the crisis isn't over Soka Moses 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 The Museum of Four in the Morning Rives 4 5 3 Thoughtful ways to conserve water Laan Mazahreh 6 The secrets I find on the mysterious ocean floor Laura Robinson 7 8 The paradox of choice Barry Schwartz 9 The surprisingly logical minds of babies Laura Schulz 10 This company pays kids to do their math homework Mohamad Jebara 11 12 Can a robot pass a university entrance exam? Noriko Arai 13 Life's third act Jane Fonda 14 Hey science teachers — make it fun Tyler DeWitt 15 16 How societies can Forgrow old peerbetter review onlyJared Diamond 17 The illusion of consciousness Dan Dennett 18 19 A pro wrestler's guide to confidence Mike Kinney 20 Living sculptures that stand for history's truths Sethembile Msezane 21 Turning powerful stats into art Chris Jordan 22 23 Obesity + hunger = 1 global food issue Ellen Gustafson 24 The art of the eco-mindshift Natalie Jeremijenko 25 Simplicity sells David Pogue 26 27 What I learned when I conquered the world's toughest triathlon Minda Dentler 28 How we can design timeless cities for our collective future Vishaan Chakrabarti 29 30 The cheap all-terrain wheelchair Amos Winter 31 Save the oceans, feed the world! Jackie Savitz 32 How web video powers global innovation Chris Anderson 33 34 The puzzle of motivation Dan Pink http://bmjopen.bmj.com/ 35 Why you should love gross science Anna Rothschild 36 A magical search for a coincidence Helder Guimarães 37 38 An underwater art museum, teeming with life Jason deCaires Taylor 39 Look up for a change Lucianne Walkowicz 40 Why the buildings of the future will be shaped by ... You Marc Kushner 41 42 The art of the interview Marc Pachter on October 2, 2021 by guest. Protected copyright. 43 The new open-source economics Yochai Benkler 44 45 The beauty of being a misfit Lidia Yuknavitch 46 A demo of wireless electricity Eric Giler 47 Dive into an ocean photographer's world Thomas Peschak 48 49 The mind behind Linux Linus Torvalds 50 Agile programming — for your family Bruce Feiler 51 How do you build a sacred space? Siamak Hariri 52 53 How we became sisters Felice Belle, Jennifer 54 Murphy 55 This app knows how you feel — from the look on your face Rana el Kaliouby 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 A delightful way to teach kids about computers Linda Liukas 4 5 Breakthrough designs for ultra-low-cost products R.A. Mashelkar 6 The genesis of Google Sergey Brin, Larry Page 7 Technology that knows what you're feeling Poppy Crum 8 9 The violin, and my dark night of the soul Ji-Hae Park 10 What's your 200-year plan? Raghava KK 11 12 We can recycle plastic Mike Biddle 13 Uber's plan to get more people into fewer cars Travis Kalanick 14 Let's raise kids to be entrepreneurs Cameron Herold 15 16 The art of asking For peer review onlyAmanda Palmer 17 Why light needs darkness Rogier van der Heide 18 How to buy happiness Michael Norton 19 20 How mobile phones power disaster relief Paul Conneally 21 4 ways to make a city more walkable Jeff Speck 22 23 A 30-year history of the future Nicholas Negroponte 24 Why we all need to practice emotional first aid Guy Winch 25 A critical look at geoengineering against climate change David Keith 26 27 Can a computer write poetry? Oscar Schwartz 28 A glimpse of the future through an augmented reality headset Meron Gribetz 29 The nerd's guide to learning everything online John Green 30 31 Cradle to cradle design William McDonough 32 The other inconvenient truth Jonathan Foley 33 34 Why not eat insects? Marcel Dicke http://bmjopen.bmj.com/ 35 How I built a toaster — from scratch Thomas Thwaites 36 6 space technologies we can use to improve life on Earth Danielle Wood 37 38 A call to reinvent liberal arts education Liz Coleman 39 The mystery box J.J. Abrams 40 Averting the climate crisis Al Gore 41 42 A new way to stop identity theft David Birch on October 2, 2021 by guest. Protected copyright. 43 What intelligent machines can learn from a school of fish Radhika Nagpal 44 45 Art made of the air we breathe Emily Parsons-Lord 46 Stunning photos of the endangered Everglades Mac Stone 47 Gaming can make a better world Jane McGonigal 48 49 Plant fuels that could power a jet Bilal Bomani 50 How games make kids smarter Gabe Zichermann 51 Two reasons companies fail — and how to avoid them Knut Haanaes 52 53 Let's teach for mastery — not test scores Sal Khan 54 A flight on solar wings Paul MacCready 55 56 The power of vulnerability Brené Brown 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 On glamour Virginia Postrel 4 5 What our language habits reveal Steven Pinker 6 What I learned from spending 31 days underwater Fabien Cousteau 7 The future race car — 150mph, and no driver Chris Gerdes 8 9 How to tame your wandering mind Amishi Jha 10 Walk the earth ... my 17-year vow of silence John Francis 11 12 Fighting viruses, defending the net Mikko Hypponen 13 What’s wrong with your pa$$w0rd? Lorrie Faith Cranor 14 Reinventing the encyclopedia game Rives 15 16 What if 3D printingFor was 100x peer faster? review onlyJoseph DeSimone 17 Playtime with Pleo, your robotic dinosaur friend Caleb Chung 18 Science-inspired design Mathieu Lehanneur 19 20 Dog-friendly dog training Ian Dunbar 21 Your brain on improv Charles Limb 22 23 Anti-gravity sculpture Tom Shannon 24 How painting can transform communities Haas&Hahn 25 To invent is to give Dean Kamen 26 27 Visualizing ourselves ... with crowd-sourced data Aaron Koblin 28 The ocean's glory — and horror Brian Skerry 29 The hunt for a supermassive black hole Andrea Ghez 30 31 How your pictures can help reclaim lost history Chance Coughenour 32 New ways to see music (with color! and fire!) Jared Ficklin 33 34 Why I'm rowing across the Pacific Roz Savage http://bmjopen.bmj.com/ 35 The Blur Building and other tech-empowered architecture Liz Diller 36 Lessons from fashion's free culture Johanna Blakley 37 38 How to pitch to a VC David S. Rose 39 7 rules for making more happiness Stefan Sagmeister 40 My mind-shifting Everest swim Lewis Pugh 41 42 The world's most boring television ... and why it's hilariously Thomas Hellum on October 2, 2021 by guest. Protected copyright. 43 addictive 44 17 words of architectural inspiration Daniel Libeskind 45 46 What it takes to do extreme astrophysics Anil Ananthaswamy 47 The next web Tim Berners-Lee 48 Photos of Africa, taken from a flying lawn chair George Steinmetz 49 50 The world's oldest living things Rachel Sussman 51 Behind the design of Seattle's library Joshua Prince-Ramus 52 Inventing instruments that unlock new music Tod Machover, Dan Ellsey 53 54 Big data is better data Kenneth Cukier 55 The hunt for General Tso Jennifer Lee 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Emergency shelters made from paper Shigeru Ban 4 Design with the blind in mind Chris Downey 5 6 The mind behind Tesla, SpaceX, SolarCity … Elon Musk 7 A futuristic vision of the age of holograms Alex Kipman 8 Put a value on nature! Pavan Sukhdev 9 How food shapes our cities Carolyn Steel 10 How I made an impossible film Martin Villeneuve 11 12 Living beyond limits Amy Purdy 13 Great cars are great art Chris Bangle 14 What I learned from going blind in space Chris Hadfield 15 Why we need to go back to Mars Joel Levine 16 7 ways games rewardFor the brain peer review onlyTom Chatfield 17 18 Design with the blind in mind Chris Downey 19 The wonderful world of life in a drop of water Simone Bianco, Tom 20 Zimmerman 21 An illustrated journey through Rome David Macaulay 22 23 The transformative power of classical music Benjamin Zander 24 How to speak up for yourself Adam Galinsky 25 26 A census of the ocean Paul Snelgrove 27 3 creative ways to fix fashion's waste problem Amit Kalra 28 The fastest ambulance? A motorcycle Eli Beer 29 30 How architecture can connect us Thom Mayne 31 Sleep is your superpower Matt Walker 32 Are athletes really getting faster, better, stronger? David Epstein 33 34 Swim with the giant sunfish Tierney Thys http://bmjopen.bmj.com/ 35 An ultra-low-cost college degree Shai Reshef 36 37 Unseen footage, untamed nature Karen Bass 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 4 4 5 6 7 Roles and responsibilities for study protocol members 8 9 10 11 Teams Roles 12 Principal investigators  Protocol design and revisions 13  AG  Preparing annual reports for funding sponsors 14  REG  Recruitment strategy aid and initiation of 15 recruitment contacts 16 For peer review only 17 Trial management  Participant randomisation and enrolment 18  AG  Participant recruitment and screening 19  REG  Budgeting and financial administration 20  KJ  Participant payments 21 22  ZB  Participant support for completion of online 23  JR assessments and intervention 24  EJ  Assistance with ethics committee applications and 25  MB amendments 26  Central recruiter  Assistance with study reports 27 28 Data management and analyses  Data compiling and storage 29  ZB  Data organization 30  JR  Data entry 31  EJ  Data verification 32 33  ND  Consultation with biostatisticians at Toronto 34  JO Rehabilitation and Rotman Research Institutes http://bmjopen.bmj.com/ 35  Other student assistants 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 57 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Model Consent Form 4 5 6 7 8 9

10 11 12 13 14 CONSENT FORM TO PARTICIPATE IN A RESEARCH STUDY 15 16 For peer review only 17 18 Study Title: Remotely delivered Environmental Enrichment interventions for acquired brain 19 injury 20 21 22 Principal Investigators/Study Doctors: Dr. Robin Green & Dr. Asaf Gilboa 23 24 25 26 Contact Information: 27 28 Dr. Robin Green 29 Research Scientist, Toronto Rehabilitation Institute 30 550 University Avenue, Room 11-207 31 Toronto, ON, M5G 2A2 32 Phone: 416-597-3422, extension 7606 33 34 http://bmjopen.bmj.com/ 35 Dr. Asaf Gilboa 36 37 Research Scientist, Rotman Research Institute at Baycrest 38 39 Centre for Stroke Recovery 40 3560 Bathurst St. 41 42 Toronto, ON, M6A 2E1 on October 2, 2021 by guest. Protected copyright. 43 Phone: 416-785-2500, extension 2908 44 45 46 47 Funding Source: The study is financed by a grant from the Ontario Neurotrauma Foundation 48

49 50 Introduction: 51 52 You are being asked to take part in a research study. Please read the information about the 53 study presented in this form. The form includes details on the study’s risks and benefits that you 54 should know before you decide if you would like to take part. You should take as much time as 55 56 you need to make your decision. You should ask the study doctor or study staff to explain 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 58 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 anything that you do not understand and make sure that all of your questions have been 4 answered before signing this consent form. Before you make your decision, feel free to talk 5 6 about this study with anyone you wish including your friends, family, and family doctor. 7 Participation in this study is voluntary. 8 9 10 Background/Purpose: 11 12 You have been asked to participate in this study because you have sustained a traumatic brain 13 injury (TBI). Past research has shown that “environmental enrichment” - engaging in effortful 14 cognitive activities on a regular basis - can have beneficial effects on recovery from brain injury. 15 16 For example, it can Forimprove cognitivepeer difficulties review and maximize only brain health after brain injury. 17 The purpose of this research project is to investigate the feasibility (i.e., the ability for us to re- 18 run the same study with a larger number of people) and effectiveness of two “environmental 19 enrichment” therapies delivered to participants online in their homes for a period of 16 weeks. 20 Up to 134 individuals may participate in this study over the course of 2 years. Through your 21 22 participation you will receive additional therapy which may be helpful to your rehabilitation. 23 24 25 Study Visits and Procedures: 26 27 If you agree to participate in the study, you will participate in a pre-therapy assessment while 28 you are an in-patient. This will take about an extra day of your time, however it will not affect 29 your length of stay at Toronto Rehab.) You will participate in a second pre-therapy 30 assessment, in-person and by phone, when you are approximately 7 months post- brain injury. 31 32 We will contact you 2 – 3 months prior to your assessment window to schedule an appointment, 33 and we will contact you 1 month prior to confirm your appointment). This assessment has two 34 components: http://bmjopen.bmj.com/ 35 36 37 38  A Cognitive Assessment: You will be asked to complete some computerized tasks 39 and some pencil and paper tasks to measure cognitive functioning. Some of the 40 computerized tasks you will do will train you on the intervention tasks that you will be 41 doing at home during the intervention phase of the study. You will also be asked to 42 complete some questionnaires about your cognitive function, mood, and level of on October 2, 2021 by guest. Protected copyright. 43 physical activity. This assessment will last for approximately 3 - 6 hours and will be 44 completed over two (2) days, consecutively. The assessment will take place at the 45 Toronto Neuroimaging Facility at the University of Toronto (325 Huron St.) on the 46 first day, and by phone on the second day. 47 48 49  A Magnetic Resonance Imaging (MRI) scan of your brain: The MRI scanner takes 50 signals emitted by the brain and turns them into pictures of the brain using magnetic 51 field. The MRI scanning will be carried out at the Toronto Neuroimaging Facility at 52 the University of Toronto (325 Huron St.). This will involve lying down on a table. 53 54 Foam pads will be placed around your head to limit head movement during the 55 study. The table will then be slid into the magnet. While in the scanner, you will be 56 asked to lie still for approximately 1.5 hours, during which time several scans will 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 59 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 take place. For obtaining some of the images, you don’t have to do any specific task, 4 other than relaxing while keeping your head and body still. Before the scan, you will 5 be asked some questions to ensure you do not have any magnetically sensitive 6 metal materials in your body. (This does not include dental fillings.) You cannot 7 participate in the rest of the study if you cannot participate in the MRI scan. 8 9 10 11 Once you have completed the above assessment you will move onto the therapy phase of the 12 study. The therapies we are investigating in this study are “environmental enrichment” exercise 13 programs to maximize brain health. The therapy phase involves: 14 15 16  CompletingFor 1 hour peer of “environmental review enrichment” onlyexercises daily for 5 days per week 17 (e.g., Monday - Friday). You will be given online access to intervention materials at 18 home each day over the course of 16 weeks. 19 20  There are two forms of environmental enrichment therapy: 21 22 o Allocentric spatial navigation therapy (or ‘bird’s eye view’ navigation therapy) 23 involving finding various landmarks while navigating different cities around the 24 world using Google Street View. 25 26 o Educational video viewing in which you will view several short educational 27 videos each day and will learn about a wide range of topics. 28 29  Study Design: this is a “randomized control trial” which means that we will compare 30 the two treatments to each other by assigning participants randomly (i.e., by chance) 31 to either the allocentric spatial navigation intervention or the educational video 32 intervention. Once you have agreed to enter the trial, a computer will perform the 33

equivalent of tossing a coin to allocate you to one of the two treatments. http://bmjopen.bmj.com/ 34 35  Once you are assigned to one of the two treatments, you will be provided with login 36 37 information to access the intervention activities on a secure Toronto Rehab –UHN 38 study website. 39 40  We will provide you with a laptop and a high-speed internet connection for the duration 41 of the therapy program (i.e., 16 weeks) if you do not have or do not wish to use your 42 own equipment. on October 2, 2021 by guest. Protected copyright. 43 44  We ask that you adhere as closely as possible to the recommended schedule for the 45 entire 16 weeks. You will be receiving reminders and be provided training support as 46 necessary 47 48  Your participation in the exercises online and your performance over time will be 49 monitored by a therapy assistant at Toronto Rehab. The therapy assistant will access 50 your activity information via the website. 51 52  You will be asked to answer some questions on a daily basis and on a weekly basis. 53 On a daily basis, you will be asked to answer 3 online questions about how you are 54 finding the activities (1-2 minutes to complete); at the end of each week of training, 55 you will also be asked to answer 3-6 online questions about the intervention (2-3 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 60 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 minutes to complete); once a month you will be asked to complete a questionnaire 4 about cognitive, physical and emotional symptoms that you may experience in 5 response to completing the cognitive intervention. 6 7 8 9  At the end of the program, some participants will also be invited to participate in a 10 15-30 minute, telephone administered, semi-structured interview with our team so 11 that we can better understand your experiences with the environmental enrichment 12 intervention. Up to 30 participants will be randomly selected from all participants in 13 the study to be invited to participate in the interview. We will also ask you for 14 permission to contact your caregiver or significant other to invite him/her to 15 participate in a similar 15-30 minute, telephone administered, semi-structured 16 interviewFor with our peerteam to further review understand your only experiences with the 17 environmental enrichment intervention. 18 19 20 ☐ I agree to being invited to participate in the telephone interview. 21 22 23 24 ☐ I agree to having my caregiver/significant other invited to participate in the 25 26 telephone interview. 27

28 29 30 31 At the end of the 16 week therapy phase you will be asked to return to the University of Toronto 32 for a post-therapy assessment. This assessment is identical to the pre-therapy assessment 33

described above. http://bmjopen.bmj.com/ 34 35 36 37 Risks: 38 Taking part in this study has risks. Some of these risks we know about. 39 40 41 42 The cognitive assessments that occur pre-and post- therapy phase involve no more risk to you on October 2, 2021 by guest. Protected copyright. 43 than there are in your routine cognitive assessments. You may get tired during the assessment 44 and if this occurs, please tell the researcher and a break will be provided or if necessary the 45 46 task will be discontinued. 47 48 49 The study therapies involve a time commitment of 5 hours per week which could cause you to 50 be more tired than usual. If fatigue prevents you from completing the specified amount of 51 therapy, you can discuss this with your study therapists and a modified schedule can be 52 53 arranged. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 61 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 The risks involved in this MRI study are minimal, and are limited to the risks present during 4 routine MRI examinations. The MRI scan is painless but noisy. There is no radiation associated 5 6 with the scan. When near an MRI scanner, there is a potential for the powerful magnetic field 7 to attract metallic objects toward the magnet. For this reason, you will be carefully screened for 8 previous exposure to metallic fragments or clips that may be inside your body. Similarly, you will 9 be asked to place all metallic and magnetic objects in your possession (e.g. keys, jewelry, credit 10 cards) in a locker outside the magnet room. 11 12 13 14 Some people may feel a little ‘closed-in’ the MRI machine, but you will be able to speak with 15 someone at all times and can stop the test at any time. 16 For peer review only 17 18 19 To reduce potential back or neck pain due to lying still in the scanner, cushions and pads 20 designed to better disperse your weight for the scan duration will be used under your knees and 21 neck and around your body. 22 23 24 Benefits: 25 26 You may not receive any direct benefit from being in this study. However, information learned 27 from this study may help with the development of a novel post-injury cognitive intervention. 28 29 30 31 Reminders and Responsibilities: 32 Tell your study team if you change your mind about being in the study. 33  34  Ask your study team about anything related to the study that worries you. http://bmjopen.bmj.com/ 35 36  Tell study staff of any health changes that you experience during the course of the study. 37 38 39 Confidentiality: 40 41 Personal Health Information 42 on October 2, 2021 by guest. Protected copyright. If you agree to join this study, the Principal Investigators and their study team will collect only 43 44 the information they need for the study which may include personal health information: 45  Name 46 47  address 48 49  email 50  telephone number 51 52  partial date of birth (month and year) 53  name of a family member/significant other (who could fill out a questionnaire for this 54 55 study) 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 62 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3  New or existing medical records, that includes types, dates and results of medical tests 4 or procedures 5 6 7 Representatives of either the University of Toronto or the University Health Network (UHN) 8 9 including the University of Toronto or UHN Research Ethics Board may look at the study 10 records and at your personal health information to check that the information collected for the 11 study is correct and to make sure the study is following proper laws and guidelines. 12 13 14 The study doctor will keep any personal health information about you in a secure and 15 confidential location for 10 years. A list linking your study number with your name 16 For peer review only 17 will be kept by the study doctor in a secure place, separate from your study file. 18 19 20 Study Information that Does Not Identify You: 21 22 Any information about you that is sent out of the hospital will have a code and will not show your 23 name or address, or any information that directly identifies you. 24 25 26 27 All information collected during this study, including your personal health information, will be 28 kept confidential and will not be shared with anyone outside the study unless required by law. 29 You will not be named in any reports, publications, or presentations that may come from this 30 31 32 33 What happens with the results of the study? http://bmjopen.bmj.com/ 34 Primarily, the results will be used to inform the ideas and design of future studies, these 35 additional future studies may build on the findings of this study to advance healthcare or 36 37 treatment options of relevance. It is very likely that a report will be published about this research 38 study and the results will be published in scientific journals or presented at scientific 39 conferences, but you will not be able to be identified. Your identity will always be kept 40 confidential. In addition, anonymous images may be provided to third parties (such as the 41 42 manufacturer of the scanner for use in connection with its product development and marketing on October 2, 2021 by guest. Protected copyright. 43 activities). All identifying information about you is removed from the images so that they are 44 anonymized before they are sent to this third party. The third party may keep the images for up 45 to 5 years. 46 47 48 49 Voluntary Participation: 50 Your participation in this study is voluntary. You may decide not to be in this study, or to be in 51 52 the study now and then change your mind later. You may leave the study at any time. You will 53 not be required to give reasons for your decision to leave the study. 54

55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 63 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 We will give you new information that is learned during the study that might affect your decision 4 to stay in the study. 5 6 7 8 Withdrawal from the Study: 9 10 The researchers can take you off the study if: 11  You are unable to comply with the instructions for participation given to you 12 13  You no longer meet the criteria for participation 14

15 16 If you wish to leave Forthe study, peer please let study review staff know. If youonly leave the study, the information 17 that was collected before you left the study will still be used in order to help answer the research 18 19 question. No new information will be collected without your permission. However, you have the 20 right to request withdrawal of information collected about you. Let the Principal Investigator 21 know. 22 23 24 Costs and Reimbursement: 25 26 You will receive $75 for your participation in each of the 2 in-person and phone assessments 27 (pre- and post- therapy) to cover travel expenses incurred to attend the in-person session. 28 29 30 31 The therapy phase of the study will last 16 weeks (i.e., 4 months). At the end of each month of 32 therapy, you will receive $75 in the form of a gift card (which can be sent to you electronically). 33

You will have an additional opportunity to receive a bonus $5 electronic gift card to a coffee http://bmjopen.bmj.com/ 34 shop for every 2 weeks of completed training, to be sent biweekly or monthly. 35 36 37 38 Rights as a Participant: 39 40 If you are harmed as a direct result of taking part in this study, all necessary medical treatment 41 will be made available to you at no cost. 42 on October 2, 2021 by guest. Protected copyright. 43 44 By signing this form you do not give up any of your legal rights against the investigators, or 45 involved institutions for compensation, nor does this form relieve the investigators, sponsor or 46 involved institutions of their legal and professional responsibilities. 47 48 49 Incidental Findings: 50 51 The magnetic resonance imaging (MRI) scan you will receive during the course of this study is 52 for research purposes only. It is not a clinical scan intended for diagnostic or therapeutic 53 54 purposes. The Brain Imaging Facility is a research center. It is NOT a clinical MRI facility in a 55 hospital. There are no neuroradiologists at the Brain Imaging Facility, therefore the staff are 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 unable to make any medical comments about your scan. Should you want to know if your scan 4 is normal or abnormal, the staff will not be able to tell you. 5 6 7 8 There is a chance, however, that, in the course of this research scanning protocol, we observe 9 an anomaly (e.g. tumor or cyst) in one or more of the MRI images. If this happens, your images 10 will be sent to a trained neuroradiologist for further investigation and you may be informed of the 11 results. An anomaly does not necessarily indicate the presence of any disorder. Because our 12 13 MRI scans are for research purposes only, they may be inadequate for the purpose of clinical 14 diagnosis. Additionally, as researchers, we are not trained to clinically interpret MRI data. 15 However, we feel it is important to inform you of any observations, as we cannot rule out the 16 possibility that this anomalyFor maypeer require medical review advice. If you only prefer not to be informed of 17 18 anomalous findings, you must check the box below. 19 ☐ I prefer NOT to be informed of any anomalous findings. 20 21 22 23 Conflict of Interest: 24 25 The researchers report no potential conflicts of interest. They have an interest in completing this 26 study. Their interest should not affect your consideration for participating. 27

28 29 Future Studies: 30 31 I authorize the MRI facility to contact me about future research within the MRI research facility in 32 the Department of Psychology. If I agree, a researcher may contact me and tell me about the 33

research. At that time, I can decide whether or not I am interested in participating in a particular http://bmjopen.bmj.com/ 34 35 study. 36 ☐ I agree to be contacted about research studies conducted at the MRI facility. 37 38 ☐ I authorize the MRI facility to use my data in future research within the MRI research facility 39 in the Department of Psychology. 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 Questions about the Study: 44 45 If you have any questions, concerns or would like to speak to the study team for any reason, 46 please call: Dr. Robin Green (416) 597-3422 ext. 7871 47 48 If you have any questions about your rights as a research participant or have concerns about 49 this study, call the Chair of the University Health Network Research Ethics Board (UHN REB) or 50 the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee 51 the ethical conduct of research studies. The UHN REB is not part of the study team. Everything 52 that you discuss will be kept confidential. 53 54 55 56 You will be given a signed copy of this consent form. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 65 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 Consent: 6 7 8 This study has been explained to me and any questions I had have been answered. 9 10 I know that I may leave the study at any time. I agree to the use of my information as described 11 in this form. I agree to take part in this study. 12 13 14 15 16 Print Study Participant’sFor Name peer review Signature only Date 17

18 19 20 21 Or for substitute decision maker: 22 23 24 This study has been explained to me and any questions I had have been answered. 25 26 I know that ______may leave the study at any time. I agree to the use of 27 28 his or her information as described in this form. I agree to have ______take 29 part in this study. 30 31 32 33 34 ______http://bmjopen.bmj.com/ 35 36 Print Name of Substitute decision maker Signature Date 37 38 39 40 41 ______42 on October 2, 2021 by guest. Protected copyright. 43 Relationship to participant 44 45 46 47 Person who obtained consent: 48 49 My signature means that I have explained the study to the participant named above and/or his 50 or her substitute decision maker named above. I have answered all questions. 51 52 53 54 55 Print Name of Person Signature Date 56 Obtaining Consent 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 66 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 Was the participant assisted during the consent process? YES NO 7 8 If YES, please check the relevant box and complete the signature space below: 9 10 11 The person signing below acted as an interpreter, and attests that the study as set out in the 12 consent form was accurately sight translated and/or interpreted, and that interpretation was 13 provided on questions, responses and additional discussion arising from this process. 14 15 16 For peer review only 17 18 Print Name of Interpreter Signature Date 19 20 21 22 23 Relationship to Participant Language 24 25 26 The consent form was read to the participant. The person signing below attests that the 27 study as set out in this form was accurately explained to, and has had any questions answered. 28 29 30 31 32 Print Name of Witness Signature Date 33

http://bmjopen.bmj.com/ 34 35 36 Relationship to Participant 37 38 39 40 41

on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 67 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 Reporting checklist for protocol of a clinical trial. 5 6 7 Based on the SPIRIT guidelines. 8 9 10 11 Instructions to authors 12 13 14 Complete this checklist by entering the page numbers from your manuscript where readers will find 15 16 each of the items listed below.For peer review only 17 18 19 Your article may not currently address all the items on the checklist. Please modify your text to 20 21 include the missing information. If you are certain that an item does not apply, please write "n/a" and 22 23 24 provide a short explanation. 25 26 27 Upload your completed checklist as an extra file when you submit to a journal. 28 29 30 In your methods section, say that you used the SPIRITreporting guidelines, and cite them as: 31 32 33 Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann 34 http://bmjopen.bmj.com/ 35 H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill W, Groves T, Schulz K, Sox H, Rockhold 36 37 38 FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard protocol items for clinical trials. 39 40 Ann Intern Med. 2013;158(3):200-207 41 42 on October 2, 2021 by guest. Protected copyright. 43 Reporting Item Page Number 44 45 46 Administrative 47 48 information 49 50 51 Title #1 Descriptive title identifying the study 1 52 53 54 design, population, interventions, and, if 55 56 applicable, trial acronym 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Trial registration #2a Trial identifier and registry name. If not 3 3 4 yet registered, name of intended registry 5 6 7 Trial registration: #2b All items from the World Health Online supplemental material 8 9 data set Organization Trial Registration Data Set (Table 1) 10 11 12 Protocol version #3 Date and version identifier 3 13 14 15 Funding #4 Sources and types of financial, material, 24 16 For peer review only 17 18 and other support 19 20 21 Roles and #5a Names, affiliations, and roles of protocol 1, 25, Online supplemental 22 23 responsibilities: contributors material (Table 4) 24 25 contributorship 26 27 28 Roles and #5b Name and contact information for the trial Online supplemental material 29 30 31 responsibilities: sponsor (Table 1) 32 33 sponsor contact 34 http://bmjopen.bmj.com/ 35 information 36 37 38 Roles and #5c Role of study sponsor and funders, if 24 39 40 41 responsibilities: any, in study design; collection, 42 on October 2, 2021 by guest. Protected copyright. 43 sponsor and management, analysis, and interpretation 44 45 funder of data; writing of the report; and the 46 47 decision to submit the report for 48 49 50 publication, including whether they will 51 52 have ultimate authority over any of these 53 54 activities 55 56 57 Roles and #5d Composition, roles, and responsibilities Online supplemental material 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 69 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 responsibilities: of the coordinating centre, steering (Table 4) 2 3 committees committee, endpoint adjudication 4 5 committee, data management team, and 6 7 8 other individuals or groups overseeing 9 10 the trial, if applicable (see Item 21a for 11 12 data monitoring committee) 13 14 15 Introduction 16 For peer review only 17 18 Background and #6a Description of research question and 5-8 19 20 rationale justification for undertaking the trial, 21 22 23 including summary of relevant studies 24 25 (published and unpublished) examining 26 27 benefits and harms for each intervention 28 29 30 Background and #6b Explanation for choice of comparators 8, 15 31 32 33 rationale: choice of 34 http://bmjopen.bmj.com/ 35 comparators 36 37 38 Objectives #7 Specific objectives or hypotheses 7-8 39 40 41 Trial design #8 Description of trial design including type 10 42 on October 2, 2021 by guest. Protected copyright. 43 of trial (eg, parallel group, crossover, 44 45 46 factorial, single group), allocation ratio, 47 48 and framework (eg, superiority, 49 50 equivalence, non-inferiority, exploratory) 51 52 53 Methods: 54 55 56 Participants, 57 58 interventions, and 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 70 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 outcomes 2 3 4 Study setting #9 Description of study settings (eg, 8, 11 5 6 community clinic, academic hospital) and 7 8 list of countries where data will be 9 10 11 collected. Reference to where list of 12 13 study sites can be obtained 14 15 16 Eligibility criteria #10ForInclusion peer and exclusion review criteria for only 8-9 17 18 participants. If applicable, eligibility 19 20 criteria for study centres and individuals 21 22 23 who will perform the interventions (eg, 24 25 surgeons, psychotherapists) 26 27 28 Interventions: #11a Interventions for each group with 12-16 29 30 description sufficient detail to allow replication, 31 32 33 including how and when they will be 34 http://bmjopen.bmj.com/ 35 administered 36 37 38 Interventions: #11b Criteria for discontinuing or modifying 22; minimal risk 39 40 modifications allocated interventions for a given trial 41 42 on October 2, 2021 by guest. Protected copyright. 43 participant (eg, drug dose change in 44 45 response to harms, participant request, 46 47 or improving / worsening disease) 48 49 50 Interventions: #11c Strategies to improve adherence to 14-15 51 52 adherence intervention protocols, and any 53 54 55 procedures for monitoring adherence 56 57 (eg, drug tablet return; laboratory tests) 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 71 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Interventions: #11d Relevant concomitant care and 9 3 4 concomitant care interventions that are permitted or 5 6 prohibited during the trial 7 8 9 Outcomes #12 Primary, secondary, and other outcomes, 16-20 10 11 including the specific measurement 12 13 14 variable (eg, systolic blood pressure), 15 16 Foranalysis peer metric (eg, review change from only 17 18 baseline, final value, time to event), 19 20 method of aggregation (eg, median, 21 22 23 proportion), and time point for each 24 25 outcome. Explanation of the clinical 26 27 relevance of chosen efficacy and harm 28 29 30 outcomes is strongly recommended 31 32 33 Participant timeline #13 Time schedule of enrolment, 11-12 34 http://bmjopen.bmj.com/ 35 interventions (including any run-ins and 36 37 washouts), assessments, and visits for 38 39 participants. A schematic diagram is 40 41 42 highly recommended (see Figure) on October 2, 2021 by guest. Protected copyright. 43 44 45 Sample size #14 Estimated number of participants needed 8 46 47 to achieve study objectives and how it 48 49 was determined, including clinical and 50 51 52 statistical assumptions supporting any 53 54 sample size calculations 55 56 57 Recruitment #15 Strategies for achieving adequate 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 72 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 participant enrolment to reach target 2 3 sample size 4 5 6 Methods: 7 8 Assignment of 9 10 11 interventions (for 12 13 controlled trials) 14 15 16 Allocation: #16aForMethod peer of generating review the allocation only 10-11 17 18 sequence sequence (eg, computer-generated 19 20 generation random numbers), and list of any factors 21 22 23 for stratification. To reduce predictability 24 25 of a random sequence, details of any 26 27 planned restriction (eg, blocking) should 28 29 30 be provided in a separate document that 31 32 is unavailable to those who enrol 33 34 participants or assign interventions http://bmjopen.bmj.com/ 35 36 37 Allocation #16b Mechanism of implementing the 10-11 38 39 concealment allocation sequence (eg, central 40 41 42 mechanism telephone; sequentially numbered, on October 2, 2021 by guest. Protected copyright. 43 44 opaque, sealed envelopes), describing 45 46 any steps to conceal the sequence until 47 48 49 interventions are assigned 50 51 52 Allocation: #16c Who will generate the allocation 10-11 53 54 implementation sequence, who will enrol participants, 55 56 and who will assign participants to 57 58 interventions 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 73 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Blinding (masking) #17a Who will be blinded after assignment to 11 3 4 interventions (eg, trial participants, care 5 6 providers, outcome assessors, data 7 8 analysts), and how 9 10 11 Blinding #17b If blinded, circumstances under which n/a; enough team members 12 13 14 (masking): unblinding is permissible, and procedure are unblinded to be able to 15 16 emergency Forfor revealing peer a participant’s review allocated only intervene if necessary 17 18 unblinding intervention during the trial 19 20 21 Methods: Data 22 23 24 collection, 25 26 management, and 27 28 analysis 29 30 31 Data collection #18a Plans for assessment and collection of 17 32 33

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Remotely delivered environmental enrichment intervention for traumatic brain injury: Study protocol for a randomised controlled trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-039767.R2

Article Type: Protocol

Date Submitted by the 24-Oct-2020 Author:

Complete List of Authors: Belchev, Zorry; University of Toronto, Psychology; Rotman Research Institute, Boulos, Mary Ellene; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Rybkina, Julia; University of Toronto, Graduate Department of Rehabilitation Science; Toronto Rehabilitation Institute, KITE Johns, Kadeen; Toronto Rehabilitation Institute, KITE Jeffay, Eliyas; Rotman Research Institute, ; Toronto Rehabilitation Institute, KITE Colella, Brenda; Toronto Rehabilitation Institute, KITE Ozubko, Jason; State University of New York College at Geneseo, Psychology Bray, Michael; University of Toronto, Graduate Department of

Rehabilitation Science; Toronto Rehabilitation Institute, KITE http://bmjopen.bmj.com/ Di Genova, Nicholas; Toronto Rehabilitation Institute, KITE; McMaster University, Computing and Software Levi, Adina; Rotman Research Institute, ; York University, Psychology Changoor, Alana; Toronto Rehabilitation Institute, KITE; McMaster University Faculty of Health Sciences, Global Health Program Worthington, Thomas; Toronto Rehabilitation Institute, KITE; York University, Psychology Gilboa, Asaf; University of Toronto, Psychology; Rotman Research

Institute, on October 2, 2021 by guest. Protected copyright. Green, Robin; Toronto Rehabilitation Institute, KITE; University of Toronto, Psychiatry

Primary Subject Rehabilitation medicine Heading:

Secondary Subject Heading: Evidence based practice

REHABILITATION MEDICINE, Neurological injury < NEUROLOGY, Keywords: THERAPEUTICS

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Running head: REMOTE ENRICHMENT PROTOCOL FOR TBI 1 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 Title: Remotely delivered environmental enrichment intervention for traumatic brain injury: 7 Study protocol for a randomised controlled trial 8 9 Authors: 1,2Belchev, Zorry, 3,4Boulos, Mary E., 3,4Rybkina, Julia, 4Johns, Kadeen, 1,2,4Jeffay, 10 Eliyas, 4Colella, Brenda, 5Ozubko, Jason, 3,4Bray, Michael J. C., 4,6Di Genova, Nicholas, 2,7Levi, 11 Adina, 4,8Changoor, Alana, 4,7Worthington, Thomas, 1,2,4Gilboa, Asaf*, 4,9Green, Robin E.* 12 *Co-senior authors 13 14 15 1Department of Psychology, University of Toronto, Toronto, ON, Canada 16 2Rotman Research InstituteFor at peer Baycrest, Toronto, review ON, Canada only 17 3Graduate Department of Rehabilitation Science, University of Toronto, Toronto, ON, Canada 18 4Toronto Rehabilitation Institute (KITE), Toronto, ON, Canada 19 5Department of Psychology, The State University of New York, Geneseo, NY, USA 20 6 21 Department of Computing and Software, McMaster University, Hamilton, ON, Canada 7 22 Department of Psychology, York University, Toronto, ON, Canada 23 8Global Health Program, Faculty of Health Sciences, McMaster University, Hamilton, ON, 24 Canada 25 9Department of Psychiatry, University of Toronto, ON, Canada 26 27 28 29 Corresponding Author Information: 30 Zorry Belchev 31 (t) 416-785-2500 x3354. (e) [email protected] 32 Rotman Research Institute at Baycrest 33 3460 Bathurst St., North York, Ontario, Canada M6A 2E1 34 http://bmjopen.bmj.com/ 35 Word Count (between Article Summary and Acknowledgments): 5731 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 2 3 ABSTRACT 4 5 6 Introduction: Individuals with moderate-severe traumatic brain injury (m-sTBI) experience 7 8 progressive brain and behavioural declines in the chronic stages of injury. Longitudinal studies 9 10 found that a majority of m-sTBI patients exhibit significant hippocampal atrophy from 5-12 11 12 months post-injury, associated with decreased cognitive environmental enrichment (EE). 13 14 15 Encouragingly, engaging in EE has been shown to lead to neural improvements, suggesting it is 16 For peer review only 17 a promising avenue for offsetting hippocampal neurodegeneration in m-sTBI. Allocentric spatial 18 19 navigation (i.e., flexible, bird’s eye view approach), is a good candidate for EE in m-sTBI 20 21 22 because it is associated with hippocampal activation and reduced aging-related volume loss. 23 24 Efficacy of EE requires intensive daily training, prohibitive within most current health delivery 25 26 systems. The present protocol is a novel, remotely delivered and self-administered intervention 27 28 29 designed to harness principles from EE and allocentric spatial navigation to offset hippocampal 30 31 atrophy and potentially improve hippocampal functions such as navigation and memory for m- 32 33 sTBI patients. 34 http://bmjopen.bmj.com/ 35 Methods and Analysis: Eighty-four chronic m-sTBI participants are being recruited from an 36 37 38 urban rehabilitation hospital and randomised into a 16-week intervention (five hours/week; total: 39 40 80 hrs.) of either targeted spatial navigation or an active control group. The spatial navigation 41 on October 2, 2021 by guest. Protected copyright. 42 group engages in structured exploration of different cities using Google Street View that includes 43 44 45 daily navigation challenges. The active control group watches and answers subjective questions 46 47 about educational videos. Following a brief orientation, participants remotely self-administer the 48 49 intervention on their home computer. In addition to feasibility and compliance measures, clinical 50 51 52 and experimental cognitive measures as well as MRI scan data are collected pre- and post- 53 54 intervention to determine behavioural and neural efficacy. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 3 Ethics and Dissemination: Ethics approval has been obtained from ethics boards at the 4 5 6 University Health Network and University of Toronto. Findings will be presented at academic 7 8 conferences and submitted to peer-reviewed journals. 9 10 Trial registration: Version 2 (25 August 2020), ClinicalTrials.gov: NCT04331392 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 4 3 ARTICLE SUMMARY 4 5 6 Strengths and limitations of this study 7 8 ● A remote, self-administered intervention will allow patients greater access to clinically 9 10 relevant resources regardless of physical and economical restrictions, and increase 11 12 current telerehabilitation offerings. 13 14 15 ● The inclusion of neuroimaging outcomes allow for the examination of structural 16 For peer review only 17 changes that may occur alongside potential cognitive improvements associated with 18 19 targeted behavioural training, increasing our understanding of the mechanisms of these 20 21 22 potential changes in humans. 23 24 ● The inclusion of an active control group is critical in determining whether targeted 25 26 rather than generalised training is effective in improving hippocampal-dependent 27 28 29 abilities, but introduces a conservative bias in observing these effects more than if it 30 31 only included a waitlisted control group. 32 33 ● Although the present protocol builds on the principles of successful environmental 34 http://bmjopen.bmj.com/ 35 enrichment observed in rodents in terms of targeted training and high dose, a potential 36 37 38 component that may mediate the benefit is the addition of vigorous physical exercise, 39 40 which will be a consideration for future studies. 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 5 3 INTRODUCTION 4 5 6 Traumatic brain injury (TBI) is a significant global public health problem, with an 7 8 estimated worldwide incidence rate of 874-1005 cases per 100,000[1]. Contrary to typical 9 10 models of the recovery trajectory, recent longitudinal studies show that degeneration continues at 11 12 least up to 2 years post-injury[2–4]. These recent lines of evidence have signaled a shift from 13 14 15 viewing TBI as a single event, to treating it as a chronic neurodegenerative disorder[5,6], 16 For peer review only 17 necessitating a need for appropriate long-term treatments for patients past their acute phase of 18 19 recovery. 20 21 22 Neurodegeneration and cognitive impairment in chronic TBI 23 24 There is evidence that moderate-severe TBI (m-sTBI) results in chronic volumetric 25 26 decline in both white matter (WM) and gray matter (GM) through the first and up to at least the 27 28 29 second year post-injury. Structures affected include the fornix[7] corpus callosum[3] (CC), and 30 31 temporal, frontal, and occipital regions[2]. Notably, the hippocampus (HPC) tends to be 32 33 particularly vulnerable to chronic degeneration, where Green and colleagues[3] found over 70% 34 http://bmjopen.bmj.com/ 35 of patients showed significant declines (over 2 standard deviations away from controls) in the 36 37 38 HPC. In another study, specific degeneration was found in the HPC, in addition to sub-cortical 39 40 regions that included the thalamus, putamen, amygdala, and caudate[2]. The heightened 41 on October 2, 2021 by guest. Protected copyright. 42 vulnerability of the HPC has been attributed to its sensitivity to excitotoxicity[8], and Wallerian 43 44 45 degeneration through damage distal to the site of the injury[9–11]. 46 47 In addition to neural declines, patients with TBI also exhibit chronic cognitive deficits, 48 49 including in spatial abilities[12] and memory[13,14]. These types of cognitive deficits have been 50 51 52 linked to the underlying degeneration in the HPC, including memory[15]. Furthermore, these 53 54 cognitive deficits may generalise to daily functioning, as lower acute volumes in areas known to 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 6 3 be associated with cognitive deficits in TBI (i.e., HPC, thalamus), predict poorer functional 4 5 6 outcome measured in the chronic stage[16]. 7 8 Impact of external factors on recovery 9 10 Tertiary factors can also negatively contribute to the continued degeneration in the 11 12 chronic stages of TBI in addition to or by compounding the persistent underlying 13 14 15 neuropathology[17,18]. As outlined by the negative neuroplasticity framework[19,20], three 16 For peer review only 17 factors can have a negative impact on neural recovery from a TBI, including: 1) reduced 18 19 schedules of activity following rehabilitation regimen in the acute periods; 2) noisy processing 20 21 22 from sensory deficits, and; 3) weakened neuromodulatory control due to neurotransmitter 23 24 dysfunction. These factors can contribute to negative learning through preference for low-level, 25 26 low-effort cognitive tasks, leading to negative neuroplasticity. Thus, the chronic period that 27 28 29 follows in-patient rehabilitative treatments is critical for ensuring continued cognitive and neural 30 31 stimulation, with therapeutic support during this period that can be scalable and does not 32 33 necessitate extensive therapist involvement. 34 http://bmjopen.bmj.com/ 35 Harnessing environmental enrichment to improve post-injury outcomes 36 37 38 The HPC is commonly impacted by TBI[2–4,16], yet also holds an innate affinity for 39 40 neurogenesis and neuroplasticity[21–23], highlighting it as a good candidate for targeted 41 on October 2, 2021 by guest. Protected copyright. 42 interventions. Evidence from animal studies show that environmental enrichment (EE) through 43 44 45 extensive maze training can support positive neuroplasticity in the HPC[24]. Support for this 46 47 intervention approach has also been shown in humans, particularly when focusing on allocentric 48 49 spatial navigation, involving flexible navigation from a bird’s eye view perspective[25,26]. For 50 51 52 example, an intensive 90 hours of training on a video game associated with allocentric 53 54 navigation resulted in increased HPC volume in those who generally use the opposite strategy 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 7 3 (i.e., egocentric[27]). Another study showed that intensive virtual navigation training in healthy 4 5 6 older adults resulted in successfully offsetting expected age-related volume declines in the 7 8 HPC[28] and increased hippocampal neural density which was moderated by genotype[29]. 9 10 Informed by the efficacy of such interventions, here we designed a novel intervention 11 12 focused on three factors: 1) targeting the HPC through training on allocentric navigation; 2) 13 14 15 high-intensity and high-dose schedules, and; 3) scalability and convenience through remote 16 For peer review only 17 training online. Google Street View (GSV) was chosen as the navigation platform because it is 18 19 easily accessible from patients’ homes and does not require specialised software, allowing 20 21 22 intensive training of allocentric navigation with only a browser and internet. Based on current 23 24 experimental evidence, we created a website with set virtual environments (cities) consisting of 25 26 routes learning and associated navigation tasks such as vector mapping, distance judgments, 27 28 29 reverse and blocked routes and landmark mapping known to significantly engage hippocampal 30 31 function. The dose of the structured navigation training is 80 hours based on previous findings 32 33 that produced significant benefits[28,29]. Different levels of difficulty are available to adjust to 34 http://bmjopen.bmj.com/ 35 patients’ ability and maintain an appropriate challenge level. To ensure compliance, intrinsic and 36 37 38 extrinsic rewards are embedded into the intervention, and remote progress tracking allows for 39 40 immediate assistance. 41 on October 2, 2021 by guest. Protected copyright. 42 Study objectives and hypotheses 43 44 45 The present protocol is a component of a multi-arm study with three types of patient 46 47 populations (m-sTBI, multiple sclerosis, TBI patients living in remote areas). The present study 48 49 specifically examines the efficacy and feasibility of a novel, remotely-delivered and self- 50 51 52 administered intervention designed to offset HPC atrophy following m-sTBI. The primary 53 54 objective includes two sub-goals examining the intervention’s ability to: 1) behaviourally 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 8 3 improve spatial abilities and memory, and; 2) reduce chronic HPC neurodegeneration. By 4 5 6 comparing the navigation intervention to an active control intervention that provides generalised 7 8 EE, we predict that the navigation intervention will lead to more HPC-specific neural and 9 10 behavioural improvements. The secondary objective takes an exploratory approach to assess the 11 12 feasibility of this intervention in this population. For a broad overview of the trial registration 13 14 15 data set, please refer to Supplementary Table 1. 16 For peer review only 17 METHODS 18 19 Participants 20 21 22 M-sTBI patients from Toronto Rehabilitation Institute’s Acquired Brain Injury Inpatient 23 24 Unit, Outpatient clinics, and Day Hospital program who are under seven months post-injury are 25 26 in the process of being recruited, with a projected recruited sample size of N = 84. This sample 27 28 29 size accounts for an estimated attrition rate of just under 20%, with an expected resultant sample 30 31 size of N = 70 (35 per group). When factoring in attrition, this target sample size will achieve 32 33 0.80 power to detect medium-large effects based on a power analysis for a linear regression with 34 http://bmjopen.bmj.com/ 35 eight predictors (using G*Power[30]). Power will be further maximised by employing dimension 36 37 38 reduction methods (i.e., principal component analysis) prior to conducting the linear regression 39 40 analyses, with the projected number of resultant predictors not exceeding eight. 41 on October 2, 2021 by guest. Protected copyright. 42 Inclusion criteria include: 1) acute care diagnosis of m-sTBI; 2) PTA of 24 hours or more 43 44 45 and/or lowest GCS <13; 3) positive CT or MRI; 4) between 18 to 55 years of age; 5) fluency in 46 47 English; 6) competency to provide informed consent or availability of a legal substitute decision 48 49 maker; 7) basic computer skills (use of internet/email, mouse and arrow keys); 8) functional use 50 51 52 of at least one upper extremity for computer use, and; 9) resident of Greater Toronto Area (to 53 54 facilitate access to the MRI). The age cut-off excluded patients over 55 to prevent potential age- 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 9 3 related confounds in brain volume and cognitive changes, as research has shown that decline 4 5 6 begins to accelerate in the fifth to sixth decade of life[31]. Exclusion criteria include: 1) 7 8 neurological disorder other than TBI (e.g., dementia, stroke); 2) diagnosis of a 9 10 neurodevelopmental disorder; 3) TBI sustained before age 18; 4) systemic comorbidities (e.g., 11 12 lupus, diabetes); 5) current diagnosis of aphasia, and; 6) presence of metal inside the body (e.g., 13 14 15 surgical clips, pacemaker) leading to ineligibility for an MRI. It is noted that although exclusion 16 For peer review only 17 on the basis of a diagnosis of aphasia is necessary for establishing proof of principle, future 18 19 development should emphasise the incorporation of aphasia-friendly materials in order to benefit 20 21 22 as many patients as possible. 23 24 Inclusion criteria pertaining to the participant’s medical history are assessed using a chart 25 26 review. During recruitment, patients are informed that they do not need to discontinue ongoing 27 28 29 rehabilitative activities to participate in the study. Basic computer skills are evaluated at the pre- 30 31 intervention assessment. Participants are compensated for their participation by receiving 32 33 $75CAD following the completion of each of the pre- and post-intervention assessments, and 34 http://bmjopen.bmj.com/ 35 $75CAD in electronic gift cards (i.e., Amazon) for each month of intervention completion. To 36 37 38 maximise retention and compliance to intervention dose, participants also have the opportunity 39 40 to receive an additional $40CAD in coffee cards ($2.50 for each completed week). A 41 on October 2, 2021 by guest. Protected copyright. 42 consideration regarding compensation is that though it is a necessary component of research 43 44 45 studies, its inclusion may impact the assessment of the feasibility of implementing the 46 47 intervention clinically, in terms of both uptake and compliance. This is partially addressed by a 48 49 debriefing question posed to participants in a post-intervention semi-structured interview, which 50 51 52 asks whether they would have completed the intervention without compensation (for more 53 54 detailed information, refer to the outcome measures and Supplementary Table 2). Based on the 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 10 3 hourly rate (4.25CAD), it is unlikely to provide significant financial incentive. Furthermore, once 4 5 6 the efficacy of the intervention is validated, this would provide an innate incentive for patients to 7 8 complete it as part of their clinical rehabilitation and recovery. 9 10 Patient and Public Involvement 11 12 Patients were not involved in the initial design and development of the research questions 13 14 15 and outcome measures. Once the intervention was developed, pilot patients were recruited to 16 For peer review only 17 complete three to five weeks of the designed intervention to gauge the feasibility of the format 18 19 and intensity of remote training; the patients were able to complete the training as designed and 20 21 22 showed improvements on the targeted training tasks. Patients in the present study will be asked 23 24 to assess the burden of the intervention through the weekly administration of the How Much Is 25 26 Too Much Scale[32]. As part of a post-intervention semi-structured interview they will also be 27 28 29 asked to identify any facilitators and barriers they encountered to completing the intervention, as 30 31 well as the average amount of time they required to participate in the intervention. The public 32 33 was not involved in the design of the study, but a number of public organizations will be engaged 34 http://bmjopen.bmj.com/ 35 for recruitment aid (e.g., March of Dimes, Community Brain Injury Services). Study contacts at 36 37 38 each organization will be provided with a recruitment flyer for circulation among their case 39 40 managers, and in communication with their members (i.e., monthly newsletters). 41 on October 2, 2021 by guest. Protected copyright. 42 Study Design 43 44 45 The present study is a randomised, controlled, patient and (partially) observer blinded, 46 47 parallel group, two arm, superiority trial with a 1:1 allocation. Participants are randomly assigned 48 49 to either the experimental targeted navigation intervention or to active control training 50 51 52 (educational videos), and are blinded to their assigned experimental vs. active control condition. 53 54 Randomisation is conducted using the rand() function in Microsoft Excel by the study 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 11 3 coordinator prior to study commencement. A central recruiter from the institutional recruitment 4 5 6 office who is not part of the study team is employed, who engages in initial contact and primary 7 8 screening. The study coordinator then conducts secondary screening and formal enrollment by 9 10 assigning participants their study identity numbers, which are not directly linked to group 11 12 allocation. The study team member conducting the in-person assessments, as well as the MRI 13 14 15 technologist, are blinded to group assignments. The experimenter conducting the remote 16 For peer review only 17 assessments and training is not blind to group assignments, as they need to train the participant 18 19 on the task, but potential bias is minimised by the absence of nonverbal cues over the phone, and 20 21 22 close adherence to standardised scripts. Participants complete their assigned intervention online, 23 24 using their computer at home. In the event that a participant does not have access to a computer 25 26 or internet connection, they are lent to them at no cost for the duration of the study. 27 28 29 Cognitive assessments are conducted at pre-intervention (Week 0) and post-intervention 30 31 (Week 17) by the study team and are each split over two days (for a CONSORT study flow 32 33 diagram, see Figure 1). Participants are scheduled to complete pre-intervention assessment at 34 http://bmjopen.bmj.com/ 35 approximately seven months post-injury, in order to target a critical recovery period when 36 37 38 chronic degeneration is known to occur[2–4]. Participants who are recruited at the acute stage 39 40 post-injury are put on a waitlist until they reach seven months post-injury. Pre-intervention 41 on October 2, 2021 by guest. Protected copyright. 42 assessment occurs one week prior to beginning the intervention, in-person at the University of 43 44 45 Toronto Neuroimaging Facility, and over the phone. At the end of the pre-intervention 46 47 assessments, participants receive an orientation to their assigned intervention by completing a 48 49 sample level on the respective intervention’s website, guided by the experimenter over the 50 51 52 phone. Participants assigned to the navigation intervention are provided with instructions on how 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 12 3 to develop their allocentric navigation strategy, conducive to flexible navigation and linked to 4 5 6 HPC activation[33,34]. 7 8 Reminder emails are sent out immediately following the orientation, and on Day 1 of the 9 10 intervention in order to support participants when they are beginning the intervention. For the 11 12 remainder of the 16-week intervention, participants receive reminder emails if they miss three 13 14 15 days of training, and a phone call if they miss an entire week of training, in order to follow-up 16 For peer review only 17 and work through any potential barriers to participation. If required, daily text-message or email 18 19 reminders are implemented. A month before the end of the intervention period, the post- 20 21 22 intervention assessments are scheduled to ensure that it is conducted a maximum of one to two 23 24 weeks following intervention completion. (For an overview of the specific roles and 25 26 responsibilities involved in conducting the study, refer to Supplementary Table 3.) 27 28 29 Targeted navigation intervention 30 31 The targeted navigation intervention involves virtual navigation training with a focus on 32 33 allocentric navigation, which is highly associated with the HPC[35,36]). The dose and intensity 34 http://bmjopen.bmj.com/ 35 match the design of a previous study with successful outcomes[28,29], with a modified format: 36 37 38 approximately one hour a day, five days a week, for 16 weeks on the designated website hosted 39 40 within the University Health Network’s (UHN) secure servers. Each week, participants learn a 41 on October 2, 2021 by guest. Protected copyright. 42 section of a new city through basic to more challenging navigation tasks, with the goal of being 43 44 45 able to independently navigate the assigned section by the end of the week. During task 46 47 development, cities were selected based on availability of GSV, presence of English street 48 49 names, sufficient size (i.e., a city centre at least 1 square kilometre), and availability of notable 50 51 52 landmarks. Participants are asked to complete tasks in new cities with increasingly challenging 53 54 layouts each week. Prior to starting the intervention, participants are administered a survey of 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 13 3 cities visited to ensure all cities are novel to participants. If a participant has visited a test city, a 4 5 6 replacement city is assigned. The challenge level of the tasks within each week vary based on the 7 8 selected level, ranging from Level 1 to 4, which differ in number of streets, turns, and landmarks 9 10 (see below) . All participants are initially placed in Level 1, and levels for subsequent weeks are 11 12 based on performance of at least 80% on all of the main task measures during the previous week. 13 14 15 If participants are performing less than 60% on any of the main task measures in subsequent 16 For peer review only 17 weeks, they will be placed in a lower level the following week. If participants are performing 18 19 between 60-79% on any of the main task measures, they will remain in the same level they were 20 21 22 assigned the previous week. 23 24 Inspired by the format of the study maps used in another study[37], each week of training 25 26 begins with studying a map stripped of all labelling except for pre-selected landmarks and street 27 28 29 names. Based on the challenge level, an initial three landmarks and 8-10 street names were 30 31 selected for Level 1 to 3, and an initial five landmarks and 11-13 street names were selected for 32 33 Level 4. Throughout the week, participants learn additional landmarks and street names, where 34 http://bmjopen.bmj.com/ 35 by the end of the week they will have learned five landmarks and 11-13 street names for Level 1 36 37 38 and 2, seven landmarks and 14-16 street names for Level 3, and nine landmarks and 17-20 street 39 40 names selected for Level 4. 41 on October 2, 2021 by guest. Protected copyright. 42 Learning is scaffolded using two types of activities that increase in difficulty throughout 43 44 45 the week. The first activity is navigation, which requires participants to navigate routes of 46 47 increasing difficulty, including: 1) passive routes, where participants are shown videos of route 48 49 navigation in GSV between each of the new landmarks; 2) active routes, which require them to 50 51 52 independently navigate the same routes shown in the videos; 3) reverse routes, which require 53 54 them to navigate to and from landmarks in the opposite direction from what was learned in the 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 14 3 videos; 4) alternate/new routes, which involves finding routes to learned landmarks or 4 5 6 intersections that had not been previously paired, and; 5) blocked routes, where participants are 7 8 instructed to find detours to landmarks or intersections when certain streets are identified as 9 10 inaccessible. When navigating each route, participants are provided a dual-map view earlier in 11 12 the week, with a map inset on one half of the screen, and GSV on the other half. Later in the 13 14 15 week, participants are required to navigate solely using GSV. Dual-maps and GSV are embedded 16 For peer review only 17 in a new page within the website using scripts incorporating Google Maps javascript API, which 18 19 collects participant path data. 20 21 22 The second activity used to scaffold and to test learning involves a set of end-of-day 23 24 multiple-choice challenges based on information learned during the day and throughout the 25 26 week. Participants are asked three types of spatial mapping questions previously used to test both 27 28 29 egocentric and allocentric spatial knowledge[38–41], including: 1) landmark sequencing (e.g., 30 31 You’re walking along X St. from Y St. to Z St. Which landmark do you most closely pass?); 2) 32 33 distance judgment (e.g., Which is closer to X?), and; 3) vector mapping (e.g., Facing X St. from 34 http://bmjopen.bmj.com/ 35 Y, which degree represents the direction of Z?). Participants also complete a map placement 36 37 38 task, which involves presenting two reproductions of the study map stripped of all information; 39 40 letters and numbers representing landmarks and streets, respectively, need to be matched to a list 41 on October 2, 2021 by guest. Protected copyright. 42 of learned landmark and street names. 43 44 45 To increase compliance and engagement, in addition to earning potential coffee cards, 46 47 auditory and written rewards are provided throughout training. Auditory rewards are presented in 48 49 the form of short audio clips about each new landmark, with information about the landmark that 50 51 52 is part of a greater fictional narrative created for each city. Written rewards are in the form of 53 54 eight different encouraging pop-up messages appearing randomly throughout the week (e.g., 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 15 3 “Good work, keep it up!”). Placement of written and coffee card rewards are based on four 4 5 6 randomised schedules, with a maximum of four combined rewards, at approximately 25%, 50%, 7 8 75%, and 100% of the way into the day. The four schedules were additionally randomised to 9 10 each be the set reward schedules of four different weeks. 11 12 Active control training 13 14 15 Participants randomly assigned to an active control counterpart to the experimental 16 For peer review only 17 intervention complete a 16-week educational video intervention at the same intensity as the 18 19 navigation training, also on a designated website hosted on the secure UHN server. Training 20 21 22 involves watching videos on educational topics (i.e., TED Talks), to control for placebo effects 23 24 and for the effects of generalised environmental enrichment of the same dose as the targeted 25 26 navigation training. For each day of training, participants are asked to select one of two possible 27 28 29 videos, watching a total of three videos. Videos were selected by two raters, basing their 30 31 decisions on the educational and engagement level. The videos were further screened for coarse 32 33 language, sexual content, and highly political, religious or polarising topics. Any videos 34 http://bmjopen.bmj.com/ 35 involving topics revolving around health, which could be regarded as providing medical advice, 36 37 38 were also excluded (refer to Supplementary Table 4 for the final list of videos). Compliance is 39 40 indexed by the amount of time patients spend on each of the videos. As an indirect measure, this 41 on October 2, 2021 by guest. Protected copyright. 42 is acknowledged as a potential limitation, but allows some insight into degree of compliance. To 43 44 45 encourage maximal attention to the videos, at the end of each video, participants rate five aspects 46 47 of the content (relevance, interest, comprehensibility, complexity, informative), and speaker 48 49 (persuasiveness, quality of delivery, facial expression, convincingness, captivation), on a scale of 50 51 52 1 (lowest) to 5 (highest). This rating task was chosen because it does not have a strong memory 53 54 component associated with it and thus ensures that the task is not targeting memory functioning. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 16 3 As an innate characteristic of self-administered therapy, and generalised questions, attention is 4 5 6 not able to be measured directly, and is acknowledged as a potential limitation. Additionally, as 7 8 with navigation participants, they are given written rewards of encouragement with the same 9 10 randomised placement as described above. 11 12 Outcome measures 13 14 15 Table 1 summarises the timeline of the collection of each of the measures throughout the 16 For peer review only 17 duration of the study, with detailed descriptions below. 18 19 Table 1 20 21 22 Summary of the timeline of collection of the outcome measures 23 24 Phase Timeline Outcome category Outcome measures 25 Pre-intervention Week 0 Day 1 Primary (imaging) MRI 26 Primary (experimental) Day 1 Medium-transfer tasksa 27 b 28 Primary (clinical) Clinical measures c 29 Control Demographics, mood 30 Week 0 Day 2 Primary (experimental) Day 2 Medium-transfer tasksd 31 Far-transfer taskse 32 Control Physical activityf 33 g

Intervention Weeks 1-16, Days 1-5 Primary (experimental) Near-transfer tasks http://bmjopen.bmj.com/ 34 h 35 Secondary (feasibility) Compliance to intervention 36 Weeks 1-16, Day 5 only Secondary (feasibility) How Much is Too Much Scale 37 Post-intervention Week 17 Day 1 Primary (imaging) MRI 38 Primary (experimental) Day 1 Medium-transfer tasksa 39 Primary (clinical) Clinical measuresb 40 Control Physical activityf 41

d on October 2, 2021 by guest. Protected copyright. 42 Week 17 Day 2 Primary (experimental) Day 2 Medium-transfer tasks e 43 Far-transfer tasks 44 Secondary (feasibility) Semi-structured interview 45 Week 17 Days 1-5 Primary (experimental) Near-transfer tasksg 46 aTasks include Different Approach Task, Path Integration Task. bDigit Span, Visual Spatial Span, SART, 47 48 Symbol Digit Modalities Test, flanker inhibitory control and attention test, dimensional change card sort 49 test, pattern comparison processing speed test, picture sequence memory test, RAVLT, RVDLT, GOSE. 50 cAge, sex, injury severity, hours of therapy, BAI, BDI. dCMFT, SBSOD, NSQ. eMIC, MST, EMQ. fIPAQ. 51 g 52 Training-related outcome measures, and comparison of performance on Week 1 and untrained city (Week 53 17) for navigation participants only. hWhether at least 80% of intervention has been completed, and 54 average percentage of daily tasks completed. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 17 3 Brain structural changes using Magnetic Resonance Imaging 4 5 6 A Siemens Prisma 3 Tesla scanner with a 32 channel head coil is used for imaging 7 8 acquisition. The primary imaging measures include total HPC volumes, and HPC sub-structures. 9 10 The secondary imaging measures include the integrity of white matter tracts involving the HPC 11 12 (i.e., fimbria-fornix pathway). 13 14 15 Cognitive changes: Experimental measures 16 For peer review only 17 The primary cognitive outcome measures include near-, medium-, and far-transfer 18 19 measures. Near-transfer outcome measures (navigation intervention only) are performance 20 21 22 outcomes in a city on which participants were not trained following the intervention. Medium- 23 24 transfer measures are used to assess changes to spatial abilities that were not trained: 1) 25 26 Cognitive Map Formation Test (CMFT; earlier version described in [42]); 2) Different Approach 27 28 29 Task[43], and; 3) Path Integration Task[44]. Far-transfer measures include memory tasks 30 31 sensitive to HPC integrity to assess generalizability of training to HPC-dependent abilities that 32 33 were not directly trained: 1) Memory Image Completion Task[45,46] (MIC), and; 2) Mnemonic 34 http://bmjopen.bmj.com/ 35 Similarity Test[47] (MST). Additional subjective outcome measures include subjective changes 36 37 38 to navigation and memory in daily life with the following self-report measures; 1) Santa Barbara 39 40 Sense of Direction Scale[48] (SBSOD); 2) Navigational Strategies Questionnaire[49] (NSQ), 41 on October 2, 2021 by guest. Protected copyright. 42 and; 3) Everyday Memory Questionnaire[50] (EMQ). Alternate forms of the primary tasks are 43 44 45 used (i.e., MST, MIC, CMFT, Different Approach Task, Path Integration Task), with the specific 46 47 form used for the pre- and post-intervention assessments counterbalanced across participants. To 48 49 maintain consistency in administration, data collection, and data entry, experimenters will 50 51 52 undergo matched training and utilise scripts and detailed instructions. Coding of the key 53 54 components of the measures will be entered and checked by multiple experimenters. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 18 3 Cognition: Clinical measures 4 5 6 A comprehensive neuropsychological assessment battery validated for use with 7 8 individuals with TBI will be administered by a trained neuropsychologist blind to group 9 10 allocation, to characterise the participants at baseline, and determine changes to performance on 11 12 traditional clinical measures following the intervention. The tests administered include: 1) the 13 14 15 Wechsler Test of Adult Reading[51] (for characterisation only); 2) Digit Span forwards and 16 For peer review only 17 backwards[52]; Visual Spatial Span (forwards and backwards); 4) the Rey Auditory Verbal 18 19 Learning Test[53] (RAVLT); 5) the Rey Visual Design Learning Test[54] (RVDLT); 6) the 20 21 22 Sustained Attention to Response Test[55] (SART); the Symbol Digit Modalities Test[56], and; 23 24 7) select sub-tests of the NIH toolbox[57], including the picture sequence memory test, flanker 25 26 inhibitory control and attention test, dimensional change card sort test, and pattern comparison 27 28 29 processing speed test. An alternate form of the picture sequence memory test is used for the post- 30 31 intervention assessment. As a broader index of functional outcome, the Glasgow Outcome Scale 32 33 Extended[58] will be administered pre- and post-intervention; this particular measure was added 34 http://bmjopen.bmj.com/ 35 after recruitment began, which will result in a small subset of participants not having completed 36 37 38 this outcome. In addition to the clinical cognitive measures outlined above, mood assessments 39 40 will also be employed, including the Beck Depression Inventory-II (BDI-II) and the Beck 41 on October 2, 2021 by guest. Protected copyright. 42 Anxiety Inventory (BAI), as part of the clinical neuropsychological feedback provided to 43 44 45 participants post-intervention[59,60]. Feedback is provided via phone call by the 46 47 neuropsychologist and one of the lead scientists (RG), to the participant and their significant 48 49 other or caregiver. Information from their clinical interview, performance across the clinical 50 51 52 measures, and medical chart is integrated. Feedback includes: 1) a review of the purpose and 53 54 expectations of the assessment; 2) a review of strengths and weaknesses across cognitive 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 19 3 domains that have been observed and connect them (if applicable) to clinical complaints or 4 5 6 symptoms; 3) a discussion regarding personal goals and how best to use identified strengths to 7 8 offset their weaknesses, and; 4) further referrals to medical professionals, if applicable. 9 10 Training-related outcome measures 11 12 To assess improvements in navigation-related, within-task intervention components, the 13 14 15 following measures are collected for navigation training participants only: 1) spatial learning 16 For peer review only 17 ability based on end-of-day questions; 2) overall spatial ability improvement based on the 18 19 difference in performance of end-of-week end-of-day questions, between earlier to later weeks of 20 21 22 training; 3) independent navigation ability improvement on GSV-only reverse, alternate, and 23 24 blocked routes, based on differences in performance between earlier to later weeks of training, 25 26 and; 4) cognitive map formation ability, based on differences in end-of-week performance 27 28 29 between earlier and later weeks of training. Because the complexity of the cities increases 30 31 throughout the 16 weeks of training, and participants may switch challenge levels, this is not a 32 33 direct comparison of pre- and post-intervention ability. Therefore, performance is also compared 34 http://bmjopen.bmj.com/ 35 between the first week of training, and an additional week following the completion of the 36 37 38 intervention, based on a novel city of similar complexity as the first city. 39 40 Assessments of feasibility 41 on October 2, 2021 by guest. Protected copyright. 42 General feasibility of the intervention will be determined by the recruitment rate, 43 44 45 retention rate (including factors influencing retention), and compliance rates, based on objective 46 47 rates and subjectively through daily, weekly, and bi-weekly self-reported questionnaires. 48 49 Recruitment rate will be determined by dividing the number of participants consented by the 50 51 52 number of eligible participants approached, retention rate will be determined by dividing the 53 54 number of consented participants at baseline by the number of consented participants retained at 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 20 3 follow-up, and compliance rate will be determined by calculating the percentage of participants 4 5 6 adhering to at least 80% of the training protocol, as well as by calculating the average of each 7 8 individual participant’s percentage of completion of each of the daily tasks across the entire 9 10 duration of the intervention. Retention and compliance rates close to 100% are desired, but 70% 11 12 or greater would be considered successfully high, based on previous studies assessing feasibility 13 14 15 of self-administered computerised interventions in this type of population[61–63]. The degree of 16 For peer review only 17 burden to the participants in completing the intervention will be assessed by The How Much is 18 19 Too Much Scale[32], administered each week to measure physical, mental, and mood symptom 20 21 22 onset following intervention participation, incorporated on the intervention website at the end of 23 24 the week’s tasks. Participants placed in the targeted navigation intervention group also complete 25 26 a semi-structured interview following all of the outcome measures. The experimenter who 27 28 29 administers the remote assessments conducts the interview over the phone by following the 30 31 interview guide (Supplementary Table 2). Each interview will last approximately 30 minutes, be 32 33 digitally recorded, and transcribed verbatim for data analysis. Participants are asked about their 34 http://bmjopen.bmj.com/ 35 experiences with the intervention, uptake of web-based technology, perceived barriers and 36 37 38 facilitators to participating, as well as strengths, weaknesses and impact of the program on their 39 40 daily life[64]. 41 on October 2, 2021 by guest. Protected copyright. 42 Control variables 43 44 45 Demographic information, injury history, and hours of therapy for all participants are 46 47 collected using a secure, online survey prior to the pre-intervention assessment. At the pre- 48 49 intervention assessment, a personal interview is conducted to validate the contents of the survey 50 51 52 and gather additional information. In addition to inclusion for clinical feedback, BAI and BDI 53 54 scores are also considered as control variables[59,60]. Participants’ current level of physical 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 21 3 activity are assessed using the International Physical Activity Questionnaire - Short Form[65] 4 5 6 (IPAQ). 7 8 PLANNED STATISTICAL ANALYSES 9 10 Primary objective: Efficacy 11 12 To address the first sub-goal of the primary objective of determining whether our 13 14 15 intervention can improve cognitive domains related to the HPC, descriptive and inferential 16 For peer review only 17 statistics will be employed to examine group-level changes in the following cognitive outcomes 18 19 (experimental and clinical): far-transfer tasks associated with executive functioning (Digit Span, 20 21 22 Visual Spatial Span, SART, Symbol Digit Modalities Test, flanker inhibitory control and 23 24 attention test, dimensional change card sort test, and pattern comparison processing speed test), 25 26 far-transfer tasks associated with memory (MIC, MST, RAVLT, RVDLT, picture sequence 27 28 29 memory test), medium-transfer associated with spatial abilities (CMFT, Different Approach 30 31 Task, Path Integration Task); near-transfer of navigating using GSV, and subjective measures 32 33 (SBSOD, NSQ, EMQ). A principal component analysis will be conducted for dimension 34 http://bmjopen.bmj.com/ 35 reduction of these measures, and the resultant components will be used as predictors in a series 36 37 38 of between-group (targeted navigation and active control) analyses, which will be used to 39 40 estimate the average causal treatment effect. Secondary control measures will then be introduced 41 on October 2, 2021 by guest. Protected copyright. 42 individually to test for interactions that, if present, indicate that the corresponding variable acts 43 44 45 as a moderator of the treatment effect, including depression (BDI-II), anxiety (BAI), age, sex, 46 47 injury severity (i.e., GCS), hours of therapy, and physical activity (IPAQ). If so, specific effects 48 49 will be estimated. Within the targeted navigation group, changes to near-transfer outcomes will 50 51 52 be assessed using single-group analyses on the training-related outcome measures. The analyses 53 54 will be carried out with mixed models using information available from all participants, 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 22 3 including those with partially missing data (combining mixed models with multiple imputation 4 5 6 for longitudinal data) to reduce potential bias due to attrition. Analyses will be carried out “as 7 8 randomised” (intent-to-treat analyses) as well as “per protocol” taking the degree of compliance 9 10 into account. We anticipate group effects and group by time interactions, with improvements in 11 12 the navigation group at post-intervention (vs. control). For navigation participants, we also 13 14 15 anticipate improvements on the training-related outcome measures. 16 For peer review only 17 To test our second sub-goal of determining the efficacy of the intervention to reduce HPC 18 19 degeneration, the same analyses described above for the cognitive measures will be undertaken 20 21 22 for our imaging outcomes. We expect specific HPC degeneration in controls and stable or 23 24 increased volumes in the navigation group. Additional HPC sub-field analyses will be completed 25 26 based on manual segmentation of the T2 volumes, where data analysts will be blinded to the 27 28 29 allocation of the participant. We expect the dentate gyrus and CA1 sub-regions to most strongly 30 31 express degeneration and preservation trajectories due to roles in allocentric navigation and 32 33 neurogenesis. For DTI, we expect an offset of previously reported fornix degeneration following 34 http://bmjopen.bmj.com/ 35 navigation training[7]. Cingulum integrity could also be expected to be modulated with 36 37 38 improved HPC function and/or structure. 39 40 Secondary objective: Feasibility 41 on October 2, 2021 by guest. Protected copyright. 42 This secondary objective will be achieved by assessing recruitment and retention in the 43 44 45 study, by measuring compliance of participants in the completion of the interventions and the 46 47 completion of all behavioural outcome measures of the study, and by assessing scores on the 48 49 How Much is Too Much Scale. A semi-structured interview will help identify barriers to 50 51 52 completion and to elicit suggestions for improvement. Descriptive statistics will be used to 53 54 summarise the outcomes of the feasibility component of the study. Inductive manual thematic 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 23 3 analysis[66] will be conducted on the recorded responses to the questions from the semi- 4 5 6 structured interviews to assess the themes, staying close to participants’ own words[67,68] . A 7 8 subset of interview transcripts will be initially coded by two experimenters to ensure agreement 9 10 and standardisation of a coding framework to be applied to the remaining transcripts. Following 11 12 this, the remainder of transcripts will be coded independently by each experimenter. Upon 13 14 15 completion, reviewers will meet to reconcile coding of major identifiable themes of each 16 For peer review only 17 transcript, allowing for enhanced reflexivity and rigor. To aid in the organisation of data and 18 19 visualisation of emergent themes (e.g. word frequency query, mind map), coding notes will be 20 21 22 entered into NVivo[69] and clustered into groups and categories. To maximise credibility and 23 24 impartiality, the broader research team will meet to discuss the developing analysis, where new 25 26 themes may be considered, and until consensus is reached and theme labels are agreed upon. 27 28 29 ETHICS AND DISSEMINATION 30 31 This study has been approved by the University Health Network Research Ethics Board 32 33 and the Research Oversight and Compliance Office at the University of Toronto. This study will 34 http://bmjopen.bmj.com/ 35 be conducted in accordance with the Declaration of Helsinki and the Tri-Council Policy 36 37 38 Statement: Ethical Conduct for Research Involving Humans, 2nd edition[70]. The present study 39 40 began on October 20, 2018 and recruitment is ongoing. Any modifications to the present 41 on October 2, 2021 by guest. Protected copyright. 42 protocol will be submitted as formal amendments to the original ethics application and reviewed 43 44 45 by the above ethics boards prior to their implementation. All participants will be recruited 46 47 through an informed consent protocol in-person and by telephone (please see online 48 49 supplemental material for a model consent form). At the time of consent, participants are assured 50 51 52 that withdrawing from the study will not affect the care they receive at Toronto Rehabilitation 53 54 Institute. Participants are informed that the study involves minimal risks (i.e., fatigue from 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 24 3 assessments or intervention, claustrophobia during MRI). Participants may leave the study at any 4 5 6 time. The protocol follows the guidelines prescribed by the Standard Protocol Items: 7 8 Recommendations for Interventional Trials Statement[71]. All collected physical data will be 9 10 stored securely in locked cabinets, and electronic data will be stored on a secure server at 11 12 Toronto Rehabilitation Institute. Only the direct study team will have access to identifying 13 14 15 information, which will be kept confidential, and to the final dataset. Data will be publicly 16 For peer review only 17 available on Dryad, with limited demographic information to reduce risk of deidentification (age 18 19 band, gender, highest education level received). Results summarising the anonymised data will 20 21 22 be presented at academic and clinical conferences and findings will be submitted to peer- 23 24 reviewed journals. Authorship for publications will be determined based on the uniform 25 26 requirements for manuscripts submitted to biomedical journals[72]. Key findings will be shared 27 28 29 directly with participantss who have participated in the study by email, summarising the broad 30 31 results in a simplified and accessible format, and will be made available to the public through 32 33 media releases shared through the Marketing and Communications departments at Toronto 34 http://bmjopen.bmj.com/ 35 Rehabilitation Institute and the Rotman Research Institute at Baycrest. 36 37 38 SIGNIFICANCE AND IMPACT 39 40 The strength and novelty of the present study is the unique design of an intervention that 41 on October 2, 2021 by guest. Protected copyright. 42 can be completed by participants in their own homes using widely available software, which can 43 44 45 therefore be delivered with minimal resources, anywhere in the world. This enhances the 46 47 scalability and reach of the intervention, allowing the study to be replicated and the intervention 48 49 to be available to large samples and other patient populations with similar neuropathology. 50 51 52 Furthermore, using the principles of EE, the intervention is designed to be continuously novel 53 54 and challenging, allowing participants to remain engaged while stimulating the HPC through 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 25 3 tasks known to be hippocampal-dependent. Additionally, the study employs an active control to 4 5 6 allow more robust conclusions to be made regarding the effectiveness of a targeted navigation 7 8 intervention for m-s TBI, compared to generalised EE. Finally, the online setting of the 9 10 intervention allows for real-time data collection to monitor compliance and performance while 11 12 maintaining accurate records. 13 14 15 Importantly, the proposed research aims to develop infrastructure for ongoing 16 For peer review only 17 neurorehabilitation in remote communities, and for individuals who may face other barriers to 18 19 obtaining necessary resources (e.g., reduced mobility, or financial burden). The self-administered 20 21 22 feasibility questionnaire as well as the post-intervention interview will help to ascertain barriers 23 24 and facilitators to retention and compliance for computerised cognitive tasks for individuals with 25 26 m-sTBI, to ultimately expand the availability of treatment options for individuals in this 27 28 29 population. 30 31 ACKNOWLEDGMENTS 32 33 We would like to thank all of the volunteers, research assistants and undergraduate 34 http://bmjopen.bmj.com/ 35 project students who graciously offered their time to assist in the development of the 36 37 38 intervention: Taha Arshad, Marta Bogacki, Priyanka Prince, Sonia Persaud, Michelle Gomez, 39 40 Robert Dydynsky, Alexander Drohobycky, Mikael Salnikov, Reid Syrydiuk, Ginelle Feliciano, 41 on October 2, 2021 by guest. Protected copyright. 42 Roy Kuo, Maleeha Khan, Gina D'Souza, Mubina Butt, Samreen Aziz, Madison Fraser. Finally, 43 44 45 we would also like to acknowledge our recruitment contacts and partners who are central in 46 47 strengthening our recruitment reach in order to assess the feasibility and efficacy of this 48 49 intervention in patients: Dr. Matthew Burke (Sunnybrook Health Sciences Center), Dr. Karl F. 50 51 52 Gunnarsson (West Park Healthcare Centre), Kamilah Francis and Crystal McCollum (March of 53 54 Dimes Canada), and Michelle Pangilinan (Community Brain Injury Services). 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 26 3 COMPETING INTERESTS 4 5 6 The authors declare no competing interests related to this study. 7 8 FUNDING 9 10 This work is supported and funded by the Ontario Neurotrauma Foundation (ONF; 2017- 11 12 ABI-INFRA-1035), the Canadian Centre for Aging & Brain Health Innovation (CABHI), the 13 14 15 Canadian Traumatic Brain Injury Research Consortium (CTRC), the Branch Out Neurological 16 For peer review only 17 Foundation, and the Canada Research Chairs (950-230647). None of the funding sources had any 18 19 role in the design of the protocol nor will be involved in its execution, analyses, data 20 21 22 interpretation, or dissemination of results. 23 24 AUTHOR CONTRIBUTIONS 25 26 AG and REG conceived the original idea for the intervention, with BC as study manager. 27 28 29 AG and REG are also supervising the study, are helping maintain recruitment avenues, and 30 31 contributed to the final manuscript. ZB developed the materials for the intervention with 32 33 assistance and supervision by AG and REG, and with the aid of AL and AC. ZB, MEB and JR 34 http://bmjopen.bmj.com/ 35 all contributed to the implementation of the intervention on the training website, with JO 36 37 38 completing the initial methodology for GSV and overseeing ND as programmer, and with 39 40 assistance from TW and AL. MJCB and MEB developed the semi-structured interview that will 41 on October 2, 2021 by guest. Protected copyright. 42 be administered to participants following completion of the study. KJ oversees the recruitment 43 44 45 and screening of patients, with help from EJ, JR, MEB, and ZB, as well as all other 46 47 administrative aspects of the study. ZB, JR, and MEB oversee data collection and training 48 49 participants on the intervention, with EJ completing the administration of neuropsychological 50 51 52 assessments and reports, and TW assisting in data collection and training. ZB, MEB, and JR 53 54 wrote the manuscript with consultation from AG and REG. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 27 3 REFERENCES 4 5 6 1 World Health Organization. World Health Statistics 2015. 7 8 2015.https://www.who.int/gho/publications/world_health_statistics/2015/en/ (accessed 22 9 10 Apr 2020). 11 12 2 Cole JH, Jolly A, de Simoni S, et al. Spatial patterns of progressive brain volume loss 13 14 15 after moderate-severe traumatic brain injury. Brain 2018;141:822–36. 16 For peer review only 17 doi:10.1093/brain/awx354 18 19 3 Green REA, Colella B, Maller JJ, et al. Scale and pattern of atrophy in the chronic stages 20 21 22 of moderate-severe TBI. Front Hum Neurosci 2014;8:67. doi:10.3389/fnhum.2014.00067 23 24 4 Ng K, Mikulis DJ, Glazer J, et al. Magnetic Resonance Imaging Evidence of Progression 25 26 of Subacute Brain Atrophy in Moderate to Severe Traumatic Brain Injury. Arch Phys Med 27 28 29 Rehabil 2008;89:S35–44. doi:10.1016/j.apmr.2008.07.006 30 31 5 Green REA. Editorial: Brain Injury as a Neurodegenerative Disorder. Front Hum 32 33 Neurosci 2016;9:615. doi:10.3389/fnhum.2015.00615 34 http://bmjopen.bmj.com/ 35 6 Masel BE, DeWitt DS. Traumatic brain injury: A disease process, not an event. J. 36 37 38 Neurotrauma. 2010;27:1529–40. doi:10.1089/neu.2010.1358 39 40 7 Adnan A, Crawley A, Mikulis D, et al. Moderate–severe traumatic brain injury causes 41 on October 2, 2021 by guest. Protected copyright. 42 delayed loss of white matter integrity: Evidence of fornix deterioration in the chronic 43 44 45 stage of injury. Brain Inj 2013;27:1415–22. doi:10.3109/02699052.2013.823659 46 47 8 McCarthy MM. Stretching the truth Why hippocampal neurons are so vulnerable 48 49 following traumatic brain injury. Exp Neurol 2003;184:40–3. 50 51 52 doi:10.1016/j.expneurol.2003.08.020 53 54 9 McKee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 76

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REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 33 3 49 Brunec IK, Bellana B, Ozubko JD, et al. Multiple Scales of Representation along the 4 5 6 Hippocampal Anteroposterior Axis in Humans. Curr Biol 2018;28:2129-2135.e6. 7 8 doi:10.1016/J.CUB.2018.05.016 9 10 50 Sunderland A, Harris JE, Baddeley AD. Do laboratory tests predict everyday memory? A 11 12 neuropsychological study. J Verbal Learning Verbal Behav 1983;22:341–57. 13 14 15 doi:10.1016/S0022-5371(83)90229-3 16 For peer review only 17 51 Wechsler D. Wechsler Test of Adult Reading (WTAR). San Antonio, TX: : The 18 19 Psychological Corporation 2001. 20 21 22 52 Wechsler D. Manual for the Wechsler Adult Intelligence Scale - Revised. 1981. 23 24 doi:Thesis_references-Converted #317 25 26 53 Rey A. L’examen Clinique en Psychologie. 2e ed. Paris: : Presses universitaires de France 27 28 29 1964. doi:10.1176/appi.psychotherapy.1959.13.4.989 30 31 54 Rey A. L’examen Clinique en Psychologie. 1. éd. Paris: : Presses universitaires de France 32 33 1958. doi:10.1176/appi.psychotherapy.1959.13.4.989 34 http://bmjopen.bmj.com/ 35 55 Robertson IH, Manly T, Andrade J, et al. ‘Oops!’: Performance correlates of everyday 36 37 38 attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 39 40 1997;35:747–58. doi:10.1016/S0028-3932(97)00015-8 41 on October 2, 2021 by guest. Protected copyright. 42 56 Smith A. Symbol Digits Modalities Test. Los Angeles: : Western Psychological Sciences 43 44 45 1982. 46 47 57 Gershon RC, Cella D, Fox NA, et al. Assessment of neurological and behavioural 48 49 function: the NIH Toolbox. Lancet Neurol. 2010;9:138–9. doi:10.1016/S1474- 50 51 52 4422(09)70335-7 53 54 58 Wilson JTL, Pettigrew LEL, Teasdale GM. Structured interviews for the glasgow outcome 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 34 3 scale and the extended glasgow outcome scale: Guidelines for their use. J. Neurotrauma. 4 5 6 1998;15:573–85. doi:10.1089/neu.1998.15.573 7 8 59 Beck AT, Epstein N, Brown G, et al. An Inventory for Measuring Clinical Anxiety: 9 10 Psychometric Properties. J Consult Clin Psychol 1988;56:893–7. doi:10.1037/0022- 11 12 006X.56.6.893 13 14 15 60 Beck AT, Steer RA, Brown GK. Manual for the Beck depression inventory-II. San 16 For peer review only 17 Antonio, TX Psychol Corp 1996;:1–82. 18 19 61 Lebowitz MS, Dams-O K, Cantor JB. Feasibility of computerized brain plasticity-based 20 21 22 cognitive training after traumatic brain injury. 2012;49. doi:10.1682/JRRD/2011.07.0133 23 24 62 O’Neil-Pirozzi TM, Hsu H. Feasibility and benefits of computerized cognitive exercise to 25 26 adults with chronic moderate-to-severe cognitive impairments following an acquired brain 27 28 29 injury: A pilot study. Brain Inj 2016;30:1617–25. doi:10.1080/02699052.2016.1199906 30 31 63 Sharma B, Tomaszczyk JC, Dawson D, et al. Feasibility of online self-administered 32 33 cognitive training in moderate–severe brain injury. Disabil Rehabil 2017;39:1380–90. 34 http://bmjopen.bmj.com/ 35 doi:10.1080/09638288.2016.1195453 36 37 38 64 Cresswell JW, Plano-Clark VL, Gutmann ML, et al. Advanced mixed methods research 39 40 designs. In: Tashakkori A, Teddlie C, eds. Handbook of Mixed Methods in Social and 41 on October 2, 2021 by guest. Protected copyright. 42 Behavioral Research. Thousand Oaks: : Sage 2003. 209–40. 43 44 45 65 Craig CL, Marshall AL, Sjöström M, et al. International physical activity questionnaire: 46 47 12-Country reliability and validity. Med Sci Sports Exerc Published Online First: 2003. 48 49 doi:10.1249/01.MSS.0000078924.61453.FB 50 51 52 66 Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol 2006;3:77– 53 54 101. doi:10.1191/1478088706qp063oa 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 76 BMJ Open

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 35 3 67 Sandelowski M. Whatever happened to qualitative description? Res Nurs Health 4 5 6 2000;23:334–40. doi:10.1002/1098-240x(200008)23:4<334::aid-nur9>3.0.co;2-g 7 8 68 Sandelowski M. What’s in a name? Qualitative description revisited. Res Nurs Heal 9 10 2010;33:77–84. doi:10.1002/nur.20362 11 12 69 International Q. NVivo Qualitative Data Analysis Software. 13 14 15 1999.https://qsrinternational.com/nvivo/nvivo-products/ 16 For peer review only 17 70 Canadian Institute of Health Research, Natural Sciences and Engineering Research 18 19 Council of Canada SS and HRC. Tri-Council Policy Statement: Ethical Conduct for 20 21 22 Research Involving Humans. 2018. 23 24 71 Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: Defining standard 25 26 protocol items for clinical trials. Ann. Intern. Med. 2013;158:200–7. doi:10.7326/0003- 27 28 29 4819-158-3-201302050-00583 30 31 72 International Committee of Medical Journal Editors. Uniform Requirements for 32 33 Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 34 http://bmjopen.bmj.com/ 35 Publication. 2010. www.ICMJE.org (accessed 22 Apr 2020). 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 76

REMOTE ENRICHMENT PROTOCOL FOR TBI BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 36 3 Figure 1 4 5 6 CONSORT study flow diagram of the present protocol 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 Figure 1. CONSORT study flow diagram of the present protocol on October 2, 2021 by guest. Protected copyright. 43 200x219mm (300 x 300 DPI) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 1 4 5 6 7 Trial registration data for the study protocol based on World Health Organization Trial 8 Registration Data Set guidelines 9 10 11 12 Data category Information 13 Primary registry and trial identifying number ClinicalTrials.gov: NCT04331392 14 Date of registration in primary registry 2 April, 2020 15 Source(s) of monetary or material support Ontario Neurotrauma Foundation (ONF); 16 For peer review only 17 Canadian Centre for Aging & Brain Health 18 Innovation (CABHI); Canadian Traumatic 19 Brain Injury Research Consortium (CTRC); 20 Branch Out Neurological Foundation 21 Primary sponsor ONF; CABHI 22 23 Name and Contact Information for Primary Judy Gargaro, ABI Program Director, ONF - 24 sponsors [email protected] 25 James Mayer, Portfolio Manager, CABHI - 26 [email protected] 27 Secondary sponsor(s) CTRC; Branch Out Neurological Foundation 28 Contact for public queries REG, AG, ZB, MB, JR 29 30 Contact for scientific queries REG, AG, ZB, MB, JR 31 Public title Remotely Delivered Environmental 32 Enrichment Intervention for Traumatic Brain 33 Injury: A Randomized Controlled Trial 34 Scientific title Remotely Delivered Environmental http://bmjopen.bmj.com/ 35 Enrichment Intervention for Traumatic Brain 36 37 Injury: A Randomized Controlled Trial 38 Countries of recruitment Canada 39 Health condition(s) or problem(s) studied Traumatic brain injury 40 Intervention(s) Experimental: Spatial navigation intervention 41

Active Comparator: Educational Videos on October 2, 2021 by guest. Protected copyright. 42 Key inclusion and exclusion criteria Inclusion: 1) acute care diagnosis of m-sTBI; 43 44 2) PTA of 24 hours or more and/or lowest 45 GCS <13; 3) positive CT or MRI; 4) between 46 18 to 55 years of age; 5) fluency in English; 47 6) competency to provide informed consent or 48 availability of a legal decision maker; 7) basic 49 computer skills (use of internet/email, mouse 50 and arrow keys); 8) functional use of at least 51 52 one upper extremity for computer use, and; 9) 53 resident of Greater Toronto Area (to facilitate 54 access to the MRI) 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Exclusion: 1) neurological disorder other than 4 TBI (e.g., dementia, stroke); 2) diagnosis of a 5 6 neurodevelopmental disorder; 3) TBI 7 sustained before age 18; 4) systemic 8 comorbidities (e.g., lupus, diabetes); 5) 9 current diagnosis of aphasia, and; 6) presence 10 of metal inside the body (e.g., surgical clips, 11 pacemaker) leading to ineligibility for an MRI 12 13 Study type Interventional (Clinical Trial), Randomized 14 Parallel Assignment Masking (Participant, 15 Investigator, Outcomes Assessor) 16 For peer reviewPrimary purpose: only Treatment 17 Date of first enrolment 9 January, 2019 18 Target sample size 70 19 20 Recruitment status Recruiting 21 Primary outcome(s) Brain structural changes; cognitive changes 22 (memory: pattern separation, pattern 23 completion; near- and medium-transfer spatial 24 abilities; self-reported spatial abilities) 25 Key secondary outcome(s) Feasibility (recruitment, retention, 26 27 compliance, self-reported barriers) 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 2 4 5 6 Post-intervention semi-structured interview questions for navigation participants 7 8 9 10 Category Questions 11 First 1. Tell me about your experience with these tasks (i.e."I would 12 impressions like to get your initial thoughts on this intervention on the 13 14 whole, what was your general impression?”) 15 2. What was it like to interact with the program? 16 For peer• Probe: The review website, the internet, only the computer? How did your 17 experience with the intervention change over the course of the 18 study?(e.g., was it easier to use over time?) 19 3. What was your impression of the pre- and post-intervention 20 21 assessments? I am referring to the neuropsychological 22 assessment on the phone and cognitive assessments on the 23 computer. (e.g., being on the phone for 2 hours, completing 24 tests without a paper, looking at screen for 2 hours, difficulty 25 level, enough breaks) 26 Targets for 4. What did you enjoy the most about this intervention? 27 28 Optimization/ • Probe: What about the tasks did you find the most engaging? 29 Enhancement • On convenience: What was it like to participate in a therapy 30 program online? 31 5. What did you enjoy the least? 32 • Probe: How did you find using the computer? The internet? 33 34 The computer program? Intensity of intervention? http://bmjopen.bmj.com/ 35 Barriers to 6. For the most part, did you manage to complete the tasks as 36 Compliance assigned? 37 • Probe: How long did you spend on the intervention each day? 38 (on average) 39 • Did you find the demands of the intervention reasonable? What 40 41 could have helped you better stick to this schedule? 42 • Did you encounter difficulties focusing on the tasks? Did you on October 2, 2021 by guest. Protected copyright. 43 find your mind wandering? 44 7. Did you run into anything which made it difficult to 45 participate? 46 47 • Probe: Did you encounter any technological issues? 48 • Probe: How did this affect your participation? Would more 49 technical support have been useful to you? In what way? 50 • What, if anything, could have made you want to quit the 51 intervention? 52 8. What, if anything, would change about the intervention? 53 54 Barriers to 9. Do you think you would continue with the training going 55 Retention forward? Why or why not? 56 10. How did the monetary rewards affect your participation? 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 • Probe: Would you complete this intervention without any 4 5 monetary rewards? 6 Impact of 11. How has this program helped you? 7 Intervention • Probe: Was there anything that helped in a way you did not 8 expect? Did you find a change in how enriching/stimulating 9 your daily environment was during the program? 10 12. Have you noticed any changes in your functioning after the 11 12 intervention? (e.g., memory, learning, attention, navigation 13 abilities) 14 • Probe: Any changes to cognition? Any changes to your mood? 15 Daily functioning? 16 For 13.peer Do you think review this is a suitable only intervention for individuals with 17 brain injuries? 18 19 • Probe: How did your brain injury impact your participation? 20 How can we improve it for people with brain injury?(e.g., 21 amount of time on the screen, level of difficulty of 22 intervention, multitasking, pace) 23 Further 14. Overall, how satisfied were you with this intervention? 24 25 Suggestions 15. Would you recommend this to a friend in a similar situation? 26 16. (Thank participant, affirm importance of their input) Do you 27 have any other suggestions which would make this program 28 more enjoyable or a better fit for you? 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 3 4 5 6 7 Roles and responsibilities for study protocol members 8 9 10 11 Teams Roles 12 Principal investigators • Protocol design and revisions 13 • AG • Preparing annual reports for funding sponsors 14 • REG • Recruitment strategy aid and initiation of 15 recruitment contacts 16 For peer review only 17 Trial management • Participant randomisation and enrolment 18 • AG • Participant recruitment and screening 19 • REG • Budgeting and financial administration 20 • KJ • Participant payments 21 22 • ZB • Participant support for completion of online 23 • JR assessments and intervention 24 • EJ • Assistance with ethics committee applications and 25 • MB amendments 26 • Central recruiter • Assistance with study reports 27 28 Data management and analyses • Data compiling and storage 29 • ZB • Data organization 30 • JR • Data entry 31 • EJ • Data verification 32 33 • ND • Consultation with biostatisticians at Toronto 34 • JO Rehabilitation and Rotman Research Institutes http://bmjopen.bmj.com/ 35 • Other student assistants 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Supplementary Table 4 4 5 6 7 List of TED Talks selected for the active control intervention 8 9 10 Title Speaker 11 12 The world needs all kinds of minds Temple Grandin 13 The best stats you've ever seen Hans Rosling 14 The enchanting music of sign language Christine Sun Kim 15 Using design to make ideas new Milton Glaser 16 Taking imaginationFor seriously peer review onlyJanet Echelman 17 18 Want to be happier? Stay in the moment Matt Killingsworth 19 The art of choosing Sheena Iyengar 20 Let's turn the high seas into the world's largest nature reserve Enric Sala 21 22 The joy of lexicology Erin McKean 23 Folding way-new origami Robert Lang 24 Your words may predict your future mental health Mariano Sigman 25 The rise of human-computer cooperation Shyam Sankar 26 How stats fool juries Peter Donnelly 27 Lead like the great conductors Itay Talgam 28 29 How architecture helped music evolve David Byrne 30 How poachers became caretakers John Kasaona 31 Why good leaders make you feel safe Simon Sinek 32 The levitating superconductor Boaz Almog 33

The birth of a word Deb Roy http://bmjopen.bmj.com/ 34 35 Your body language shapes who you are Amy Cuddy 36 The beautiful math of coral Margaret Wertheim 37 Your brain is more than a bag of chemicals David Anderson 38 A universal translator for surgeons Steven Schwaitzberg 39 40 Thorium, an alternative nuclear fuel Kirk Sorensen 41 What makes us feel good about our work? Dan Ariely 42 Let's use video to reinvent education Sal Khan on October 2, 2021 by guest. Protected copyright. 43 44 Natural pest control ... using bugs! Shimon Steinberg 45 A performance of "Mathemagic" Arthur Benjamin 46 Life in the "digital now" Abha Dawesar 47 48 Imaging at a trillion frames per second Ramesh Raskar 49 Your elusive creative genius Elizabeth Gilbert 50 Retrofitting suburbia Ellen Dunham-Jones 51 52 Stanford University Commencement 2005 Steve Jobs 53 The mysterious workings of the adolescent brain Sarah-Jayne Blakemore 54 The shareable future of cities Alex Steffen 55 56 How to learn? From mistakes Diana Laufenberg 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 How I discovered DNA James Watson 4 5 Music and emotion through time Michael Tilson Thomas 6 The surprising science of happiness Nancy Etcoff 7 What we learned from 5 million books Erez Lieberman Aiden, 8 9 Jean-Baptiste Michel 10 Pool medical patents, save lives Ellen 't Hoen 11 Different ways of knowing Daniel Tammet 12 13 How I fell in love with a fish Dan Barber 14 Robots with "soul" Guy Hoffman 15 Healthier men, one moustache at a time Adam Garone 16 For peer review only 17 Everyday inventions Saul Griffith 18 What makes a good life? Lessons from the longest study on Robert Waldinger 19 happiness 20 Visualizing the wonder of a living cell David Bolinsky 21 22 A light switch for neurons Ed Boyden 23 Symmetry, reality's riddle Marcus du Sautoy 24 Are you a giver or a taker? Adam Grant 25 Actually, the world isn't flat Pankaj Ghemawat 26 27 How state budgets are breaking US schools Bill Gates 28 Dance vs. PowerPoint, a modest proposal John Bohannon, Black 29 Label Movement 30 Time-lapse proof of extreme ice loss James Balog 31 32 String theory Brian Greene 33 The weird, wonderful world of bioluminescence Edith Widder 34 A leap from the edge of space Steve Truglia http://bmjopen.bmj.com/ 35 The magic ingredient that brings Pixar movies to life Danielle Feinberg 36 Questioning the universe Stephen Hawking 37 38 The power of introverts Susan Cain 39 Stroke of insight Jill Bolte Taylor 40 A future beyond traffic gridlock Bill Ford 41 42 Building the Seed Cathedral Thomas Heatherwick on October 2, 2021 by guest. Protected copyright. 43 Every city needs healthy honey bees Noah Wilson-Rich 44 A shark-deterrent wetsuit (and it's not what you think) Hamish Jolly 45 Mosquitos, malaria and education Bill Gates 46 47 In the Internet age, dance evolves … The LXD 48 A Rosetta Stone for the Indus script Rajesh Rao 49 Why some of us don't have one true calling Emilie Wapnick 50 51 How to speak so that people want to listen Julian Treasure 52 Why you should talk to strangers Kio Stark 53 54 The beauty of data visualization David McCandless 55 On exploring the oceans Robert Ballard 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Shedding light on dark matter Patricia Burchat 4 5 The ancient ingenuity of water harvesting Anupam Mishra 6 How I teach kids to love science Cesar Harada 7 How human noise affects ocean habitats Kate Stafford 8 9 How bacteria "talk" Bonnie Bassler 10 How Benjamin Button got his face Ed Ulbrich 11 12 On spaghetti sauce Malcolm Gladwell 13 The 3 A's of awesome Neil Pasricha 14 The game layer on top of the world Seth Priebatsch 15 16 Psychedelic scienceFor peer review onlyFabian Oefner 17 A new ecosystem for electric cars Shai Agassi 18 Four principles for the open world Don Tapscott 19 20 The sound the universe makes Janna Levin 21 My dream of a flying car Paul Moller 22 23 The best kindergarten you've ever seen Takaharu Tezuka 24 When you reply to spam email James Veitch 25 26 Brain magic Keith Barry 27 Creative houses from reclaimed stuff Dan Phillips 28 Why a good book is a secret door Mac Barnett 29 30 The museum of you Jake Barton 31 The math behind basketball's wildest moves Rajiv Maheswaran 32 Why the secret to success is setting the right goals John Doerr 33 34 How to manage for collective creativity Linda Hill http://bmjopen.bmj.com/ 35 Watson, Jeopardy and me, the obsolete know-it-all Ken Jennings 36 37 My obsession with objects and the stories they tell Adam Savage 38 The business benefits of doing good Wendy Woods 39 Inside an Antarctic time machine Lee Hotz 40 41 Silk, the ancient material of the future Fiorenzo Omenetto 42 Thoughts on humanity, fame and love Shah Rukh Khan on October 2, 2021 by guest. Protected copyright. 43 How adaptive clothing empowers people with disabilities Mindy Scheier 44 45 Art that looks back at you Golan Levin 46 The unexpected benefit of celebrating failure Astro Teller 47 48 Why I live in mortal dread of public speaking Megan Washington 49 Why sneakers are a great investment Josh Luber 50 My solar-powered adventure Bertrand Piccard 51 52 The power of time off Stefan Sagmeister 53 To the South Pole and back — the hardest 105 days of my life Ben Saunders 54 Why we laugh Sophie Scott 55 56 How to design a library that makes kids want to read Michael Bierut 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Excuse me, may I rent your car? Robin Chase 4 5 The DIY orchestra of the future Ge Wang 6 The birth of virtual reality as an art form Chris Milk 7 How a driverless car sees the road Chris Urmson 8 9 Science is for everyone, kids included Beau Lotto, Amy O'Toole 10 Why we should build wooden skyscrapers Michael Green 11 12 A practical way to help the homeless find work and safety Richard J. Berry 13 4 lessons in creativity Julie Burstein 14 Unleash your creativity in a Fab Lab Neil Gershenfeld 15 16 A map of the brainFor peer review onlyAllan Jones 17 Don't fear intelligent machines. Work with them Garry Kasparov 18 Why you should love statistics Alan Smith 19 20 Adventures of an interplanetary architect Xavier De Kestelier 21 Why I fell in love with monster prime numbers Adam Spencer 22 23 The visual magic of comics Scott McCloud 24 Every piece of art you've ever wanted to see — up close and Amit Sood 25 searchable 26 How better tech could protect us from distraction Tristan Harris 27 28 Ancient wonders captured in 3D Ben Kacyra 29 A smog vacuum cleaner and other magical city designs Daan Roosegaarde 30 How to find a wonderful idea OK Go 31 32 Gorgeous portraits of the world's vanishing people Jimmy Nelson 33 Art with wire, sugar, chocolate and string Vik Muniz 34 http://bmjopen.bmj.com/ 35 A primer on 3D printing Lisa Harouni 36 Smart failure for a fast-changing world Eddie Obeng 37 The passing of time, caught in a single photo Stephen Wilkes 38 39 An honest look at the personal finance crisis Elizabeth White 40 The mad scientist of music Mark Applebaum 41 42 The voice of the natural world Bernie Krause on October 2, 2021 by guest. Protected copyright. 43 A multimedia theatrical adventure Natasha Tsakos 44 How to build with clay ... and community Diébédo Francis Kéré 45 46 3 reasons why we can win the fight against poverty Andrew Youn 47 How I became 100 artists Shea Hembrey 48 49 My journey in design John Maeda 50 How I teach kids to love science Cesar Harada 51 The thrilling potential for off-grid solar energy Amar Inamdar 52 53 4 larger-than-life lessons from soap operas Kate Adams 54 How many lives can you live? Sarah Kay 55 Rhythm is everything, everywhere Sivamani 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Optical illusions show how we see Beau Lotto 4 5 7 principles for building better cities Peter Calthorpe 6 The debut of the British Paraorchestra Charles Hazlewood, British 7 Paraorchestra 8 The shared experience of absurdity Charlie Todd 9 10 Discover the physical side of the internet Andrew Blum 11 A plea for bees Dennis van Engelsdorp 12 13 The astounding athletic power of quadcopters Raffaello D'Andrea 14 How we can turn the cold of outer space into a renewable resource Aaswath Raman 15 The painter and the pendulum Tom Shannon, John 16 For peer review onlyHockenberry 17 18 A forgotten Space Age technology could change how we grow Lisa Dyson 19 food 20 Asking for help is a strength, not a weakness Michele L. Sullivan 21 Ingenious homes in unexpected places Iwan Baan 22 Robots that fly ... and cooperate Vijay Kumar 23 24 Success stories from Kenya's first makerspace Kamau Gachigi 25 See invisible motion, hear silent sounds Michael Rubinstein 26 Two nerdy obsessions meet — and it's magic David Kwong 27 Turning dunes into architecture Magnus Larsson 28 29 Demo: A needle-free vaccine patch that's safer and way cheaper Mark Kendall 30 Using biology to rethink the energy challenge Juan Enriquez 31 Hack a banana, make a keyboard! Jay Silver 32 33 Fashion has a pollution problem — can biology fix it? Natsai Audrey Chieza 34 The art of puzzles Scott Kim http://bmjopen.bmj.com/ 35 36 How we found the worst place to park in New York City — using Ben Wellington 37 big data 38 The hidden influence of social networks Nicholas Christakis 39 Memes and "temes" Susan Blackmore 40 41 An ode to envy Parul Sehgal 42 Can clouds buy us more time to solve climate change? Kate Marvel on October 2, 2021 by guest. Protected copyright. 43 How college loans exploit students for profit Sajay Samuel 44 45 Electrical experiments with plants that count and communicate Greg Gage 46 Let my dataset change your mindset Hans Rosling 47 48 It's time to question bio-engineering Paul Root Wolpe 49 My green school dream John Hardy 50 How to turn a group of strangers into a team Amy Edmondson 51 52 How to build your creative confidence David Kelley 53 10 ways to have a better conversation Celeste Headlee 54 How to escape education's death valley Ken Robinson 55 56 A reality check on renewables David MacKay 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 How I use sonar to navigate the world Daniel Kish 4 5 The warmth and wisdom of mud buildings Anna Heringer 6 Pirates, nurses and other rebel designers Alice Rawsthorn 7 Synthetic voices, as unique as fingerprints Rupal Patel 8 9 How we wrecked the ocean Jeremy Jackson 10 The intriguing sound of marine mammals Peter Tyack 11 12 Dragonflies that fly across oceans Charles Anderson 13 The first secret of design is ... Noticing Tony Fadell 14 Embrace the near win Sarah Lewis 15 How to make filthy water drinkable Michael Pritchard 16 For peer review only 17 Victims of the city Mark Raymond 18 My subversive (garden) plot Roger Doiron 19 20 Learning from leadership's missing manual Fields Wicker-Miurin 21 Math class needs a makeover Dan Meyer 22 Older people are happier Laura Carstensen 23 24 A thought experiment on the intelligence of crows Joshua Klein 25 How trees talk to each other Suzanne Simard 26 27 Organic design, inspired by nature Ross Lovegrove 28 The art of creating awe Rob Legato 29 Between music and medicine Robert Gupta 30 31 Meet the dazzling flying machines of the future Raffaello D'Andrea 32 How to air-condition outdoor spaces Wolfgang Kessling 33 34 How not to be ignorant about the world Hans and Ola Rosling http://bmjopen.bmj.com/ 35 The wonderful and terrifying implications of computers that can Jeremy Howard 36 learn 37 Optical illusions show how we see Beau Lotto 38 39 Intricate beauty by design Marian Bantjes 40 Be an opportunity maker Kare Anderson 41

The world is one big dataset. Now, how to photograph it … Dan Berkenstock on October 2, 2021 by guest. Protected copyright. 42 43 Wiring an interactive ocean John Delaney 44 How public spaces make cities work Amanda Burden 45 46 Why great architecture should tell a story Ole Scheeren 47 Open science now! Michael Nielsen 48 The beautiful math behind the world's ugliest music Scott Rickard 49 50 Embrace the remix Kirby Ferguson 51 Listening to global voices Ethan Zuckerman 52 The mysterious lives of giant trees Richard Preston 53 54 How loss helped one artist find beauty in imperfection Alyssa Monks 55 New York - before the City Eric Sanderson 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 For argument's sake Daniel H. Cohen 4 5 Cooking as alchemy Homaro Cantu, Ben Roche 6 The secret structure of great talks Nancy Duarte 7 The future of lying Jeff Hancock 8 9 The anthropology of mobile phones Jan Chipchase 10 Let's save the last pristine continent Robert Swan 11 12 Why architects need to use their ears Julian Treasure 13 Why we will rely on robots Rodney Brooks 14 Discovering ancient climates in oceans and ice Rob Dunbar 15 16 Paper beats plastic?For How to peerrethink environmental review folklore onlyLeyla Acaroglu 17 Why bees are disappearing Marla Spivak 18 The science of scent Luca Turin 19 20 Play with smart materials Catarina Mota 21 Let's bridge the digital divide! Aleph Molinari 22 23 The science of cells that never get old Elizabeth Blackburn 24 A free digital library Brewster Kahle 25 Nature is everywhere — we just need to learn to see it Emma Marris 26 27 How Arduino is open-sourcing imagination Massimo Banzi 28 Why design should include everyone Sinéad Burke 29 The discoveries awaiting us in the ocean's twilight zone Heidi M. Sosik 30 31 A new ecosystem for electric cars Shai Agassi 32 The new power of collaboration Howard Rheingold 33 34 The magnificence of spider silk Cheryl Hayashi http://bmjopen.bmj.com/ 35 What a bike ride can teach you Shimon Schocken 36 Global population growth, box by box Hans Rosling 37 38 How the "ghost map" helped end a killer disease Steven Johnson 39 The birth of Wikipedia Jimmy Wales 40 Plug into your hard-wired happiness Srikumar Rao 41 42 The search for "aha!" moments Matt Goldman on October 2, 2021 by guest. Protected copyright. 43 A robot that runs and swims like a salamander Auke Ijspeert 44 45 Crop insurance, an idea worth seeding Rose Goslinga 46 Why jobs of the future won't feel like work David Lee 47 The surprising science of happiness Dan Gilbert 48 49 The case for optimism Larry Brilliant 50 Technology crafts for the digitally underserved Vinay Venkatraman 51 The secret to great opportunities? The person you haven't met yet Tanya Menon 52 53 A new weapon in the fight against superbugs David Brenner 54 Let's clean up the space junk orbiting Earth Natalie Panek 55 56 The science of sync Steven Strogatz 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Tagging tuna in the deep ocean Barbara Block 4 5 Lifesaving scientific tools made of paper Manu Prakash 6 Scientists must be free to learn, to speak and to challenge Kirsty Duncan 7 8 A printable, flexible, organic solar cell Hannah Bürckstümmer 9 The linguistic genius of babies Patricia Kuhl 10 The next 5,000 days of the web Kevin Kelly 11 12 The sticky wonder of gecko feet Robert Full 13 Glow-in-the-dark sharks and other stunning sea creatures David Gruber 14 15 Demo: A needle-free vaccine patch that's safer and way cheaper Mark Kendall 16 Reviving New York'sFor rivers peer— with oysters! review onlyKate Orff 17 Biohacking — you can do it, too Ellen Jorgensen 18 19 Robots inspired by cockroach ingenuity Robert Full 20 The riddle of experience vs. memory Daniel Kahneman 21 22 My $500 house in Detroit — and the neighbors who helped me Drew Philp 23 rebuild it 24 Great piano performances, recreated John Q. Walker 25 26 Special Olympics let me be myself — a champion Matthew Williams 27 Revealing the lost codex of Archimedes William Noel 28 Let the environment guide our development Johan Rockstrom 29 30 Connected, but alone? Sherry Turkle 31 How adaptive clothing empowers people with disabilities Mindy Scheier 32 What happens when an NGO admits failure David Damberger 33 34 3 new ways to kill mosquitoes Bart Knols http://bmjopen.bmj.com/ 35 How to build an information time machine Frederic Kaplan 36 37 My wish: Protect our oceans Sylvia Earle 38 What are animals thinking and feeling? Carl Safina 39 6 ways to save the internet Roger McNamee 40 41 Make data more human Jer Thorp 42 Teachers need real feedback Bill Gates on October 2, 2021 by guest. Protected copyright. 43 Using nature to grow batteries Angela Belcher 44 45 A powerful idea about ideas Alan Kay 46 The thinking behind 50x15 Hector Ruiz 47 48 Sculpted space, within and without Antony Gormley 49 An art made of trust, vulnerability and connection Marina Abramović 50 What makes something go viral? Dao Nguyen 51 52 Why the best hire might not have the perfect resume Regina Hartley 53 A solar energy system that tracks the sun Bill Gross 54 What do babies Think? Alison Gopnik 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Extreme swimming with the world's most dangerous jellyfish Diana Nyad 4 5 A forgotten ancient grain that could help Africa prosper Pierre Thiam 6 How artists can (finally) get paid in the digital age Jack Conte 7 To eliminate waste, we need to rediscover thrift Andrew Dent 8 9 The way we think about charity is dead wrong Dan Pallotta 10 Kids can teach themselves Sugata Mitra 11 12 How we're using drones to deliver blood and save lives Keller Rinaudo 13 A choreographer's creative process in real time Wayne McGregor 14 Buildings that blend nature and city Jeanne Gang 15 16 Learning from the Forgecko's tail peer review onlyRobert Full 17 What we're learning from online education Daphne Koller 18 Robots will invade our lives Rodney Brooks 19 20 Everyday moments, caught in time Billy Collins 21 Software (as) art Golan Levin 22 23 How to gain control of your free time Laura Vanderkam 24 The coolest animal you know nothing about ... and how we can Patrícia Medici 25 save it 26 Hooked by an octopus Mike deGruy 27 28 My wish: Build the Encyclopedia of Life E.O. Wilson 29 This is your brain on communication Uri Hasson 30 Fly with the Jetman Yves Rossy 31 32 What a driverless world could look like Wanis Kabbaj 33 This virtual lab will revolutionize science class Michael Bodekaer 34 http://bmjopen.bmj.com/ 35 The era of open innovation Charles Leadbeater 36 Animate characters by evolving them Torsten Reil 37 A virtual choir 2,000 voices strong Eric Whitacre 38 39 How record collectors find lost music and preserve our cultural Alexis Charpentier 40 heritage 41 Don't misrepresent Africa Leslie Dodson on October 2, 2021 by guest. Protected copyright. 42 How an old loop of railroads is changing the face of a city Ryan Gravel 43 44 Organic algorithms in architecture Greg Lynn 45 Flow, the secret to happiness Mihaly Csikszentmihalyi 46 47 How to engineer a viral music video Adam Sadowsky 48 Why wildfires have gotten worse — and what we can do about it Paul Hessburg 49 Inside the secret shipping industry Rose George 50 51 How to get better at the things you care about Eduardo Briceño 52 Hedonistic sustainability Bjarke Ingels 53 To create for the ages, let's combine art and engineering Bran Ferren 54 55 For survivors of Ebola, the crisis isn't over Soka Moses 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 The Museum of Four in the Morning Rives 4 5 3 Thoughtful ways to conserve water Laan Mazahreh 6 The secrets I find on the mysterious ocean floor Laura Robinson 7 8 The paradox of choice Barry Schwartz 9 The surprisingly logical minds of babies Laura Schulz 10 This company pays kids to do their math homework Mohamad Jebara 11 12 Can a robot pass a university entrance exam? Noriko Arai 13 Life's third act Jane Fonda 14 Hey science teachers — make it fun Tyler DeWitt 15 16 How societies can Forgrow old peerbetter review onlyJared Diamond 17 The illusion of consciousness Dan Dennett 18 19 A pro wrestler's guide to confidence Mike Kinney 20 Living sculptures that stand for history's truths Sethembile Msezane 21 Turning powerful stats into art Chris Jordan 22 23 Obesity + hunger = 1 global food issue Ellen Gustafson 24 The art of the eco-mindshift Natalie Jeremijenko 25 Simplicity sells David Pogue 26 27 What I learned when I conquered the world's toughest triathlon Minda Dentler 28 How we can design timeless cities for our collective future Vishaan Chakrabarti 29 30 The cheap all-terrain wheelchair Amos Winter 31 Save the oceans, feed the world! Jackie Savitz 32 How web video powers global innovation Chris Anderson 33 34 The puzzle of motivation Dan Pink http://bmjopen.bmj.com/ 35 Why you should love gross science Anna Rothschild 36 A magical search for a coincidence Helder Guimarães 37 38 An underwater art museum, teeming with life Jason deCaires Taylor 39 Look up for a change Lucianne Walkowicz 40 Why the buildings of the future will be shaped by ... You Marc Kushner 41 42 The art of the interview Marc Pachter on October 2, 2021 by guest. Protected copyright. 43 The new open-source economics Yochai Benkler 44 45 The beauty of being a misfit Lidia Yuknavitch 46 A demo of wireless electricity Eric Giler 47 Dive into an ocean photographer's world Thomas Peschak 48 49 The mind behind Linux Linus Torvalds 50 Agile programming — for your family Bruce Feiler 51 How do you build a sacred space? Siamak Hariri 52 53 How we became sisters Felice Belle, Jennifer 54 Murphy 55 This app knows how you feel — from the look on your face Rana el Kaliouby 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 A delightful way to teach kids about computers Linda Liukas 4 5 Breakthrough designs for ultra-low-cost products R.A. Mashelkar 6 The genesis of Google Sergey Brin, Larry Page 7 Technology that knows what you're feeling Poppy Crum 8 9 The violin, and my dark night of the soul Ji-Hae Park 10 What's your 200-year plan? Raghava KK 11 12 We can recycle plastic Mike Biddle 13 Uber's plan to get more people into fewer cars Travis Kalanick 14 Let's raise kids to be entrepreneurs Cameron Herold 15 16 The art of asking For peer review onlyAmanda Palmer 17 Why light needs darkness Rogier van der Heide 18 How to buy happiness Michael Norton 19 20 How mobile phones power disaster relief Paul Conneally 21 4 ways to make a city more walkable Jeff Speck 22 23 A 30-year history of the future Nicholas Negroponte 24 Why we all need to practice emotional first aid Guy Winch 25 A critical look at geoengineering against climate change David Keith 26 27 Can a computer write poetry? Oscar Schwartz 28 A glimpse of the future through an augmented reality headset Meron Gribetz 29 The nerd's guide to learning everything online John Green 30 31 Cradle to cradle design William McDonough 32 The other inconvenient truth Jonathan Foley 33 34 Why not eat insects? Marcel Dicke http://bmjopen.bmj.com/ 35 How I built a toaster — from scratch Thomas Thwaites 36 6 space technologies we can use to improve life on Earth Danielle Wood 37 38 A call to reinvent liberal arts education Liz Coleman 39 The mystery box J.J. Abrams 40 Averting the climate crisis Al Gore 41 42 A new way to stop identity theft David Birch on October 2, 2021 by guest. Protected copyright. 43 What intelligent machines can learn from a school of fish Radhika Nagpal 44 45 Art made of the air we breathe Emily Parsons-Lord 46 Stunning photos of the endangered Everglades Mac Stone 47 Gaming can make a better world Jane McGonigal 48 49 Plant fuels that could power a jet Bilal Bomani 50 How games make kids smarter Gabe Zichermann 51 Two reasons companies fail — and how to avoid them Knut Haanaes 52 53 Let's teach for mastery — not test scores Sal Khan 54 A flight on solar wings Paul MacCready 55 56 The power of vulnerability Brené Brown 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 On glamour Virginia Postrel 4 5 What our language habits reveal Steven Pinker 6 What I learned from spending 31 days underwater Fabien Cousteau 7 The future race car — 150mph, and no driver Chris Gerdes 8 9 How to tame your wandering mind Amishi Jha 10 Walk the earth ... my 17-year vow of silence John Francis 11 12 Fighting viruses, defending the net Mikko Hypponen 13 What’s wrong with your pa$$w0rd? Lorrie Faith Cranor 14 Reinventing the encyclopedia game Rives 15 16 What if 3D printingFor was 100x peer faster? review onlyJoseph DeSimone 17 Playtime with Pleo, your robotic dinosaur friend Caleb Chung 18 Science-inspired design Mathieu Lehanneur 19 20 Dog-friendly dog training Ian Dunbar 21 Your brain on improv Charles Limb 22 23 Anti-gravity sculpture Tom Shannon 24 How painting can transform communities Haas&Hahn 25 To invent is to give Dean Kamen 26 27 Visualizing ourselves ... with crowd-sourced data Aaron Koblin 28 The ocean's glory — and horror Brian Skerry 29 The hunt for a supermassive black hole Andrea Ghez 30 31 How your pictures can help reclaim lost history Chance Coughenour 32 New ways to see music (with color! and fire!) Jared Ficklin 33 34 Why I'm rowing across the Pacific Roz Savage http://bmjopen.bmj.com/ 35 The Blur Building and other tech-empowered architecture Liz Diller 36 Lessons from fashion's free culture Johanna Blakley 37 38 How to pitch to a VC David S. Rose 39 7 rules for making more happiness Stefan Sagmeister 40 My mind-shifting Everest swim Lewis Pugh 41 42 The world's most boring television ... and why it's hilariously Thomas Hellum on October 2, 2021 by guest. Protected copyright. 43 addictive 44 17 words of architectural inspiration Daniel Libeskind 45 46 What it takes to do extreme astrophysics Anil Ananthaswamy 47 The next web Tim Berners-Lee 48 Photos of Africa, taken from a flying lawn chair George Steinmetz 49 50 The world's oldest living things Rachel Sussman 51 Behind the design of Seattle's library Joshua Prince-Ramus 52 Inventing instruments that unlock new music Tod Machover, Dan Ellsey 53 54 Big data is better data Kenneth Cukier 55 The hunt for General Tso Jennifer Lee 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 57 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Emergency shelters made from paper Shigeru Ban 4 5 Design with the blind in mind Chris Downey 6 The mind behind Tesla, SpaceX, SolarCity … Elon Musk 7 A futuristic vision of the age of holograms Alex Kipman 8 Put a value on nature! Pavan Sukhdev 9 How food shapes our cities Carolyn Steel 10 How I made an impossible film Martin Villeneuve 11 12 Living beyond limits Amy Purdy 13 Great cars are great art Chris Bangle 14 What I learned from going blind in space Chris Hadfield 15 Why we need to go back to Mars Joel Levine 16 7 ways games rewardFor the brain peer review onlyTom Chatfield 17 18 Design with the blind in mind Chris Downey 19 The wonderful world of life in a drop of water Simone Bianco, Tom 20 Zimmerman 21 An illustrated journey through Rome David Macaulay 22 23 The transformative power of classical music Benjamin Zander 24 How to speak up for yourself Adam Galinsky 25 26 A census of the ocean Paul Snelgrove 27 3 creative ways to fix fashion's waste problem Amit Kalra 28 The fastest ambulance? A motorcycle Eli Beer 29 30 How architecture can connect us Thom Mayne 31 Sleep is your superpower Matt Walker 32 33 Are athletes really getting faster, better, stronger? David Epstein 34 Swim with the giant sunfish Tierney Thys http://bmjopen.bmj.com/ 35 An ultra-low-cost college degree Shai Reshef 36 37 Unseen footage, untamed nature Karen Bass 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 58 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 Model Consent Form 4 5 6 7 8 9 10 11 12 13 14 CONSENT FORM TO PARTICIPATE IN A RESEARCH STUDY 15 16 For peer review only 17 18 Study Title: Remotely delivered Environmental Enrichment interventions for acquired brain 19 injury 20 21 22 23 Principal Investigators/Study Doctors: Dr. Robin Green & Dr. Asaf Gilboa 24 25 26 Contact Information: 27 28 Dr. Robin Green 29 Research Scientist, Toronto Rehabilitation Institute 30 550 University Avenue, Room 11-207 31 Toronto, ON, M5G 2A2 32 Phone: 416-597-3422, extension 7606 33 34 http://bmjopen.bmj.com/ 35 Dr. Asaf Gilboa 36 37 Research Scientist, Rotman Research Institute at Baycrest 38 39 Centre for Stroke Recovery 40 3560 Bathurst St. 41 42 Toronto, ON, M6A 2E1 on October 2, 2021 by guest. Protected copyright. 43 Phone: 416-785-2500, extension 2908 44 45 46 47 Funding Source: The study is financed by a grant from the Ontario Neurotrauma Foundation 48 49 50 Introduction: 51 52 You are being asked to take part in a research study. Please read the information about the 53 study presented in this form. The form includes details on the study’s risks and benefits that you 54 should know before you decide if you would like to take part. You should take as much time as 55 56 you need to make your decision. You should ask the study doctor or study staff to explain 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 59 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 anything that you do not understand and make sure that all of your questions have been 4 answered before signing this consent form. Before you make your decision, feel free to talk 5 6 about this study with anyone you wish including your friends, family, and family doctor. 7 Participation in this study is voluntary. 8 9 10 Background/Purpose: 11 12 You have been asked to participate in this study because you have sustained a traumatic brain 13 injury (TBI). Past research has shown that “environmental enrichment” - engaging in effortful 14 cognitive activities on a regular basis - can have beneficial effects on recovery from brain injury. 15 16 For example, it can Forimprove cognitivepeer difficulties review and maximize only brain health after brain injury. 17 The purpose of this research project is to investigate the feasibility (i.e., the ability for us to re- 18 run the same study with a larger number of people) and effectiveness of two “environmental 19 enrichment” therapies delivered to participants online in their homes for a period of 16 weeks. 20 Up to 134 individuals may participate in this study over the course of 2 years. Through your 21 22 participation you will receive additional therapy which may be helpful to your rehabilitation. 23 24 25 Study Visits and Procedures: 26 27 If you agree to participate in the study, you will participate in a pre-therapy assessment while 28 you are an in-patient. This will take about an extra day of your time, however it will not affect 29 your length of stay at Toronto Rehab.) You will participate in a second pre-therapy 30 assessment, in-person and by phone, when you are approximately 7 months post- brain injury. 31 32 We will contact you 2 – 3 months prior to your assessment window to schedule an appointment, 33 and we will contact you 1 month prior to confirm your appointment). This assessment has two 34 components: http://bmjopen.bmj.com/ 35 36 37 38 • A Cognitive Assessment: You will be asked to complete some computerized tasks 39 and some pencil and paper tasks to measure cognitive functioning. Some of the 40 computerized tasks you will do will train you on the intervention tasks that you will be 41 doing at home during the intervention phase of the study. You will also be asked to 42 complete some questionnaires about your cognitive function, mood, and level of on October 2, 2021 by guest. Protected copyright. 43 physical activity. This assessment will last for approximately 3 - 6 hours and will be 44 completed over two (2) days, consecutively. The assessment will take place at the 45 Toronto Neuroimaging Facility at the University of Toronto (325 Huron St.) on the 46 first day, and by phone on the second day. 47 48 49 • A Magnetic Resonance Imaging (MRI) scan of your brain: The MRI scanner takes 50 signals emitted by the brain and turns them into pictures of the brain using magnetic 51 field. The MRI scanning will be carried out at the Toronto Neuroimaging Facility at 52 the University of Toronto (325 Huron St.). This will involve lying down on a table. 53 54 Foam pads will be placed around your head to limit head movement during the 55 study. The table will then be slid into the magnet. While in the scanner, you will be 56 asked to lie still for approximately 1.5 hours, during which time several scans will 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 60 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 take place. For obtaining some of the images, you don’t have to do any specific task, 4 other than relaxing while keeping your head and body still. Before the scan, you will 5 be asked some questions to ensure you do not have any magnetically sensitive 6 metal materials in your body. (This does not include dental fillings.) You cannot 7 participate in the rest of the study if you cannot participate in the MRI scan. 8 9 10 11 Once you have completed the above assessment you will move onto the therapy phase of the 12 study. The therapies we are investigating in this study are “environmental enrichment” exercise 13 programs to maximize brain health. The therapy phase involves: 14 15 16 • CompletingFor 1 hour peer of “environmental review enrichment” onlyexercises daily for 5 days per week 17 (e.g., Monday - Friday). You will be given online access to intervention materials at 18 home each day over the course of 16 weeks. 19 20 • There are two forms of environmental enrichment therapy: 21 22 o Allocentric spatial navigation therapy (or ‘bird’s eye view’ navigation therapy) 23 involving finding various landmarks while navigating different cities around the 24 world using Google Street View. 25 26 o Educational video viewing in which you will view several short educational 27 videos each day and will learn about a wide range of topics. 28 29 • Study Design: this is a “randomized control trial” which means that we will compare 30 the two treatments to each other by assigning participants randomly (i.e., by chance) 31 to either the allocentric spatial navigation intervention or the educational video 32 intervention. Once you have agreed to enter the trial, a computer will perform the 33

equivalent of tossing a coin to allocate you to one of the two treatments. http://bmjopen.bmj.com/ 34 35 • Once you are assigned to one of the two treatments, you will be provided with login 36 37 information to access the intervention activities on a secure Toronto Rehab –UHN 38 study website. 39 40 • We will provide you with a laptop and a high-speed internet connection for the duration 41 of the therapy program (i.e., 16 weeks) if you do not have or do not wish to use your 42 own equipment. on October 2, 2021 by guest. Protected copyright. 43 44 • We ask that you adhere as closely as possible to the recommended schedule for the 45 entire 16 weeks. You will be receiving reminders and be provided training support as 46 necessary 47 48 • Your participation in the exercises online and your performance over time will be 49 monitored by a therapy assistant at Toronto Rehab. The therapy assistant will access 50 your activity information via the website. 51 52 • You will be asked to answer some questions on a daily basis and on a weekly basis. 53 On a daily basis, you will be asked to answer 3 online questions about how you are 54 finding the activities (1-2 minutes to complete); at the end of each week of training, 55 you will also be asked to answer 3-6 online questions about the intervention (2-3 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 61 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 minutes to complete); once a month you will be asked to complete a questionnaire 4 about cognitive, physical and emotional symptoms that you may experience in 5 response to completing the cognitive intervention. 6 7 8 9 • At the end of the program, some participants will also be invited to participate in a 10 15-30 minute, telephone administered, semi-structured interview with our team so 11 that we can better understand your experiences with the environmental enrichment 12 intervention. Up to 30 participants will be randomly selected from all participants in 13 the study to be invited to participate in the interview. We will also ask you for 14 permission to contact your caregiver or significant other to invite him/her to 15 participate in a similar 15-30 minute, telephone administered, semi-structured 16 interviewFor with our peerteam to further review understand your only experiences with the 17 environmental enrichment intervention. 18 19 20 ☐ I agree to being invited to participate in the telephone interview. 21 22 23 24 ☐ I agree to having my caregiver/significant other invited to participate in the 25 26 telephone interview. 27 28 29 30 31 At the end of the 16 week therapy phase you will be asked to return to the University of Toronto 32 for a post-therapy assessment. This assessment is identical to the pre-therapy assessment 33

described above. http://bmjopen.bmj.com/ 34 35 36 37 Risks: 38 Taking part in this study has risks. Some of these risks we know about. 39 40 41 42 The cognitive assessments that occur pre-and post- therapy phase involve no more risk to you on October 2, 2021 by guest. Protected copyright. 43 than there are in your routine cognitive assessments. You may get tired during the assessment 44 and if this occurs, please tell the researcher and a break will be provided or if necessary the 45 46 task will be discontinued. 47 48 49 The study therapies involve a time commitment of 5 hours per week which could cause you to 50 be more tired than usual. If fatigue prevents you from completing the specified amount of 51 therapy, you can discuss this with your study therapists and a modified schedule can be 52 53 arranged. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 62 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 The risks involved in this MRI study are minimal, and are limited to the risks present during 4 routine MRI examinations. The MRI scan is painless but noisy. There is no radiation associated 5 6 with the scan. When near an MRI scanner, there is a potential for the powerful magnetic field 7 to attract metallic objects toward the magnet. For this reason, you will be carefully screened for 8 previous exposure to metallic fragments or clips that may be inside your body. Similarly, you will 9 be asked to place all metallic and magnetic objects in your possession (e.g. keys, jewelry, credit 10 cards) in a locker outside the magnet room. 11 12 13 14 Some people may feel a little ‘closed-in’ the MRI machine, but you will be able to speak with 15 someone at all times and can stop the test at any time. 16 For peer review only 17 18 19 To reduce potential back or neck pain due to lying still in the scanner, cushions and pads 20 designed to better disperse your weight for the scan duration will be used under your knees and 21 neck and around your body. 22 23 24 Benefits: 25 26 You may not receive any direct benefit from being in this study. However, information learned 27 from this study may help with the development of a novel post-injury cognitive intervention. 28 29 30 31 Reminders and Responsibilities: 32 33 • Tell your study team if you change your mind about being in the study. 34 • Ask your study team about anything related to the study that worries you. http://bmjopen.bmj.com/ 35 36 • Tell study staff of any health changes that you experience during the course of the study. 37 38 39 Confidentiality: 40 41 Personal Health Information 42 on October 2, 2021 by guest. Protected copyright. If you agree to join this study, the Principal Investigators and their study team will collect only 43 44 the information they need for the study which may include personal health information: 45 • Name 46 47 • address 48 49 • email 50 • telephone number 51 52 • partial date of birth (month and year) 53 54 • name of a family member/significant other (who could fill out a questionnaire for this 55 study) 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 63 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 • New or existing medical records, that includes types, dates and results of medical tests 4 or procedures 5 6 7 Representatives of either the University of Toronto or the University Health Network (UHN) 8 9 including the University of Toronto or UHN Research Ethics Board may look at the study 10 records and at your personal health information to check that the information collected for the 11 study is correct and to make sure the study is following proper laws and guidelines. 12 13 14 The study doctor will keep any personal health information about you in a secure and 15 16 confidential locationFor for 10 years. peer A list linking review your study number only with your name 17 will be kept by the study doctor in a secure place, separate from your study file. 18 19 20 Study Information that Does Not Identify You: 21 22 Any information about you that is sent out of the hospital will have a code and will not show your 23 name or address, or any information that directly identifies you. 24 25 26 27 All information collected during this study, including your personal health information, will be 28 kept confidential and will not be shared with anyone outside the study unless required by law. 29 You will not be named in any reports, publications, or presentations that may come from this 30 31 32 33 What happens with the results of the study? http://bmjopen.bmj.com/ 34 Primarily, the results will be used to inform the ideas and design of future studies, these 35 additional future studies may build on the findings of this study to advance healthcare or 36 37 treatment options of relevance. It is very likely that a report will be published about this research 38 study and the results will be published in scientific journals or presented at scientific 39 conferences, but you will not be able to be identified. Your identity will always be kept 40 confidential. In addition, anonymous images may be provided to third parties (such as the 41 42 manufacturer of the scanner for use in connection with its product development and marketing on October 2, 2021 by guest. Protected copyright. 43 activities). All identifying information about you is removed from the images so that they are 44 anonymized before they are sent to this third party. The third party may keep the images for up 45 to 5 years. 46 47 48 49 Voluntary Participation: 50 Your participation in this study is voluntary. You may decide not to be in this study, or to be in 51 52 the study now and then change your mind later. You may leave the study at any time. You will 53 not be required to give reasons for your decision to leave the study. 54

55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 We will give you new information that is learned during the study that might affect your decision 4 to stay in the study. 5 6 7 8 Withdrawal from the Study: 9 10 The researchers can take you off the study if: 11 • You are unable to comply with the instructions for participation given to you 12 13 • You no longer meet the criteria for participation 14 15 16 If you wish to leave Forthe study, peer please let study review staff know. If youonly leave the study, the information 17 that was collected before you left the study will still be used in order to help answer the research 18 19 question. No new information will be collected without your permission. However, you have the 20 right to request withdrawal of information collected about you. Let the Principal Investigator 21 know. 22 23 24 Costs and Reimbursement: 25 26 You will receive $75 for your participation in each of the 2 in-person and phone assessments 27 (pre- and post- therapy) to cover travel expenses incurred to attend the in-person session. 28 29 30 31 The therapy phase of the study will last 16 weeks (i.e., 4 months). At the end of each month of 32 therapy, you will receive $75 in the form of a gift card (which can be sent to you electronically). 33

You will have an additional opportunity to receive a bonus $5 electronic gift card to a coffee http://bmjopen.bmj.com/ 34 shop for every 2 weeks of completed training, to be sent biweekly or monthly. 35 36 37 38 Rights as a Participant: 39 40 If you are harmed as a direct result of taking part in this study, all necessary medical treatment 41 will be made available to you at no cost. 42 on October 2, 2021 by guest. Protected copyright. 43 44 By signing this form you do not give up any of your legal rights against the investigators, or 45 involved institutions for compensation, nor does this form relieve the investigators, sponsor or 46 involved institutions of their legal and professional responsibilities. 47 48 49 Incidental Findings: 50 51 The magnetic resonance imaging (MRI) scan you will receive during the course of this study is 52 for research purposes only. It is not a clinical scan intended for diagnostic or therapeutic 53 54 purposes. The Brain Imaging Facility is a research center. It is NOT a clinical MRI facility in a 55 hospital. There are no neuroradiologists at the Brain Imaging Facility, therefore the staff are 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 65 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 unable to make any medical comments about your scan. Should you want to know if your scan 4 is normal or abnormal, the staff will not be able to tell you. 5 6 7 8 There is a chance, however, that, in the course of this research scanning protocol, we observe 9 an anomaly (e.g. tumor or cyst) in one or more of the MRI images. If this happens, your images 10 will be sent to a trained neuroradiologist for further investigation and you may be informed of the 11 results. An anomaly does not necessarily indicate the presence of any disorder. Because our 12 13 MRI scans are for research purposes only, they may be inadequate for the purpose of clinical 14 diagnosis. Additionally, as researchers, we are not trained to clinically interpret MRI data. 15 However, we feel it is important to inform you of any observations, as we cannot rule out the 16 possibility that this anForomaly maypeer require medical review advice. If you only prefer not to be informed of 17 18 anomalous findings, you must check the box below. 19 ☐ I prefer NOT to be informed of any anomalous findings. 20 21 22 23 Conflict of Interest: 24 25 The researchers report no potential conflicts of interest. They have an interest in completing this 26 study. Their interest should not affect your consideration for participating. 27

28 29 Future Studies: 30 31 I authorize the MRI facility to contact me about future research within the MRI research facility in 32 the Department of Psychology. If I agree, a researcher may contact me and tell me about the 33

research. At that time, I can decide whether or not I am interested in participating in a particular http://bmjopen.bmj.com/ 34 35 study. 36 ☐ I agree to be contacted about research studies conducted at the MRI facility. 37 38 ☐ I authorize the MRI facility to use my data in future research within the MRI research facility 39 in the Department of Psychology. 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 Questions about the Study: 44 45 If you have any questions, concerns or would like to speak to the study team for any reason, 46 please call: Dr. Robin Green (416) 597-3422 ext. 7871 47 48 If you have any questions about your rights as a research participant or have concerns about 49 this study, call the Chair of the University Health Network Research Ethics Board (UHN REB) or 50 the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee 51 the ethical conduct of research studies. The UHN REB is not part of the study team. Everything 52 that you discuss will be kept confidential. 53 54 55 56 You will be given a signed copy of this consent form. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 66 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 Consent: 6 7 8 This study has been explained to me and any questions I had have been answered. 9 10 I know that I may leave the study at any time. I agree to the use of my information as described 11 in this form. I agree to take part in this study. 12 13 14 15 16 Print Study Participant’sFor Name peer reviewSignature only Date 17

18 19 20 21 Or for substitute decision maker: 22 23 24 This study has been explained to me and any questions I had have been answered. 25 26 I know that ______may leave the study at any time. I agree to the use of 27 28 his or her information as described in this form. I agree to have ______take 29 part in this study. 30 31 32 33 34 ______http://bmjopen.bmj.com/ 35 36 Print Name of Substitute decision maker Signature Date 37 38 39 40 41 ______42 on October 2, 2021 by guest. Protected copyright. 43 Relationship to participant 44 45 46 47 Person who obtained consent: 48 49 My signature means that I have explained the study to the participant named above and/or his 50 or her substitute decision maker named above. I have answered all questions. 51 52 53 54 55 Print Name of Person Signature Date 56 Obtaining Consent 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 67 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 5 6 Was the participant assisted during the consent process? YES NO 7 8 If YES, please check the relevant box and complete the signature space below: 9

10 11 The person signing below acted as an interpreter, and attests that the study as set out in the 12 consent form was accurately sight translated and/or interpreted, and that interpretation was 13 provided on questions, responses and additional discussion arising from this process. 14 15 16 For peer review only 17 18 Print Name of Interpreter Signature Date 19 20 21 22 23 Relationship to Participant Language 24 25 26 The consent form was read to the participant. The person signing below attests that the 27 study as set out in this form was accurately explained to, and has had any questions answered. 28 29 30 31 32 Print Name of Witness Signature Date 33

http://bmjopen.bmj.com/ 34 35 36 Relationship to Participant 37 38 39 40 41

on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 3 4 Reporting checklist for protocol of a clinical trial. 5 6 7 Based on the SPIRIT guidelines. 8 9 10 11 Instructions to authors 12 13 14 Complete this checklist by entering the page numbers from your manuscript where readers will find 15 16 each of the items listed below.For peer review only 17 18 19 Your article may not currently address all the items on the checklist. Please modify your text to 20 21 include the missing information. If you are certain that an item does not apply, please write "n/a" and 22 23 24 provide a short explanation. 25 26 27 Upload your completed checklist as an extra file when you submit to a journal. 28 29 30 In your methods section, say that you used the SPIRITreporting guidelines, and cite them as: 31 32 33 Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann 34 http://bmjopen.bmj.com/ 35 H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill W, Groves T, Schulz K, Sox H, Rockhold 36 37 38 FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard protocol items for clinical trials. 39 40 Ann Intern Med. 2013;158(3):200-207 41 42 on October 2, 2021 by guest. Protected copyright. 43 Reporting Item Page Number 44 45 46 Administrative 47 48 information 49 50 51 Title #1 Descriptive title identifying the study design, 1 52 53 54 population, interventions, and, if applicable, trial 55 56 acronym 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 69 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Trial registration #2a Trial identifier and registry name. If not yet 3 3 4 registered, name of intended registry 5 6 7 Trial registration: #2b All items from the World Health Organization Online supplemental 8 9 data set Trial Registration Data Set material (Table 1) 10 11 12 Protocol version #3 Date and version identifier 3 13 14 15 Funding #4 Sources and types of financial, material, and 26 16 For peer review only 17 18 other support 19 20 21 Roles and #5a Names, affiliations, and roles of protocol 1, 26, Online 22 23 responsibilities: contributors supplemental 24 25 contributorship material (Table 4) 26 27 28 Roles and #5b Name and contact information for the trial Online supplemental 29 30 31 responsibilities: sponsor material (Table 1) 32 33 sponsor contact 34 http://bmjopen.bmj.com/ 35 information 36 37 38 Roles and #5c Role of study sponsor and funders, if any, in 26 39 40 41 responsibilities: study design; collection, management, analysis, 42 on October 2, 2021 by guest. Protected copyright. 43 sponsor and funder and interpretation of data; writing of the report; 44 45 and the decision to submit the report for 46 47 publication, including whether they will have 48 49 50 ultimate authority over any of these activities 51 52 53 Roles and #5d Composition, roles, and responsibilities of the Online supplemental 54 55 responsibilities: coordinating centre, steering committee, material (Table 4) 56 57 committees endpoint adjudication committee, data 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 70 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 management team, and other individuals or 2 3 groups overseeing the trial, if applicable (see 4 5 Item 21a for data monitoring committee) 6 7 8 Introduction 9 10 11 Background and #6a Description of research question and justification 5-8 12 13 14 rationale for undertaking the trial, including summary of 15 16 Forrelevant peer studies review(published and unpublished)only 17 18 examining benefits and harms for each 19 20 intervention 21 22 23 24 Background and #6b Explanation for choice of comparators 8, 15 25 26 rationale: choice of 27 28 comparators 29 30 31 Objectives #7 Specific objectives or hypotheses 7-8 32 33 http://bmjopen.bmj.com/ 34 Trial design #8 Description of trial design including type of trial 10 35 36 37 (eg, parallel group, crossover, factorial, single 38 39 group), allocation ratio, and framework (eg, 40 41 superiority, equivalence, non-inferiority, 42 on October 2, 2021 by guest. Protected copyright. 43 exploratory) 44 45 46 Methods: 47 48 49 Participants, 50 51 interventions, and 52 53 outcomes 54 55 56 Study setting #9 Description of study settings (eg, community 8, 11 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 71 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 clinic, academic hospital) and list of countries 2 3 where data will be collected. Reference to where 4 5 list of study sites can be obtained 6 7 8 Eligibility criteria #10 Inclusion and exclusion criteria for participants. If 8-9 9 10 11 applicable, eligibility criteria for study centres and 12 13 individuals who will perform the interventions (eg, 14 15 surgeons, psychotherapists) 16 For peer review only 17 18 Interventions: #11a Interventions for each group with sufficient detail 12-16 19 20 description to allow replication, including how and when they 21 22 23 will be administered 24 25 26 Interventions: #11b Criteria for discontinuing or modifying allocated 23-24; minimal risk 27 28 modifications interventions for a given trial participant (eg, drug 29 30 dose change in response to harms, participant 31 32 33 request, or improving / worsening disease) 34 http://bmjopen.bmj.com/ 35 36 Interventions: #11c Strategies to improve adherence to intervention 14-15 37 38 adherence protocols, and any procedures for monitoring 39 40 adherence (eg, drug tablet return; laboratory 41 42 on October 2, 2021 by guest. Protected copyright. 43 tests) 44 45 46 Interventions: #11d Relevant concomitant care and interventions that 9 47 48 concomitant care are permitted or prohibited during the trial 49 50 51 Outcomes #12 Primary, secondary, and other outcomes, 16-21 52 53 including the specific measurement variable (eg, 54 55 56 systolic blood pressure), analysis metric (eg, 57 58 change from baseline, final value, time to event), 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 72 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 method of aggregation (eg, median, proportion), 2 3 and time point for each outcome. Explanation of 4 5 the clinical relevance of chosen efficacy and 6 7 8 harm outcomes is strongly recommended 9 10 11 Participant timeline #13 Time schedule of enrolment, interventions 11-12 12 13 (including any run-ins and washouts), 14 15 assessments, and visits for participants. A 16 For peer review only 17 schematic diagram is highly recommended (see 18 19 20 Figure) 21 22 23 Sample size #14 Estimated number of participants needed to 8 24 25 achieve study objectives and how it was 26 27 determined, including clinical and statistical 28 29 30 assumptions supporting any sample size 31 32 calculations 33 34 http://bmjopen.bmj.com/ 35 Recruitment #15 Strategies for achieving adequate participant 10 36 37 enrolment to reach target sample size 38 39 40 Methods: 41 42 on October 2, 2021 by guest. Protected copyright. 43 Assignment of 44 45 interventions (for 46 47 controlled trials) 48 49 50 Allocation: #16a Method of generating the allocation sequence 10-11 51 52 sequence (eg, computer-generated random numbers), and 53 54 55 generation list of any factors for stratification. To reduce 56 57 predictability of a random sequence, details of 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 73 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 any planned restriction (eg, blocking) should be 2 3 provided in a separate document that is 4 5 unavailable to those who enrol participants or 6 7 8 assign interventions 9 10 11 Allocation #16b Mechanism of implementing the allocation 10-11 12 13 concealment sequence (eg, central telephone; sequentially 14 15 mechanism numbered, opaque, sealed envelopes), 16 For peer review only 17 describing any steps to conceal the sequence 18 19 20 until interventions are assigned 21 22 23 Allocation: #16c Who will generate the allocation sequence, who 10-11 24 25 implementation will enrol participants, and who will assign 26 27 participants to interventions 28 29 30 Blinding (masking) #17a Who will be blinded after assignment to 11 31 32 33 interventions (eg, trial participants, care 34 http://bmjopen.bmj.com/ 35 providers, outcome assessors, data analysts), 36 37 and how 38 39 40 Blinding (masking): #17b If blinded, circumstances under which unblinding n/a; enough team 41 42 on October 2, 2021 by guest. Protected copyright. 43 emergency is permissible, and procedure for revealing a members are 44 45 unblinding participant’s allocated intervention during the trial unblinded to be able 46 47 to intervene if 48 49 necessary 50 51 52 Methods: Data 53 54 55 collection, 56 57 management, and 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 74 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 analysis 2 3 4 Data collection plan #18a Plans for assessment and collection of outcome, 17 5 6 baseline, and other trial data, including any 7 8 related processes to promote data quality (eg, 9 10 11 duplicate measurements, training of assessors) 12 13 and a description of study instruments (eg, 14 15 questionnaires, laboratory tests) along with their 16 For peer review only 17 reliability and validity, if known. Reference to 18 19 20 where data collection forms can be found, if not 21 22 in the protocol 23 24 25 Data collection #18b Plans to promote participant retention and 11-12, 14-15 26 27 plan: retention complete follow-up, including list of any outcome 28 29 30 data to be collected for participants who 31 32 discontinue or deviate from intervention protocols 33 34 http://bmjopen.bmj.com/ 35 Data management #19 Plans for data entry, coding, security, and 17, 24 36 37 storage, including any related processes to 38 39 promote data quality (eg, double data entry; 40 41 42 range checks for data values). Reference to on October 2, 2021 by guest. Protected copyright. 43 44 where details of data management procedures 45 46 can be found, if not in the protocol 47 48 49 Statistics: outcomes #20a Statistical methods for analysing primary and 21-23 50 51 52 secondary outcomes. Reference to where other 53 54 details of the statistical analysis plan can be 55 56 found, if not in the protocol 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 75 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Statistics: additional #20b Methods for any additional analyses (eg, 21-23 3 4 analyses subgroup and adjusted analyses) 5 6 7 Statistics: analysis #20c Definition of analysis population relating to 22 8 9 population and protocol non-adherence (eg, as randomised 10 11 missing data analysis), and any statistical methods to handle 12 13 14 missing data (eg, multiple imputation) 15 16 For peer review only 17 Methods: 18 19 Monitoring 20 21 22 Data monitoring: #21a Composition of data monitoring committee n/a: study team 23 24 formal committee (DMC); summary of its role and reporting members will be 25 26 27 structure; statement of whether it is independent monitoring data 28 29 from the sponsor and competing interests; and 30 31 reference to where further details about its 32 33

charter can be found, if not in the protocol. http://bmjopen.bmj.com/ 34 35 36 Alternatively, an explanation of why a DMC is not 37 38 needed 39 40 41 Data monitoring: #21b Description of any interim analyses and stopping n/a; present study 42 on October 2, 2021 by guest. Protected copyright. 43 interim analysis guidelines, including who will have access to does not have 44 45 46 these interim results and make the final decision potentially serious 47 48 to terminate the trial outcomes 49 50 51 Harms #22 Plans for collecting, assessing, reporting, and 21-23 52 53 managing solicited and spontaneously reported 54 55 56 adverse events and other unintended effects of 57 58 trial interventions or trial conduct 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 76 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Auditing #23 Frequency and procedures for auditing trial n/a; study team 3 4 conduct, if any, and whether the process will be meets regularly to 5 6 independent from investigators and the sponsor address and review 7 8 operating 9 10 11 procedures 12 13 14 Ethics and 15 16 dissemination For peer review only 17 18 19 Research ethics #24 Plans for seeking research ethics committee / 23 20 21 approval institutional review board (REC / IRB) approval 22 23 24 Protocol #25 Plans for communicating important protocol 23 25 26 27 amendments modifications (eg, changes to eligibility criteria, 28 29 outcomes, analyses) to relevant parties (eg, 30 31 investigators, REC / IRBs, trial participants, trial 32 33

registries, journals, regulators) http://bmjopen.bmj.com/ 34 35 36 37 Consent or assent #26a Who will obtain informed consent or assent from 23 38 39 potential trial participants or authorised 40 41 surrogates, and how (see Item 32) 42 on October 2, 2021 by guest. Protected copyright. 43 44 Consent or assent: #26b Additional consent provisions for collection and n/a 45 46 ancillary studies use of participant data and biological specimens 47 48 49 in ancillary studies, if applicable 50 51 52 Confidentiality #27 How personal information about potential and 24 53 54 enrolled participants will be collected, shared, 55 56 and maintained in order to protect confidentiality 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 77 of 76 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 before, during, and after the trial 2 3 4 Declaration of #28 Financial and other competing interests for 25-26 5 6 interests principal investigators for the overall trial and 7 8 each study site 9 10 11 Data access #29 Statement of who will have access to the final 24 12 13 14 trial dataset, and disclosure of contractual 15 16 Foragreements peer that review limit such access only for 17 18 investigators 19 20 21 Ancillary and post #30 Provisions, if any, for ancillary and post-trial care, Online supplemental 22 23 24 trial care and for compensation to those who suffer harm material (Model 25 26 from trial participation consent form) 27 28 29 Dissemination #31a Plans for investigators and sponsor to 24 30 31 policy: trial results communicate trial results to participants, 32 33

healthcare professionals, the public, and other http://bmjopen.bmj.com/ 34 35 36 relevant groups (eg, via publication, reporting in 37 38 results databases, or other data sharing 39 40 arrangements), including any publication 41 42 on October 2, 2021 by guest. Protected copyright. 43 restrictions 44 45 46 Dissemination #31b Authorship eligibility guidelines and any intended 26 47 48 policy: authorship use of professional writers 49 50 51 Dissemination #31c Plans, if any, for granting public access to the full 24 52 53 policy: reproducible protocol, participant-level dataset, and statistical 54 55 56 research code 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 78 of 76 BMJ Open: first published as 10.1136/bmjopen-2020-039767 on 11 February 2021. Downloaded from 1 2 Appendices 3 4 5 Informed consent #32 Model consent form and other related Online supplemental 6 7 materials documentation given to participants and material (Model 8 9 authorised surrogates consent form) 10 11 12 Biological #33 Plans for collection, laboratory evaluation, and n/a 13 14 15 specimens storage of biological specimens for genetic or 16 For peer review only 17 molecular analysis in the current trial and for 18 19 future use in ancillary studies, if applicable 20 21 22 None The SPIRIT checklist is distributed under the terms of the Creative Commons Attribution 23 24 License CC-BY-ND 3.0. This checklist can be completed online using https://www.goodreports.org/, a 25 26 27 tool made by the EQUATOR Network in collaboration with Penelope.ai 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml