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The effects of an 8-week computerized cognitive training program in older adults: a study protocol for… ten Brinke, Lisanne F; Best, John R; Crockett, Rachel A; Liu-Ambrose, Teresa Jan 30, 2018

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STUDY PROTOCOL Open AccessThe effects of an 8-week computerizedcognitive training program in older adults:a study protocol for a randomizedcontrolled trialLisanne F. ten Brinke1, John R. Best1, Rachel A. Crockett1 and Teresa Liu-Ambrose2*AbstractBackground: Given the world’s aging population, it is important to identify strategies that promote healthycognitive aging and minimize cognitive decline. Currently, no curative pharmaceutical therapy exists forcognitive impairment and dementia. As a result, there is much interest in lifestyle approaches. Specifically,complex mental activity, such as cognitive training, may be a promising method to combat cognitive declinein older adults. As such, the industry of commercial computerized cognitive training (CCT) applications hasrapidly grown in the last decade. However, the efficacy of these commercial products is largely notestablished. Moreover, exercise is a recognized strategy for promoting cognitive outcomes in older adults andmay augment the efficacy of computerized cognitive training applications. Therefore, we propose a proof-of-concept randomized controlled trial (RCT) to examine the effect of a commercial CCT program in community-dwelling older adults.Methods: An 8-week RCT to examine the effect of a commercial CCT program, alone and preceded by a15-min brisk walk, on cognitive function and explore the underlying neural mechanisms in adults aged65–85 years old. Participants will be randomized to one of three intervention groups: 1) Computerizedcognitive training (FBT); 2) A 15-min brisk walk followed by computerized cognitive training (Ex-FBT); or 3)A combination of educational classes, sham cognitive training, and balanced and tone exercises (activecontrol, BAT). Participants in all intervention groups will attend three one-hour classes per week over thecourse of the intervention. Participants will be assessed at baseline, trial completion, and 1-year post studycompletion (1-year follow-up).Discussion: If results from this study show benefits for cognition at trial completion, CCT programs, alone orin combination with walking, might be a strategy to promote healthy cognitive aging in older adults. Inaddition, results from the 1-year follow-up measurement could provide important information regarding thelong-term benefits of these CCT programs.Trial registration: ClinicalTrials.gov Protocol Registration System: NCT02564809; registered September 1, 2015.Keywords: Computerized cognitive training, Community-dwelling older adults, Mild cognitive impairment,Cognitive function, Magnetic resonance imaging* Correspondence: teresa.ambrose@ubc.ca2Aging, Mobility, and Cognitive Neuroscience Laboratory, Department ofPhysical Therapy, Djavad Mowafaghian Centre for Brain Health, Centre forHip Health and Mobility, University of British Columbia, 2215 Wesbrook Mall,Vancouver, BC V6T 1Z3, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.ten Brinke et al. BMC Geriatrics  (2018) 18:31 DOI 10.1186/s12877-018-0730-6BackgroundThe world’s population is aging, and the promotion ofactive aging is a global priority [1]. Cognitive impairmentand dementia are now the leading cause of disablementand death in later life. The incidence of dementia is ris-ing rapidly, and over 47 million people worldwide are di-agnosed with dementia and this number is expected totriple by 2050 [1]. As an effective treatment or cure fordementia remains elusive, there are increased efforts toestablish the efficacy of non-pharmaceutical strategies,such as targeted exercise training and cognitive training,on cognitive health in older adults. Even when an effect-ive pharmacological therapy is available, lifestyle ap-proaches (i.e., exercise, nutrition, and cognitive training)can be used as a complementary approach, as lifestyleinterventions result in multidimensional benefits [2].Interest in strategies such as cognitive training, a formof complex mental activities, has increased over the lastdecade. Tasks aimed to train for example executive func-tions, memory, or learning a language are consideredcomplex mental activities, as long as they challenge anindividual cognitively [3]. Improvements in cognitivefunction, such as episodic memory (e.g., delayed recall),were found in older adults who participated in video-games [4] or computer lessons [5]. Moreover, auditoryperception training for 6 weeks, 1 h per day, resulted inimprovements in problem solving and reasoning [6],which is considered to be positive far transfer. Thus, be-sides improvements in the trained domains, cognitivetraining could also show benefits of transfer [4, 6]. Asidefrom immediate benefits, the ACTIVE study [7] foundthat ten years post intervention, participants who re-ceived either speed-of-processing training or reasoningtraining for 5–6 weeks maintained effects of targetedcognitive abilities (i.e., speed-of-processing, reasoning).A meta-analysis of human cohort studies demon-strates that the amount of time involved in complexmental activities in early, mid- and late-life, was asso-ciated with a reduction in dementia incidence in laterlife [8]. Specifically, they found that increased com-plex mental activity in later life was associated withlower dementia rates, independent of other predictors,where more involvement in complex mental activitieswas found to lower dementia risk [8].One example of complex mental activity that receivedincreasing attention as a strategy to promote healthycognitive aging is computerized cognitive training(CCT). The number of commercialized CCT programshas increased rapidly over the last years. A meta-analysisof CCT in older adults showed that CCT is able toimprove overall cognitive function, memory (verbal,non-verbal), processing speed, working memory andvisuospatial skills [9]. No improvements were found forexecutive functions and attention [9]. A recentrandomized controlled trial (RCT) comparing multido-main CCT with an active control group found improve-ments in global cognition, memory and processing speed[10]. Improvements in memory and processing speedwere maintained at 1-year follow up, indicating mainten-ance of CCT benefits [10]. Thus, CCT is a promisingstrategy to promote healthy cognitive aging, and is also afeasible strategy for those who are limited in their abil-ities to participate in other lifestyle strategies, such asexercise.Aerobic exercise is a promising strategy to promotecognitive health, while benefiting cardiovascular func-tion at the same time [11]. Research shows that aer-obic exercise, such as walking, could benefit cognitivefunction such as executive functions (e.g., inhibition,processing speed), memory [11–14], as well as brainstructure [13, 15] and function [16]. As both exerciseand cognitive training are promising strategies toprevent or delay cognitive decline [17], perhaps bycombining them the benefit may be increased.Importantly, whereas aerobic exercise can facilitateneuroplasticity by increasing the number of newlyformed neurons, additional experience-dependentcognitive activity is necessary to promote synapticplasticity and the survival and functional integrationof the newly formed neurons into neural networks[18–21]. Moreover, due to the transient nature of theupregulation of neurotrophic factors [22] it has beensuggested that cognitive training preferably takesplace in temporal proximity to exercise training [23].The objective of the current proof-of-concept RCTwill be to examine the effect of CCT, alone and precededby a 15-min brisk walk, on cognitive function and to ex-plore the underlying neural mechanism in communitydwelling older adults. Therefore, our aim is four-fold: 1)To compare the effects of an 8-week CCT program (i.e.,Fit Brains® Training: FBT), as well as the effects of a 15-min brisk walk prior to FBT (i.e., Ex-FBT), with an ac-tive control (i.e., Balanced And Toned, BAT) on cogni-tive performance in older adults aged 65–85 years old;2) Using structural and functional Magnetic ResonanceImaging (MRI), to explore the effect of FBT and Ex-FBTcompared with BAT on brain structure and function; 3)To explore whether the effects of FBT and Ex-FBT aremoderated by baseline cognitive status (i.e., Mild Cogni-tive Impairment (MCI) versus non-MCI); 4) To explorewhether Ex-FBT has additional benefits compared withFBT; and 5) To explore whether potential benefits fromCCT are maintained at 1-year follow-up.MethodsTrial designvThis proof-of-concept RCT in community-dwellingolder adults will have three experimental arms. We willten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 2 of 11include 120 community-dwelling adults aged 65–85 years old who will be randomized to one of threeexperimental groups: 1) Computerized cognitive train-ing (FBT); 2) Exercise plus computerized cognitivetraining (Ex-FBT); or 3) Balanced and Toned (BAT,i.e., active control, see Fig. 1). There will be threemeasurement sessions: baseline, trial completion (i.e.,8 weeks), and 1-year follow-up. The study protocolfollows the Consolidated Standard of Reporting Trials(CONSORT) statement [24] and basic requirementsfrom the Standard Protocol Items: Recommendationsfor Interventional Trials (SPIRIT) [25]. The trial isregistered at ClinicalTrials.gov (NCT02564809).Study settingThe study will be conducted at two locations in MetroVancouver, BC (Canada): the Djavad MowafaghianCentre for Brain Health at the University of BritishColumbia (UBC) and the Centre for Hip Health andMobility at Vancouver General Hospital (VGH).ParticipantsParticipants will be recruited from the community(Greater Vancouver, BC Canada) as well as through ourdatabase of previous research participants. Individualsshowing interest in the study via advertisements in com-munity centres or local newspapers will receive a shortsummary of the study and if still interested, will bescreened over the telephone to determine eligibility. Par-ticipants from previous studies in our laboratory whoexpressed interest in future studies will be contacted ei-ther via mail or email.EligibilityInclusion criteriaFor this study, we will include individuals who: 1) areaged between 65 and 85 years; 2) completed high schooleducation; 3) live in their own home; 4) read, write, andspeak English with acceptable visual and auditory acuity;5) have preserved general cognitive function as indicatedby a Mini-Mental State Examination [26] score of ≥24/30; 6) score > 6/8 on the Lawton and Brody InstrumentalActivities of Daily Living Scale [27]; 7) are not expectedto start or are stable on a fixed dose of anti-dementiamedications (e.g., donepezil, galantamine, etc.) duringthe 8-week study period; 8) are able to walk independ-ently; 9) are suitable to engage in 15 min of brisk walk-ing based on the Physical Activity ReadinessQuestionnaire [28]; and 10) provide a personally signedand dated informed consent document indicating thatthe individual (or a legally acceptable representative) hasbeen informed of all pertinent aspects of the study.Exclusion criteriaWe will exclude individuals who: 1) are diagnosed withdementia of any type; 2) are clinically suspected to havea neurodegenerative disease as the cause of MCI that isnot AD, vascular dementia (VaD), or both (e.g. multiplesclerosis, Parkinson’s disease, Huntington’s disease,fronto-temporal dementia, etc.); 3) have clinically signifi-cant peripheral neuropathy or severe musculoskeletal orjoint disease that impairs mobility, as determined by his/her family physician; 4) are taking medications that maynegatively affect cognitive function, such as anticholiner-gics, including agents with pronounced anticholinergicAssessed for eligibility n=379  Excluded (n = 256) Not meeting inclusion criteria  (n = 39) Declined to participate  (n = 217) Randomized  n = 123  Active: 14 Complete: 27Active: 13 Complete: 28Active: 14 Completed: 27 Allocated to FBT n = 41 Allocated to Ex-FBT n = 41 Allocated to BAT n = 41 Fig. 1 Overview of participant flowten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 3 of 11properties (e.g., amitriptyline), major tranquilizers (i.e.,typical and atypical antipsychotics), and anticonvul-sants (e.g., gabapentin, valproic acid, etc.); and 5)are planning to participate, or already enrolled in, aconcurrent clinical drug trial.A subset of participants will undergo MRI scanning.For this MRI subset, we will exclude individuals who donot meet the specific scanning requirements of the UBCMRI Research Centre. Specifically, we will exclude any-one with: pacemaker, brain aneurysm clip, cochlear im-plant, surgery or tattoos within the past 6 weeks,electrical stimulator for nerves or bones, implanted infu-sion pump, history of any eye injury involving metalfragments, artificial heart valve, orthopedic hardware,other metallic prostheses, coil, catheter or filter in anyblood vessel, ear or eye implant, bullets, or other metal-lic fragments.Classification by baseline cognitive statusTo explore whether the intervention effects (i.e., FBTand Ex-FBT) are moderated by baseline cognitive status,we will classify individuals based on their baseline Mon-treal Cognitive Assessment (MoCA) [29]. The MoCA isa 30-point test that covers multiple cognitive domains[29]. The MoCA has been found to have good internalconsistency and test-retest reliability and was able tocorrectly identify 90% of a large sample of individualswith MCI from two different clinics [29]. Thus,participants with a baseline MoCA score ≤ 26/30 will beclassified as probable MCI and those with a MoCAscore > 26/30 will be classified as cognitively normal.InterventionsFor the 8-week intervention period, all participantswill be asked to come to the study location (i.e., VGHor UBC) 3 times per week for 1 h. Thus, all partici-pants will attend 24 1-hour classes at VGH or UBC.These classes will have a set time, and thus afterrandomization participants will come in on Monday,Wednesday and Friday at the same time each day.Over the course of the four study cohorts, grouptimes will be kept consistent (+/− 15 min). Inaddition, study staff will be kept consistent over allfour cohorts to ensure training consistency. Depend-ing on group size, students/staff will help facilitatestudy classes to meet the participants’ needs.Fit brains® training (FBT)Participants randomized to the FBT group will be re-quired to attend 3 formal training sessions per week, for8 weeks, at the Djavad Mowafaghian Centre for BrainHealth (UBC) or the Centre for Hip Health and Mobility(VGH). Each session will be for 60 min. Additionally,participants will be asked to complete 3 1-hour trainingsessions at home per week. Thus, FBT participants willcomplete a total of 48 h of cognitive training over the 8-week intervention.There is currently no consensus as to the “best dos-age”. However, we based our proposed dosage on thecollective work by Strenziok and colleagues [6], Basakand colleagues [4], Engvig and colleagues [30], andSmith and colleagues [31]. Overall, the total number oftraining hours ranged from 23.5 h to 40 h, each trainingsession ranged from 60 min to 90 min, and total inter-vention period ranged from 5 weeks to 8 weeks. Import-antly, the study population included by Envig andcolleagues [30] (i.e., older adults with subjective memorycomplaints) is the most similar to our target population.They employed an 8-week intervention period with oneformal training session of 90 min and five home-basedsessions. Each home-based session was approximately30 min. Thus, their total number of training hours was~ 32 h (12 h of formal training and 20 h of at hometraining). Notably, Envig and colleagues [30] demon-strated that after 8-weeks of training, there was signifi-cant improvement in verbal memory (i.e., long verbaldelay recall) and increases in gray matter volumes. Tobe conservative, we increased our total number of train-ing hours to 48 as data extracted from existing FitBrains® subscribers suggest that compared with youngadults, older adults may require more frequent cognitivetraining to maintain benefit [32].Fit Brains®, a program by Rosetta Stone Inc., offers 59different training games, of which 38 are available on amobile platform (e.g., iPad). The games are designed tobe targeting one of six cognitive domains – focus, speed,memory, visual, problem solving, and language. The ma-jority of the games last exactly 60 s during which indi-vidual aims to answer as many questions as quickly andaccurately as possible. Other games have a set numberof trials the participants have to complete before movingon to the next game. The difficulty of the game increasesafter each correct answer. Each game has three levels ofdifficulty: 1) novice; 2) intermediate; and 3) advanced.During the FBT intervention, all participants will beginthe training at the beginner level. Difficulty will increasethroughout the intervention period based on their per-formance. At the end of each training session, FBT gameprogress will be saved and participants will begin thenext session at that point. Each block of games will con-sist of 5 games. The first 5 blocks of games will be pre-scribed to offer an introduction to the user. After that,the sequencing of the games will be random, where eachblock will consist of games that need the most attention(i.e., games that showed the lowest performance), andgames that will be randomly selected based on a set al-gorithm. Game performance will be recorded for eachparticipant. Moreover, for their training sessions atten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 4 of 11home, participants will be asked to train at the sametime of the day as their classes at VGH/UBC.Exercise + fit brains® training (ex-FBT)Participants randomized to the Ex-FBT group will be re-quired to attend 3 formal training sessions per week, for8 weeks, at the Djavad Mowafaghian Centre for BrainHealth (UBC) or the Centre for Hip Health and Mobility(VGH). Each session will be for 1 h. Participants willstart the training with a 15-min walk outside. Partici-pants will monitor the intensity of their walk usingthe 20-point Borg’s Rating of Perceived Exertion [33].For the first two weeks the participants will aim for a10–11 on the Borg scale (i.e., between very light andfairly light). The aim for weeks 3 and 4 will be to reachfor 12–13 on the Borg scale (i.e., up to somewhat hard).During the remaining 4 weeks the participants will aimfor 13–14 on the Borg scale (i.e., somewhat hard). The15-min walk will be followed by a 45-min Fit Brains®training session (see FBT program, mentioned above) onthe iPad. Additionally, participants will be asked tocomplete 3 1-h training sessions at home (i.e., 15-minwalk followed by 45-min of FBT). The participants willbe recording their Borg-scale scores and the number ofsteps they walked during their 15-min walks on a calen-dar that will be provided at the start of the study.Balanced and toned (BAT)Participants randomized to the BAT group will be re-quired to attend 3 formal 1-h training sessions perweek, for 8 weeks, at the Djavad Mowafaghian Centrefor Brain Health (UBC) and/or the Centre for HipHealth and Mobility (VGH). Specifically, the BATparticipants will complete a total of 8 h of sham cog-nitive training, 8 h of sham exercise training, and 8 hof education regarding brain health over the 8-weektraining.We have largely designed the sham cognitive trainingof the BAT protocol based on the work of Baniqued andcolleagues [34] who examined the nature of cognitiveabilities tapped by casual online games. They identifiedonline games that largely tapped solely into visuo-motorspeed, such as Alphattack and Crashdown. Alphattackrequires players to prevent bombs from landing bypressing the character specified by the approachingbomb (source: miniclip.com). Crashdown requiresplayers to prevent the wall from reaching the top of thedisplay by clipping on three or more adjacent same-coloured bricks to remove them (source: miniclip.com).As these online games do not significantly tap intomemory abilities, we use similar online games in ourBAT protocol. In addition to exercises on the iPad weinclude group-based games, such as drawing using boththeir dominant and non-dominant hand, writing cap-tions on cartoons, and word games.The exercise component of the BAT program will con-sist of once weekly balance and tone classes. The exer-cise program will be led by certified fitness instructors(i.e., CPR certified and NCAA certified or equivalent)and includes stretching exercises, range of motion exer-cises, basic core-strength exercises including kegals (i.e.,exercises to strengthen the pelvic floor muscles), balanceexercises and relaxation techniques. Key balance exer-cises include Tai Chi-based forms (i.e., Crane, TreePose), tandem stand, tandem walking, and single legstance (eyes open and closed). Previous use of thisprotocol showed no improvements of cognitive func-tioning as a result of the BAT program [35]. These ses-sions will be held at the Centre for Hip Health andMobility.Additionally, once a week the participants will attendeducational classes. For the first four 1-hour educationsessions, participants will attend lectures relating tobrain health, such as sleep and goal setting. During theremaining four weeks, participants will create their indi-vidual photo book using the iPad.AdherenceParticipants’ adherence to the interventions will be re-corded using three methods. First, class attendance will berecorded by study team members. Second, monitoringCCT training at home will be done by the study teamusing the number of minutes trained per day registered bythe program and provided by Rosetta Stone Inc. Third, wewill ask participants to record their training minutes on ahomework calendar provided by the study team.Outcome measuresAll participants in the current study will attend threemeasurement sessions at VGH: baseline, trial completion,and 1-year follow-up. Each visit to VGH will be up to 3 hin duration. In addition, if interested and eligible, a subsetof participants will attend two MRI scans (1.5 h perappointment) at UBC over the duration of the study (i.e.,at baseline and trial completion). Our trained researchstaff, which will assess enrolled participants at baseline,trial completion, and 1-year follow-up, will be blinded togroup allocation.Descriptive measuresAt baseline, general health, demographics, socioeco-nomic status, and education will be ascertained by aquestionnaire. Descriptive measures such as age inyears, standing and sitting height in centimetres, massin kilograms, and waist and hip circumference incentimetres will be obtained.ten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 5 of 11Global cognitive function Global cognitive functionwill be measured using both the Mini-Mental StateExamination (MMSE) and the Montreal Cognitive As-sessment (MoCA). The MoCA is a valid and reliablemeasure [29], and assesses eight cognitive domains suchas attention, concentration, executive functions, mem-ory, language and visuoconstructional skills. The totalpossible score is 30 points; a score of less than 26 pointsindicates MCI. The MoCA has with a score of 26 a 90%sensitivity to for detecting MCI [29].General health, falls history, and socioeconomic sta-tus We will administer questionnaires to obtain infor-mation about their level of education, employmentstatus and general health information (e.g., medication,fall and fracture history).Instrumental activities of daily living scale The Law-ton and Brody Instrumental Activities of Daily Living(IADL) [27] Questionnaire will be administered to assessthe participants’ ability to perform tasks of daily livingsuch as housekeeping, laundry, transportation, and man-agement of finances. The questionnaire looks at eightdifferent types of daily activities, and therefore it has amaximum achievable score of eight.Co-morbidity To assess the presence of any medicalconditions, the functional comorbidity index (FCI) [36]will be used. In this scale, which contains 18 conditions,participants will indicate whether the condition ispresent currently, in the past or not at all.Cognitive activity over lifetime At baseline, we will ad-minister a questionnaire focusing on lifetime stimulationof cognitively stimulating activities in a subset of partici-pants [37]. This questionnaire measures the involvementin cognitively stimulating activities during their lifetime,namely at age 6, 12, 18, 40, and at their present age.Cognitively stimulating activities include visits to thelibrary, read a newspaper, read a book, write a letter,and play a game. The involvement on all 25 itemsincluded will be rated on a 5-point scale, with 1)Once per year or less; 2) Several times per year; 3)Several times per month; 4) Several times per week;or 5) Every day or nearly every day.Primary outcome: Episodic memoryOur primary cognitive outcome will be (verbal) episodicmemory as measured by the Rey Auditory Verbal Learn-ing Test (RAVLT) [38]. The RAVLT is a valid, reliable,and widely used instrument of (verbal) episodic memory.Notably, a 2013 prospective study showed that among acombination of neuropsychological, neuroimaging, andcerebrospinal fluid markers, RAVLT performance wasthe best individual predictor of MCI conversion to de-mentia [39]. For the RAVLT, a list of 15 common words(List A) will be read to participants five times. Immedi-ately after each time, they will be asked to recall as manywords as possible. After the fifth trial, an interference list(List B) will be presented, after which participants willbe asked to spontaneously recall the words form the ori-ginal list (List A). Then, participants will be asked tospontaneously recall the original words (List A) after a20-min delay (i.e., long delay free recall), and finally, theywill be asked to circle words from the original list (ListA) in a paragraph of text containing thirty underlinedwords (i.e., words from the original list plus distractorwords). Scores will be calculated as the total number ofwords recalled: 1) across the five trials (total acquisition);2) after the interference list (recall after interference); 3)on the fifth trial minus after the interference (loss afterinterference); 4) at recognition (number of words cor-rectly identified from list A); and 5) after the 20-mindelay (long delay free recall – our primary RAVLT meas-ure of interest). We will focus on changes in memory(trial completion minus baseline) over the course of thestudy.Secondary outcomes measuresComprehensive neuropsychological battery (iPad)We will use the National Institute of Health (NIH) Tool-box Cognition Battery [40–42], a comprehensive neuro-psychological battery with normative values. Thecognitive battery of this toolbox includes tests thatmeasure: 1) Executive Functions: Executive functions isthe capacity to plan, organize, and monitor the execu-tion of behaviours that are strategically directed in agoal-oriented manner. The NIH Toolbox measures twocomponents of executive functions: 1) inhibition and 2)set shifting. The NIH Toolbox focuses on the inhibitionof automatic response tendencies that may interfere withachieving a goal. Set shifting is considered the capacityfor switching among multiple aspects of a strategy ortask. Inhibition will be measured with the NIH ToolboxDimensional Change Card Sort Test. Set shifting will bemeasured with the NIH Toolbox Flanker InhibitoryControl and Attention Test; 2) Attention: Attention re-fers to the allocation of one’s limited capacities to dealwith an abundance of environmental stimulation. It isthe foundation for all other types of mental processes.Attention will be measured with the NIH ToolboxFlanker Inhibitory Control and Attention Test; 3) Epi-sodic Memory: Episodic memory refers to cognitive pro-cesses involved in the acquisition, storage and retrievalof new information. It involves conscious recollection ofinformation learned within context. Episodic memorycan be verbal (i.e., remembering a conversation or list ofgrocery items) or nonverbal (i.e., imagining a picture oneten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 6 of 11saw a week ago). Episodic memory will be assessed withthe NIH Toolbox Picture Sequence Memory Test. As asupplemental measure we will use the NIH ToolboxAuditory Verbal Learning Test (Rey); 4) Language: Lan-guage refers to a set of mental processes that translateinto symbols (words, gestures) that can be shared amongindividuals for purposes of communication. The NIHToolbox focuses on two aspects of language: 1) Vocabu-lary knowledge, which will be measured with the NIHToolbox Picture Vocabulary Test, and 2) Oral readingskill, which will be assessed by the NIH Toolbox OralReading Recognition Test; 5) Processing Speed: Process-ing speed refers to either the amount of time it takes toprocess a set amount of information, or the amount ofinformation that can be processed within a certain unitof time. It is a measure that reflects mental efficiencyand is central for many cognitive functions and domains.Processing Speed will be measured by the NIH ToolboxPattern Comparison Processing Speed Test; and 6)Working Memory: Working Memory refers to a limited-capacity storage buffer that becomes overloaded whenthe amount of information exceeds capacity. WorkingMemory refers to the capacity of an individual toprocess information across a series of tasks, hold infor-mation in a short-term buffer, manipulate the informa-tion, and hold the products in the same short-termbuffer. Working Memory will be assessed with the NIHToolbox List Sorting Working Memory Test.Executive functions For executive functions, we will in-clude three executive cognitive processes based on thework of Miyake and colleagues [43] and frequency of in-clusion in clinical batteries [38]: 1) response inhibition,2) set shifting; and 3) working memory. Response inhib-ition involves deliberately inhibiting dominant, auto-matic, or prepotent responses. Set shifting requires oneto go back and forth between multiple tasks or mentalsets [43]. Working memory involves monitoring in-coming information for relevance to the task at handand then appropriately updating the informationalcontent by replacing old, no longer relevant informa-tion with new incoming information. We will assess:1) response inhibition using the Stroop Colour-WordTest [44], 2) set shifting using the Trail Making Test(Parts A & B) [45]; and 3) working memory using theDigit Symbol Substitution Test (DSST; 90 s) [46].Balance and mobility The Short Physical PerformanceBattery (SPPB) [47] will be used to capture domains ofstrength, gait speed and balance, by performing standingbalance, walking and sit-to-stand exercises. The SPPB isscored out of 4 points per component and has a max-imum score of 12. Low scores on the SPPB reflect poorperformance.Cardiovascular capacity The Six Minute Walk Test(6-MWT) [48] will be used to measure cardiovascularcapacity. This test asks participants to walk as far as theycan (meters) in six minutes (breaks allowed). Before andafter the walk, the participants’ blood pressure will bemeasured. The participants will be asked to rate theirwalk on the Borg Rating of Perceived Exertion [33]. Thescore on the 6-MWT is the distance (in meters) coveredduring six minutes.Physical activity level To obtain information abouttheir physical activity, the Physical Activity Scale for theElderly (PASE) [49, 50] will be administered. This 12-item questionnaire assesses the amount of time spentper day in the previous week on leisure activity time(light, moderate and strenuous activities), householdwork, and time spent volunteering.Magnetic resonance imaging Prior research has dem-onstrated that significant changes in brain volume canbe observed after 32 h of computer-based cognitivetraining over a span of 8 weeks among older adults withsubjective memory complaints [30] – a population verysimilar to ours. Thus, we will include neuroimaging out-comes in our proof-of-concept RCT. Our neuroimagingoutcomes will include: 1) hippocampal volume and cor-tical thickness as determined by structural MRI; and 2)functional connectivity as determined by resting statefunctional MRI and seed-based approach. If interestedand eligible, a subset of participants will be asked to doone MRI scan before and one after the completion ofthe 8-week training. Participants will be asked to cometo the UBC for 1.5 h each visit. The scanning protocolwill take approximately 50 min, and a series of anatom-ical scans will be performed in addition to a resting-statefunctional MRI scan.Acquired structural and functional neuroimaging datawill be analyzed using different pipelines. The Freesur-fer image analysis suite [51] will be used for structuraldata analysis. Freesurfer is developed at the MartinosCenter for Biomedical Imaging by Laboratory for Com-putational Neuroimaging (http://surfer.nmr.mgh.har-vard.edu/). Data processing will include skull-stripping[52], motion correction [53], Talairach transformation[54, 55], atlas registration [56] and brain parcellation[55, 57]. The data will be manually checked, and if ne-cessary corrected. Functional connectivity analysis willbe using resting-state functional MRI (rsfMRI) data toinvestigate the effect of CCT (alone and preceding a15-min walk) on functional connectivity. Resting-statefMRI data will be preprocessed using FSL (FMRIB’sSoftware Library). Data processing will include skull-stripping using Brain Extraction Tool (BET), motioncorrection using MCFLIRT, and spatial smoothing.ten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 7 of 11Data will be manually checked, and if necessary cor-rected. Model-free independent component analysis(ICA) will be performed using FSL-MELODIC to exam-ine whole-brain connectivity patterns, and with select-ing independent resting-state components, we will lookat between group differences. Seed-based functionalconnectivity analysis (SBA) will be performed to look atthe correlations between regions of interest within andbetween networks. Connectivity maps will be created toshow connections with the seed region (i.e., region ofinterest).Participant timelineEligible participants will attend a 1-hour informationsession at either the UBC or at VGH. During this one-hour information session, the study coordinator willgive a short presentation that provides the potentialparticipants with important details of the study. Inaddition, the potential participants will receive a copyof the consent form during this visit. Once writtenconsent is obtained, a research assistant will schedulea baseline assessment. After completion of their base-line assessment, participants will be randomized intoone of 3 training groups (i.e., FBT, Ex-FBT, or BAT).Following the 8-week intervention, participants willattend the final assessment session(s). For a completetimeline, see Fig. 2.Sample size and randomizationThe required sample size for this study is calculatedbased on changes in the RAVLT (retention score). Spe-cifically, we predict a mean change of 0.31 for the FBTgroup, a mean change of 0.40 for the Ex-FBT group, anda mean change of −0.31 for the BAT group. We madethese estimates based on the work of Diamond and col-leagues [58]. With a pooled standard deviation of 1.1,and alpha of 0.05, we will need 36 participants for apower of 0.80. To accommodate for a 10% drop-out rate,our total sample size comes to 120 participants (i.e., 40FBT, 40 Ex-FBT, and 40 BAT).Participants will be randomly allocated (1:1:1) toFBT, Ex-FBT, or BAT. The randomization sequencewill be generated by an independent member of theteam using computer software (www.randomization.-com). Blocked randomization will be used, with ablock size of 12. The group allocation will be con-cealed for the study coordinator. After enrolment,performed by a research assistant, and completion ofthe baseline assessment, the study coordinator willsend a list of participant identification numbers tothe independent member responsible for therandomization. This independent member will providethe study coordinator with the group assignment forthe enrolled participants. After completion of baselineassessment at VGH, the participants will be informedof their group assignment. Outcome assessors will beblinded after treatment allocation.Adverse events monitoringAdverse events will be monitored using adverse eventforms. All adverse events will be discussed with theprincipal investigator and the study team to seewhether any adaptations to the protocol or programshould be made as a result of the adverse event andto insure safety for all participants.Recruitment: Telephone screen, followed by an information session (consent form provided) or phone call (consent per mail) Follow-up phone call: Enrollment Baseline Assessment  Cognitive, physical MRI (optional) Fit Brains Training (FBT) 8-week intervention Exercise and Fit Brains Training  (Ex-FBT) 8-week intervention Balanced and Toned (BAT) 8-week intervention Trial Completion Assessment  Cognitive, physical MRI (optional) 1-Year Follow-up Assessment Cognitive, physical Fig. 2 Participant timelineten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 8 of 11Data managementData will be entered ongoing over the study period. Datawill be securely stored in a locked cabinet and in a se-cured online database. Random data checks will be per-formed to promote data quality.Statistical analysisEffects of CCTThe primary and secondary outcomes will be analyzedusing an identical analytic model, which will follow theintention-to-treat principle, such that all randomizedparticipants will be included to estimate treatment ef-fects irrespective of deviations from treatment protocol(e.g., loss to follow-up, non-compliance). This will bedone using linear mixed models using maximum likeli-hood estimation. The model will include random inter-cepts, and fixed effects of time (baseline, trialcompletion), intervention assignment (FBT, Ex-FBT,BAT), and their interaction. Baseline MoCA score andage will also be included as fixed effect covariates. Treat-ment effects will be indicated by a statistically significanttreatment by time interaction. Two planned simple con-trasts will be performed to assess differences in changesin the primary and secondary outcomes between: 1) theFBT group and the BAT group; and 2) the ex-FBT groupand the BAT group. A secondary planned contrast willdetermine whether FBT and ex-FBT will differ inchanges in the primary and secondary outcomes overtime. To explore maintenance of treatment effects, wewill perform repeated measures with linear mixedmodels using maximum likelihood estimation. Themodels will include random intercepts, and fixed effectsof time (baseline, trial completion, 1-year follow up),intervention assignment, and their interaction. BaselineMoCA score and age will also be included as fixed effectcovariates.Follow-up sensitivity analyses will restrict the studysample to individuals with valid data at all three timepoints (baseline, trial completion, and 1-year follow-up).The same linear mixed models describe above will beemployed to determine whether inferences will be similarfor the intention-to-treat and complete-case studysamples.Baseline cognitive status as a moderatorTo determine whether treatment effects are similarfor individuals identified as having MCI, we will addMCI status as an additional fixed effect in the linearmixed models described above. Moderation will be in-dicated by a statistically significant MCI status bytreatment by time interaction. In the presence ofmoderation, the planned contrasts described abovewill be re-computed after stratifying by MCI status.This will identify how MCI status moderated theeffects of treatment on the outcome of interest.DiscussionCurrently there are a limited number of high qualitystudies investigating the efficacy of CCT programs;therefore findings from this randomized controlledtrial will contribute to the existing research. Inaddition, a gap currently exists in literature investigat-ing the effect of these programs in an older adultpopulation with MCI. If this research demonstratesbenefits of an 8-week CCT intervention, both short-term (i.e., trial completion) and long-term (1-yearfollow-up), CCT might serve as an easy accessiblestrategy to combat cognitive decline in healthy olderadults and as a potential effective way to alter thetrajectory of cognitive decline in older adults withMCI.Neural mechanismsEvidence regarding the underlying neural mechanisms ofCCT in both healthy older adults and older adults withMCI is limited. If the current study provides evidence ofchanges in neural structure or neural activity (e.g., func-tional connectivity), it would be a considerable contribu-tion to research in this field.Abbreviations6-MWT: 6-Minute Walk Test; BAT: Balanced and Toned; BET: Brain ExtractionTool; CCT: Computerized Cognitive Training; CONSORT: ConsolidatedStandard of Reporting Trials; Ex-FBT: Exercise plus Fit Brains Training; FBT: FitBrains Training; FCI: Functional Comorbidity Index; FSL: FMRIB’s SoftwareLibrary; IADL: Instrumental Activities of Daily Living; ICA: IndependentComponent Analysis; MCI: Mild Cognitive Impairment; MMSE: Mini-MentalState Examination; MoCA: Montreal Cognitive Assessment; MRI: MagneticResonance Imaging; NIH: National Institute of Health; PASE: Physical ActivityScale for the Elderly; RAVLT: Rey Auditory Verbal Learning Test;RCT: Randomized Controlled Trial; rsfMRI: resting-state functional MagneticResonance Imaging; SBA: Seed Based Analysis; SPIRIT: Standard ProtocolItems Recommendations for Interventional Trials; SPPB: Short PhysicalPerformance Battery; UBC: University of British Columbia; VGH: VancouverGeneral HospitalFundingThis work will be supported by the Jack Brown and Family AlzheimerResearch Foundation Society to TLA and by Rosetta Stone Inc. Specifically,Rosetta Stone Inc. will provide funding for the training and neuroimaging of26 of the total 120 participants. For the training, Rosetta Stone Inc. willprovide access to the mobile Fit Brains® platform and support during thecourse of the study. “Fit Brains®” is a registered trademark of Rosetta Stone,Ltd. All rights reserved.Availability of data and materialsData sharing: no additional data available.Authors’ contributionsTLA, JRB, and LTB were involved in protocol development. LTB wrote thefirst draft of the manuscript. TLA, JRB, and RAC wrote portions of themanuscript and critically reviewed the manuscript. All authors (TLA, JRB, RAC,and LTB) have read and approved the manuscript.ten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 9 of 11Authors’ informationLTB is a Mitacs Accelerate Doctoral Trainee. TLA is a Canada Research Chairin Physical Activity, Mobility and Cognitive Neuroscience. JRB is a CanadianInstitutes of Health Research and Michael Smith Foundation for HealthResearch Postdoctoral Fellow.Ethics approval and consent to participateFor this study, ethical approval has been obtained from UBC CREB (H14–02438,December 3 2014) and from the Vancouver Coastal Health Research Institute(V14–02438, July 13 2015). Informed consent from all participants will beobtained prior to study commencement.Consent for publicationData sharing is not applicable to this article as no datasets were generatedor analysed during the current study.Competing interestsThe authors declare that they have no competing interests. The contractbetween the university and industry partner (i.e., Rosetta Stone Inc.) statesthat the researchers are not restricted by Rosetta Stone Inc. in any way topublish the outcomes of this RCT.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Aging, Mobility, and Cognitive Neuroscience Laboratory, Department ofPhysical Therapy, Djavad Mowafaghian Centre for Brain Health, University ofBritish Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.2Aging, Mobility, and Cognitive Neuroscience Laboratory, Department ofPhysical Therapy, Djavad Mowafaghian Centre for Brain Health, Centre forHip Health and Mobility, University of British Columbia, 2215 Wesbrook Mall,Vancouver, BC V6T 1Z3, Canada.Received: 22 August 2017 Accepted: 24 January 2018References1. 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Diamond K, Mowszowski L, Cockayne N, Norrie L, Paradise M, Hermens DF,Lewis SJ, Hickie IB, Naismith SL: randomized controlled trial of a healthybrain ageing cognitive training program: effects on memory, mood, andsleep. J Alzheimers Dis 2015, 44(4):1181–1191.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:ten Brinke et al. BMC Geriatrics  (2018) 18:31 Page 11 of 11

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