CLINICAL TRIAL published: 29 October 2020 doi: 10.3389/fnagi.2020.590168 Effects of Aerobic Exercise, Cognitive and Combined Training on Cognition in Physically Inactive Healthy Late-Middle-Aged Adults: The Projecte Moviment Randomized Controlled Trial Francesca Roig-Coll 1† , Alba Castells-Sánchez 1,2† , Noemí Lamonja-Vicente 1,2,3 , Pere Torán-Monserrat 4 , Guillem Pera 4 , Alberto García-Molina 5 , José Maria Tormos 5 , Pilar Montero-Alía 4 , Maria Teresa Alzamora 4 , Rosalía Dacosta-Aguayo 1 , Juan José Soriano-Raya 1,2 , Cynthia Cáceres 6 , Kirk I. Erickson 7,8 and Maria Mataró 1,2,3* 1 Department of Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain, 2 Institut Edited by: de Neurociències, University of Barcelona, Barcelona, Spain, 3 Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Tamas Fulop, Esplugues de Llobregat, Spain, 4 Unitat de Suport a la Recerca Metropolitana Nord, Fundació Institut Universitari per a la Université de Sherbrooke, Canada recerca a l’Atenció Primària de Salut Jordi Gol i Gurina, Mataró, Spain, 5 Institut Guttmann, Institut Universitari Reviewed by: de Neurorehabilitació, Universitat Autònoma de Barcelona, Barcelona, Spain, 6 Department of Neurosciences, Hospital Talitha Best, Universitari Germans Trias i Pujol, Barcelona, Spain, 7 Department of Psychology, University of Pittsburgh, Pittsburgh, PA, Central Queensland University, United States, 8 Discipline of Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Australia Perth, WA, Australia David W. Russ, University of South Florida, United States Background: Lifestyle interventions are promising strategies to promote cognitive *Correspondence: health in aging. Projecte Moviment examines if aerobic exercise (AE), computerized Maria Mataró cognitive training (CCT), and their combination (COMB) improves cognition, mmataro@ub.edu † These psychological health, and physical status compared to a control group. We assessed authors have contributed equally to this work the moderating role of age and sex and the mediating effects of cardiorespiratory fitness (CRF), physical activity (PA), and psychological health on intervention-related Received: 31 July 2020 Accepted: 07 October 2020 cognitive benefits. Published: 29 October 2020 Methods: This was a 12-week multi-domain, single-blind, proof-of-concept Citation: randomized controlled trial (RCT). 96 healthy adults aged 50–70 years were assigned Roig-Coll F, Castells-Sánchez A, Lamonja-Vicente N, to AE, CCT, COMB, and a wait-list control group. The per protocol sample, which Torán-Monserrat P, Pera G, completed the intervention with a level of adherence > 80%, consisted of 82 García-Molina A, Tormos JM, Montero-Alía P, Alzamora MT, participants (62% female; age = 58.38 ± 5.47). We assessed cognition, psychological Dacosta-Aguayo R, Soriano-Raya JJ, health, CRF, and energy expenditure in PA at baseline and after the intervention. Cáceres C, Erickson KI and Mataró M We regressed change in each outcome on the treatment variables, baseline score, (2020) Effects of Aerobic Exercise, Cognitive and Combined Training on sex, age, and education. We used PROCESS Macro to perform the mediation and Cognition in Physically Inactive moderation analyses. Healthy Late-Middle-Aged Adults: The Projecte Moviment Randomized Results: AE benefited Working Memory (SMD = 0.29, p = 0.037) and Attention Controlled Trial. Front. Aging Neurosci. 12:590168. (SMD = 0.33, p = 0.028) including the Attention-Speed (SMD = 0.31, p = 0.042) domain, doi: 10.3389/fnagi.2020.590168 compared to Control. COMB improved Attention (SMD = 0.30, p = 0.043), Speed Frontiers in Aging Neuroscience | www.frontiersin.org 1 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT (SMD = 0.30, p = 0.044), and the Attention-Speed (SMD = 0.30, p = 0.041) domain. CTT group did not show any cognitive change compared to Control. Sportive PA (S-PA) and CRF increased in AE and COMB. Age and sex did not moderate intervention-related cognitive benefits. Change in S-PA, but not in CRF, significantly mediated improvements on Attention-Speed in AE. Conclusion: A 12-week AE program improved Executive Function and Attention- Speed in healthy late-middle-aged adults. Combining it with CCT did not provide further benefits. Our results add support to the clinical relevance of even short-term AE as an intervention to enhance cognition and highlight the mediating role of change in S-PA in these benefits. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03123900. Keywords: neuropsychology, lifestyle interventions, computerized cognitive training, physical activity (exercise), aging INTRODUCTION cardiorespiratory fitness (CRF) (Schroeder et al., 2019), which has been linked to brain and cognitive health. However, one Luckily, most of us are going to age. remaining question is the mediating role of psychological health Dementia and late-life normal cognitive impairment is and CRF in the cognitive benefits related to AE interventions related to loss of function and quality of life (Murman, 2015; (Etnier et al., 2006; Young et al., 2015). Christiansen et al., 2019). Therefore, it is a global responsibility Cognitive training has also been associated with cognitive to promote healthy aging. Healthy aging, conceptualized as “the gains in healthy older adults (Ball et al., 2002). Systematic process of developing and maintaining the functional ability that reviews and meta-analysis reported that computerized cognitive enables well-being in older age” (World Health Organization training (CCT) interventions are an effective tool to improve [WHO], 2015), has become a social, economic, and scientific memory, processing speed, and visual spatial ability (Lampit challenge. Specific lifestyle behaviors have been associated with et al., 2014; Shao et al., 2015). CCT is less efficacious for better general health (Peel et al., 2005), cognition (Klimova attention and executive function (Lampit et al., 2014; Shao et al., 2017), and well-being (Prendergast et al., 2016) not et al., 2015). However, one of the main challenges is to assess only in Alzheimer’s disease patients but also in healthy older the degree of transfer between the trained task and untrained adults. Evidence shows that exercise and cognitive training may tasks (Nguyen et al., 2019). FITT parameters of CCT might maintain or improve cognition (Kane et al., 2017). be another issue related to inconsistencies in the field. For In a meta-analysis in 2003, Colcombe and Kramer reported example, Lampit et al. (2014) found no significant effects when that aerobic exercise (AE) interventions improved cognitive sessions lasted less than 30 min and frequency was more than performance especially for executive function in healthy older three sessions of training per week, whereas Chiu et al. (2017) adults. Current systematic reviews have replicated those results showed greater effectiveness with =3 sessions per week and =24 reporting modest effect sizes of AE interventions on executive total training sessions. As suggested in the literature (Nguyen function, attention, processing speed, and memory (Smith et al., et al., 2019), individual difference variables such as age could 2010; Barha et al., 2017; Northey et al., 2018). However, also moderate CCT-related cognitive changes. Other studies other reviews have questioned the literature and findings have also studied the effect of CCT to improve psychological of AE interventions on cognition (Young et al., 2015) and and self-perceived performance in daily activities. For example, refer to significant variation in intervention parameters such the ACTIVE study found less decline in quality of life for as frequency, intensity, time, and type (FITT) to explain the processing-speed training group. However, memory or heterogeneity across the field. Gomes-Osman et al. (2018) reasoning CCT groups did not show any significant change reviewed the relationship between these parameters and positive (Wolinsky et al., 2006). Therefore, more research is warranted changes in cognition and concluded that at least 52 h of exercise to better understand the CCT effect on psychological health and is required to observe beneficial effects. It is also known that cognitive outcomes. the cognitive effects of AE may be moderated by individual Current evidence suggests that the combination of AE and factors such as age and sex (Colcombe and Kramer, 2003; Barha CCT interventions (COMB) promotes healthy cognitive aging et al., 2017) that are sometimes understudied in randomized in older adults (Bamidis et al., 2014). Evidence from RCT controlled trials (RCTs). Other studies have focused on the revealed positive effects from combined training on executive effects of AE interventions on psychological health and daily functions (Anderson-Hanley et al., 2012), processing speed (León activities. Stillman et al. (2016) concluded that increased physical et al., 2015), memory (Fabre et al., 2002), and general cognitive activity (PA) is associated with improved sleep quality and mood. function (Oswald et al., 2006). However, results differ across Moreover, AE promotes cardiovascular health by increasing trials depending on the type of comparative group and FITT Frontiers in Aging Neuroscience | www.frontiersin.org 2 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT parameters of the intervention (Fabre et al., 2002; Oswald et al., et al., 2015)]; (iv) were competent in Catalan or Spanish; and (v) 2006; León et al., 2015). A current hypothesis in reviews is had adequate visual, auditory, and fine motor skills. Participants that the combination of AE and CCT may be more efficient were excluded if they: (i) participated in any cognitive training than singular interventions (Kraft, 2012; Lauenroth et al., 2016). program during last 6 months > 2 h/week; (ii) had dementia For example, Ten Brinke et al. (2020) concluded that the or mild cognitive impairment diagnosis; (iii) had neurological combination of 15 min of brisk walking before CCT for 8 weeks disorder diagnosis; (iv) had psychiatric diagnosis; (v) scored > 9 provided greater benefits for executive functions, specifically in the Geriatric Depression Scale, GDS-15 (Martínez et al., 2002); for set shifting. However, more evidence is needed to draw (vi) consumed psychopharmacological drugs; (vii) had history of firm conclusions. drug abuse or alcoholism; (viii) had history of chemotherapy; and Projecte Moviment aims to study the effect of AE, CCT, (iv) had any contraindication to magnetic resonance imaging. or COMB on cognition and psychological status in healthy Extended details are included in Castells-Sánchez et al. (2019). physically inactive older adults (Castells-Sánchez et al., 2019). In this paper, we first addressed our primary objective: to Randomization test if AE, CCT, and COMB training—5 times per week Randomization was performed after the baseline assessments. for 3 months—improves cognitive performance compared to The allocation sequence was generated by a statistician and it a control group. Second, we examined whether AE, CCT, consisted of a random combination of demographic variables and COMB interventions positively impact psychological and that allowed us to balance groups accounting for sex, age, and subjective daily functioning compared to a control group and if years of education. Participants were randomly assigned to each AE and COMB training increase CRF and daily PA compared to condition: AE, CCT, COMB, and control group. The intervention the control condition. Finally, we assessed the moderating role team was responsible for the allocation and the sequence and the of age and sex and the mediating effects of significant changes in group assignment remained blind for the assessors. PA, CRF, and psychological health in the relationship between the intervention and cognitive benefits. Interventions The protocol for each intervention condition is explained in more detail elsewhere (Castells-Sánchez et al., 2019). Interventions METHODS were applied as individual programs. Study Design Aerobic Exercise (AE) Projecte Moviment is a multi-center, single-blind, proof-of- Participants randomized to AE group had to walk briskly, concept RCT that consisted of four parallel groups undergoing increasing intensity and duration progressively. The first week AE, CCT, COMB interventions and a control group during they had to walk 30 min per day, 5 days per week, up to 9–10 12 weeks with assessments at baseline and trial completion. The on the Borg Rating of Perceived Exertion Scale (BRPES; Borg, study took place between November 2015 and April 2018. It was 1982) perceived as light intensity; during the second week, the developed by the University of Barcelona in collaboration with duration was increased to 45 min and the intensity 9–10 and Institut Universitari d’Investigació en Atenció Primària Jordi frequency (5 days per week) were maintained; the following Gol, Hospital Germans Trias i Pujol, and Institut Guttmann, 10 weeks they maintained the duration (45 min) and frequency and approved by the responsible ethics committees following the (5 days per week) and increased the intensity up to 12–14 on Declaration of Helsinki. BRPES perceived as moderate-high effort. The protocol has been published (Castells-Sánchez et al., Computerized Cognitive Intervention (CCT) 2019) and registered in ClinicalTrials.gov (NCT031123900). Participants randomized to CCT group performed a We synthesize the procedures adhering to the Consolidated multidomain computerized home-based cognitive training Standards of Reporting Trials guidelines. using the Gutmann Neuropersonal Trainer R (GNPT , Spain) R (Solana et al., 2014, 2015) in sessions of 45 min, 5 days per Participants week for 12 weeks. Cognitive tasks targeted executive function, Participants were recruited from the Barcelona metropolitan area visual and verbal memory, and sustained, divided, and selective using lists of patients of general physicians, volunteers from attention. The GNPT platform calculated an individual profile previous studies, advertisements and oral presentations in health and adjusted the demand of the tasks depending on the care centers, other local community centers, and local media participant level in each domain. (newspapers, radio, and TV). Individuals were informed and screened over the phone and in an on-site personal session. Combined Training (COMB) If eligible, participants gave written informed consent prior to Participants randomized to COMB group engaged in AE and study commencement. CCT following the same previously described instructions. AE Participants were eligible if they: (i) were aged between 50 and CCT were performed separately in single continuous bouts and 70 years; (ii) performed ≤ 120 min/week of PA during last of 45 min for each intervention. They did not have any restriction 6 months; (iii) had preserved general cognitive function [Mini- about the order of the interventions during the day or time- Mental State Examination, MMSE ≥ 24 (Blesa et al., 2001), point at which they had to be applied. Therefore, the intervention Montreal Cognitive Assessment 5 min, MoCA 5 min ≥ 6 (Wong consisted of 90 min of activity, 5 days per week, for 12 weeks. Frontiers in Aging Neuroscience | www.frontiersin.org 3 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT Control Group Secondary Outcomes Participants randomized to the control group were on the wait Psychological health and daily activity list for 12 weeks and were asked to keep their regular lifestyle. We assessed depressive symptoms (GDS-15; Martínez et al., 2002), emotional status (Modified Version of Visual Analog Mood Scale, VAMS; Stern et al., 1997 and Short Informant Compliance and Adverse Events Questionnaire in Routine Evaluation-Outcome Measure, CORE- Participants were monitored during the intervention: they OM; Trujillo et al., 2016), sleep quality (Pittsburgh Sleep received phone calls every 2 weeks, a mid-point visit after Quality Index, PSQI; Rico and Fernández, 1997), and subjective 6 weeks of the intervention, and a final visit where they performance in daily activities (Short Informant Questionnaire were asked about the level of compliance, interfering events, on Cognitive Decline in the Elderly, S-IQCODE; Morales- satisfaction, motivation, and level of difficulty. They registered Gónzalez et al., 1992). Change (post-test minus pretest) was the frequency of the training and the adverse events occurring calculated from raw data and used as a secondary outcome. during the intervention in a follow-up diary. The AE group was asked to record intensity in which they performed the exercise Physical activity based on BRPES values. CCT compliance was registered in the Minnesota Leisure Time PA Questionnaire (VREM; Ruiz et al., software platform too. We ensured that all sources of information 2012) was used to evaluate PA of participants. They reported about compliance were coherent and allowed us to obtain the frequency and duration of the following activities during the level of adherence. last month: sportive walking, sport/dancing, gardening, climbing stairs, shopping walking, and cleaning house. We transformed hours per month into units of metabolic equivalent tasks Outcomes (METs) estimating the energy expenditure for each category. Primary Outcomes We calculated Sportive PA (S-PA) and Non-Sportive PA (NS- Cognitive performance PA) by adding up the METs spent in different activities and An extensive neuropsychological battery was designed by grouping them into the following categories: S-PA—sportive Projecte Moviment including standard tests selected for their walking and sport/dancing activities—and NS-PA—gardening, psychometric qualities and high relevance in the area of study. climbing stairs, shopping walking, and cleaning house. Change The neuropsychological battery was administered in at baseline (post-test minus pretest) NS-PA and S-PA was used as a and again within 2 weeks after the completion of the intervention. secondary outcome. It was applied before the CRF test or any type of exercise in order to control for the effect of acute exercise on cognitive Cardiorespiratory fitness performance. Tests were performed in a single session of The Rockport 1-Mile Test was administered to assess the CRF. 60–90 min and in the same order for all the participants Participants walked 1 mile on a treadmill (Technogym , Italy)R These tests provided measures of multiple cognitive functions adjusting their speed in order to be as fast as possible without grouped following a theoretical-driven approach (Strauss and running. We collected average speed during the test, time to Spreen, 1998; Lezak et al., 2012): Flexibility (Trail Making complete the mile, and heart rate once they finished. Maximal Test B-A time; Tombaugh, 2004), Fluency (letter and category aerobic capacity (VO2 max) was estimated with the standard fluency; Peña-Casanova et al., 2009), Inhibition (interference- equation developed by Kline et al. (1987). Change (post-test Stroop Test; Golden, 2001), Working Memory (backward-WAIS- minus pretest) in CRF was used as a secondary outcome. III; Wechsler, 2001), Visuospatial Function (copy accuracy- Rey Osterrieth Complex Figure; Rey, 2009), Language (Boston Naming Test-15; Goodglass et al., 2001), Attention (forward Statistical Analysis span, digit symbol coding, and symbol search WAIS-III; Statistical procedures were conducted with IBM SPSS Statistics Wechsler, 2001), Speed (Trail Making Test-A; Tombaugh, 2004; 24. The distribution of raw scores was examined in order copy time-Rey Osterrieth Complex Figure; Rey, 2009), Visual to assess data quality (i.e., outliers, skewness). Change (post- Memory (memory accuracy-Rey Osterrieth Complex Figure; test minus pretest) in primary and secondary outcomes was Rey, 2009), and Verbal Memory (total learning and recall- obtained as described above. Baseline comparisons and cross- II Rey Auditory Verbal Learning Test; Schmidt, 1996). Six time partial correlations were performed in order to identify general domains were designed: (1) Executive Function, (2) potential confounds. Visuospatial Function, (3) Language, (4) Attention-Speed, (5) In order to compare each intervention group to the control Memory, and (6) Global Cognitive Function. Extended details are group, we performed linear regression models in the intention- in Supplementary Table 1. to-treat (ITT) and per-protocol (PP) sample using a dummy The primary outcome was change in cognitive performance codification for the treatment variable. We regressed change in the assessed cognitive domains. We calculated change from in each cognitive outcome on the baseline outcome score, sex, raw data (post-test minus pretest), we obtained z-sample scores age, and years of education and the treatment variables (AE for each outcome, and, finally, we averaged z-scores for each vs controls, CCT vs controls, and COMB vs controls) for both cognitive domain and created a global cognitive function score ITT and PP samples. Linear regression models for changes in as a sum of all domains. secondary outcomes were executed only in the PP sample. Frontiers in Aging Neuroscience | www.frontiersin.org 4 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT We used the PROCESS Macro for SPSS (Hayes, 2017) to COMB group improved Attention (SMD = 0.30, p = 0.043) and analyze the moderating effect of individual difference variables— Speed (SMD = 0.30, p = 0.044) and the domain of Attention- age, sex, and years of education—when the intervention-related Speed (SMD = 0.30, p = 0.041) compared with the Control changes in cognition were significant. group. However, there were not significant changes in cognitive We applied mediation analyses using the PROCESS Macro outcomes when comparing CTT to the Control group. Results when the intervention was related to a significant cognitive showed greater improvements on Flexibility (SMD = −0.33, change compared to the control group. We analyzed the p = 0.016) in the Control group compared with AE. These mediation effect of intervention-related significant changes analyses revealed similar but less significant results in the ITT in secondary outcomes for those primary outcomes where sample (see Supplementary Table 6). the intervention was significant compared to controls. We introduced a treatment variable (condition vs control) as the Intervention-Related Changes in independent variable, change in cognition for those functions Secondary Outcomes that showed significant intervention-related changes as the Contrasts between each intervention and control group for dependent variable, and change in secondary outcomes as secondary outcomes are reported in Table 3. The results for mediators controlling for baseline performance score, age, sex, psychological health outcomes and daily activity showed no and years of education. These analyses were computed with bias- significant improvements in AE and COMB group compared to corrected bootstrap 95% confidence intervals (CIs) based on 5000 Control for any outcome. The CCT group showed significant bootstrap samples. Significance of mediation was indicated if the changes in PSQI (SMD = 0.30, p = 0.028) compared with CIs in Path AB did not overlap with 0 (Hayes, 2017). the Control group. Results related to PA showed significant improvements for S-PA in AE (B = 4515.46, 95% CI: 3611.44, 5419.49) and in COMB (B = 4214.04, 95% CI: 3214.97, 5213.12) RESULTS compared with the Control group. There was also a significant positive change for CRF in AE (B = 7.63, 95% CI: 3.93, 11.33) Participants and COMB (B = 4.75, 95% CI: 0.73, 8.78) groups. However, as we A total of 401 participants were screened by phone and 211 expected, the CCT group did not improve in PA levels or CRF. were interviewed in an on-site personal visit (Figure 1). Of the 109 participants who completed baseline assessments, 96 were Intervention-Related Potential randomized to the intervention. Only four individuals withdrew from the study for health-related reasons not related to the Moderators and Mediators intervention and for time commitment issues. The ITT sample We applied moderation analysis for those cognitive domains consisted of 92 participants who completed the intervention that significantly changed with the intervention. The results and the follow-up assessment (see Supplementary Table 2 showed that age and sex did not significantly moderate effects for demographic characteristics). Participants with a level of of the intervention on cognitive outcomes. Mediation analyses adherence > 80% were included in the PP sample (n = 82, 62% performed for those primary outcomes that experienced a female; age = 58.38 ± 5.47). There were not significant differences significant change showed that increases in S-PA significantly in demographic characteristics between ITT and PP analyses (see mediated the improvements for the domain of Attention-Speed Supplementary Table 3). The PP sample did not show notable in the AE group (Path C’: B = −0.01, SE = 0.23, p = 0.973; 95% differences between groups in demographics (Table 1) nor in CI: −0.46, 0.45; Path AB: B = 0.31, SE = 0.17, 95% CI: 0.02, cognitive, physical and psychological outcomes at baseline, except 0.68) and in the COMB group (Path C’: B = 0.02, SE = 0.23, in NS-PA and S-IQCODE (extended details in Supplementary p = 0.926; 95% CI: −0.43, 0.48; Path AB: B = 0.29, SE = 0.15, Tables 4.1–4.3). Compliance for the aerobic training was 90% 95% CI: 0.01, 0.62). For the other significant intervention-related for AE group and 90.7% for COMB group while for CCT was cognitive changes, when increases in S-PA were introduced in the 94.1% for CCT group and 91.1% for COMB group. There were model as a mediator, it diminished the association between AE- no significant differences in levels of compliance between groups. or COMB- and cognitive changes (direct effects), but indirect Levels of adherence were not related to sex or age neither. BRPES effects indicating mediation were not significant. Change in mean values per week for the AE and COMB are included in CRF did not significantly mediate the effect of interventions on Supplementary Table 5. cognition in any group. Intervention-Related Changes in Primary DISCUSSION Outcomes Contrasts between each intervention and control group for Projecte Moviment is a proof-of-concept RCT that contributes to cognitive outcomes are reported in Table 2. For the PP analysis, the understanding of the effects and mechanisms of AE, CCT, or results showed a significant improvement in AE compared COMB in healthy physically inactive adults aged 50–70 years. In to Control for Working Memory (SMD = 0.29, p = 0.037), this paper, we addressed our main objectives of the project. Attention (SMD = 0.33, p = 0.028), and for the domain of First, we hypothesized that the intervention would improve Attention-Speed (SMD = 0.31, p = 0.042). There was also a performance in the assessed cognitive domains compared to positive, but not significant, effect of this intervention on Fluency a control group. In the PP sample (≥80% adherence), a 12- (SMD = 0.29, p = 0.063) and Speed (SMD = 0.28, p = 0.068). The week 5-days per week AE program showed significant benefits Frontiers in Aging Neuroscience | www.frontiersin.org 5 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT FIGURE 1 | CONSORT flow diagram. TABLE 1 | Participants characteristics at baseline. Total Sample AE CCT COMB Control Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Group comparison n total/n females 82/51 25/13 23/16 19/14 15/8 X2 (3) = 3.20, p = 0.361 Age (years) 58.38 (5.47) 58.40 (5.12) 57.91 (5.31) 60.32 (5.54) 56.60 (5.97) H(3) = 3.53, p = 0.317 Years of education 12.52 (5.57) 12.44 (5.75) 12.04 (4.94) 12.37 (5.43) 13.60 (6.72) H(3) = 0.28, p = 0.963 Vocabulary subtest (WAIS-III) 44.14 (8.30) 43.92 (9.53) 44.26 (7.16) 44.53 (8.02) 43.80 (8.98) F(3,77) = 0.03, p = 0.993 Note: AE, aerobic exercise group; CCT, computerized cognitive training group; COMB, combined group; WAIS-III, Wechsler Adult Intelligence Scale. SD: standard deviation X2 = chi square; H = Kruskall–Wallis H test; F = Anova test. See Supplementary Tables 4.1–4.3 for more cognitive, physical, and psychological outcomes at baseline. on a measure of Executive Function (Working Memory) and et al., 2018). We observed these intervention-related changes Attention-Speed (Attention) compared to controls. There was after 45 h of AE, which is less than the 52 h required to detect also a tendency for positive effects on measures of Fluency cognitive change suggested in previous literature (Gomes-Osman and Speed. Our findings concur with previous systematically et al., 2018). One plausible explanation about the non-significant reviewed literature (Smith et al., 2010; Barha et al., 2017; Northey results for the Memory domain is that the timeframe of the Frontiers in Aging Neuroscience | www.frontiersin.org 6 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT TABLE 2 | Intervention-related changes in primary outcomes. AE vs Controls CCT vs Control COMB vs Control B (95%CI), B (95%CI), B (95%CI), SMD, p-value SMD, p-value SMD, p-value Executive function 0.16 (−0.14, 0.45), 0.03 (−0.27, 0.33), 0.15 (−0.16, 0.46), SMD = 0.17, p = 0.296 SMD = 0.03, p = 0.849 SMD = 0.16, p = 0.331 Flexibility −0.71 (−1.29, −0.13), −0.23 (−0.81, 0.36), −0.21 (−0.83, 0.42), SMD = −0.33, p = 0.016* SMD = −0.10, p = 0.445 SMD = −0.09, p = 0.509 Fluency 0.42 (−0.02, 0.87), 0.13 (−0.33, 0.58), 0.14 (−0.34, 0.61), SMD = 0.29, p = 0.063 SMD = 0.08, p = 0.588 SMD = 0.09, p = 0.571 Inhibition −0.10 (−0.69, 0.50), −0.17 (−0.78, 0.45) 0.20 (−0.44, 0.84), SMD = −0.04, p = 0.749 SMD = −0.08, p = 0.592 SMD = 0.09, p = 0.540 Working memory 0.63 (0.04, 1.23), 0.47 (−0.14, 1.09), 0.52 (−0.13, 1.17), SMD = 0.29, p = 0.037* SMD = 0.21, p = 0.127 SMD = 0.22, p = 0.113 Visuospatial function −0.31 (−0.89, 0.27), −0.08 (−0.67, 0.52), −0.14 (−0.77, 0.49), SMD = −0.14, p = 0.294 SMD = −0.04, p = 0.795 SMD = −0.06, p = 0.654 Language 0.11 (−0.43, 0.66), −0.19 (−0.74, 0.37), −0.28 (−0.87, 0.31), SMD = 0.05, p = 0.683 SMD = −0.09, p = 0.503 SMD = −0.12, p = 0.353 Attention-Speed 0.31 (0.01, 0.61), 0.16 (−0.15, 0.46), 0.34 (0.01, 0.66), SMD = 0.31, p = 0.042* SMD = 0.15, p = 0.316 SMD = 0.30, p = 0.041* Attention 0.46 (0.05, 0.88), 0.27 (−0.15, 0.70), 0.46 (0.01, 0.90), SMD = 0.33, p = 0.028* SMD = 0.19, p = 0.202 SMD = 0.30, p = 0.043* Speed 0.28 (−0.02, 0.59), 0.13 (−0.18, 0.43) 0.33 (0.01, 0.66), SMD = 0.28, p = 0.068 SMD = 0.12, p = 0.411 SMD = 0.30, p = 0.044* Memory 0.10 (−0.29, 0.49), −0.03 (−0.43, 0.37) −0.04 (−0.46, 0.38), SMD = 0.08, p = 0.602 SMD = −0.03, p = 0.869 SMD = −0.03, p = 0.852 Visual memory −0.40 (−1.01, 0.20), −0.16 (−0.78, 0.46), 0.32 (−0.33, 0.97) SMD = −0.19, p = 0.189 SMD = −0.07, p = 0.607 SMD = 0.14, p = 0.331 Verbal memory 0.39 (−0.11, 0.89), 0.07 (−0.45, 0.58), −0.21 (−0.75, 0.33), SMD = 0.22, p = 0.127 SMD = 0.04, p = 0.798 SMD = −0.11, p = 0.444 Global cognitive function 0.12 (−0.07, 0.32), 0.02 (−0.18, 0.21) 0.12 (−0.09, 0.32), SMD = −0.20, p = 0.218 SMD = 0.03, p = 0.872 SMD = 0.18, p = 0.259 Note: AE, aerobic exercise group; CCT, computerized cognitive training; COMB, combined group; SPA, sportive physical activity; NS-PA, non-sportive physical activity; Total-PA, total physical activity; CRF, cardiorespiratory fitness. SMD = β. Positive SMD values favor AE or CCT or COMB vs Control group. Covariates: sex, age, years of education, and baseline. *p < 0.05. trial and a late-middle-aged healthy sample could have lead to subjective measures (Nguyen et al., 2019), which suggest a a ceiling effect in the Memory measures. Another hypothesis is potential habituation effect rather than a cognitive enhancement. whether a higher frequency, greater intensity, dose, or length Another possible explanation for the non-significant results is of the activity is necessary to observe changes in Memory. that FITT parameters of the program, such as the frequency, It is also possible that changes in Executive Function and length, or type of activity, may need to be adjusted to observe Attention-Speed have different time-effects from those related to a significant effect on cognition. As it is suggested by Lampit Memory since they involve different brain areas. As previously et al. (2014), the design of the CCT program is a key factor: published (Weinstein et al., 2012; Hyodo et al., 2016), AE-related home-based interventions may not be an effective design and improvements in CRF are associated to greater changes in blood multidomain interventions tend to produce a small effect on flow and metabolic short-term changes and, therefore, greater cognition as there is not a specific function targeted. However, changes in the prefrontal cortex; area involved with executive another hypothesis that should be addressed in future studies is and attentional tasks. Interestingly, these findings support the that CCT-related changes could have just produced changes in debate about different molecular physiological mechanisms and the structure and function of the brain but not translated into patterns of AE effects. cognitive improvements (Lampit et al., 2015). Regarding CCT, we did not find a significant transfer In agreement with previous literature (León et al., 2015), a effect of CCT to any of the assessed cognitive domains 12-week 5-days per week COMB intervention showed significant (Lampit et al., 2014) despite the potential improvements in positive changes in Attention-Speed, including both subdomains, the trained tasks. These results are consistent with other trials Attention and Speed, compared to the control condition. that found improvements for the trained tasks but not a There was also a modest, but non-significant positive effect generalization of the effects to other untrained objective or on Working Memory. Our results did not demonstrate greater Frontiers in Aging Neuroscience | www.frontiersin.org 7 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT TABLE 3 | Intervention-related changes in secondary outcomes. AE vs Controls CCT vs Control COMB vs Control B (95%CI), B (95%CI), B (95%CI), SMD, p-value SMD, p-value SMD, p-value Phsycological health and daily activitya GDS 0.03 (−0.87, 0.93), 0.14 (−0.80, 1.08), −0.30 (−1.30, 0.70), SMD = 0.01, p = 0.940 SMD = 0.04, p = 0.769 SMD = −0.08, p = 0.554 VAMS −0.14 (−0.95, 0.67), −0.21 (−1.03, 0.60), −0.29 (−1.17, 0.58), SMD = −0.04, p = 0.731 SMD = −0.06, p = 0.605 SMD = −0.08, p = 0.508 S-IQCODE 0.66 (−0.83, 2.15), −1.27 (−2.79, 0.26), −0.77 (−2.50, 0.96), SMD = 0.12, p = 0.380 SMD = −0.22, p = 0.101 SMD = −0.13, p = 0.377 PSQI 0.74 (−0.56, 2.04), 1.49 (0.16, 2.82), 1.01 (−0.41, 2.43), SMD = 0.15, p = 0.261 SMD = 0.30, p = 0.028* SMD = 0.19, p = 0.161 Total CORE-OM −1.98 (−5.15, 1.18), −1.17 (−4.44, 2.11), −2.60 (−6.05, 0.86), SMD = −0.17, p = 0.216 SMD = −0.10, p = 0.480 SMD = −0.20, p = 0.139 Well-being CORE-OM −0.96 (−2.17, 0.26), −0.90 (−2.17, 0.36), −0.58 (−1.90, 0.75), SMD = −0.23, p = 0.123 SMD = −0.21, p = 0.158 SMD = −0.13, p = 0.389 Problems CORE-OM −1.25 (−2.84, 0.33), −0.40 (−2.02, 1.23), −1.11(−2.85, 0.62), SMD = −0.21, p = 0.120 SMD = −0.07, p = 0.628 SMD = −0.17, p = 0.205 Functioning CORE-OM 0.02 (−1.39, 1.42), 0.38 (−1.06, 1.82), −0.73 (−2.26, 0.80), SMD = 0.00, p = 0.980 SMD = 0.07, p = 0.600 SMD = −0.12, p = 0.344 Risk CORE-OM 0.10 (−0.18, 0.38), −0.14 (−0.42, 0.13), −0.07 (−0.37, 0.22), SMD = 0.09, p = 0.473 SMD = −0.13, p = 0.300 SMD = −0.06, p = 0.619 Physical activity and cardiorespiratory fitnessb S-PA 4515.46 (3611.44, 5419.49), 17.07 (−917.10, 951.24), 4214.04 (3214.97, 5213.12), SMD = 0.83, p < 001*** SMD = 0.00, p = 0.971 SMD = 0.71, p < 001*** NS-PA 1797.55 (−1316.63, 4911.72), 1947.28 (−1261.49, 5156.04), 1864.36 (−1524.03, 5252.74), SMD = 0.17, p = 0.254 SMD = 0.17, p = 0.230 SMD = 0.16, p = 0.276 CRF 7.63 (3.93, 11.33), 2.12 (−1.59, 5.82), 4.75 (0.73, 8.78), SMD = 0.49, p < 001*** SMD = 0.13, textitp = 0.258 SMD = 0.29, p = 0.021* Note: AE, aerobic exercise group; CCT, computerized cognitive training; COMB, combined group; S-PA, sportive physical activity; NS-PA, non-sportive physical activity; Total-PA, total physical activity; CRF, cardiorespiratory fitness; GDS, Geriatric Depression Scale; VAMS, Modified Version of Visual Analog Mood Scale; S-IQCODE, Short Informant Questionnaire on Cognitive Decline in the Elderly; PSQI, Pittsburg Sleep Quality Index; CORE-OM, Clinical Outcome in Routine Evaluation-Outcome Measure. SMD = β. a Negative SMD values favor AE or CCT or COMB vs Control group. b Positive SMD values favor AE or CCT or COMB vs Control group. Covariates: sex, age, years of education, and baseline. *p < 0.05. ***p < 0.001. cognitive benefits when combining AE and CCT as suggested controls except for poorer sleeping quality in CCT compared to elsewhere (Kraft, 2012; Bamidis et al., 2014; Lauenroth et al., the Control group. This result is coherent with previous literature 2016). Null results for General Cognitive Function (Fabre reporting that participants spending the most time in front of the et al., 2002), Executive Function, and Memory (Legault et al., screen showed more probability of sleep problems (Vallance et al., 2011) have also been reported for similar interventions. Our 2015). As expected, we found significant intervention-related results suggest that COMB-related changes are consistent with changes for S-PA only in the AE and COMB groups compared to the AE-related effects on cognition identified in this study, controls. Interestingly, and in accordance to other studies (Fabre specifically on Attention, Speed, and Working Memory. More et al., 2002; Schroeder et al., 2019), AE and COMB had positive research is needed to better understand how these two types effects on cardiovascular health since there was an increase in of interventions should be implemented in order to promote CRF compared to the control condition. The CCT group did not greater benefits. experience intervention-related changes in the amount of S-PA We found a similar pattern but less significant results nor levels of CRF. in the ITT sample, which included all participants that Finally, we assessed the moderating effect of individual finished the intervention independently of their adherence. This difference parameters when the intervention had significant result supports prescribing AE to promote cognitive health effects on cognition compared to control. There were no and adds support to the relevance of frequency or dose to significant interaction effects for age. This null effect may produce significant changes in cognition as published elsewhere be explained by a narrow range of age in our sample or (Gomes-Osman et al., 2018). a small sample size to detect this interaction. There were We also addressed the effect of AE, CCT, and COMB on also no significant interaction effects for sex. However, as our secondary outcomes: psychological health, PA, and CRF. suggested by Barha et al. (2017), positive AE-related effects There were no significant changes in psychological health and may be associated with the higher percentage of females in daily activity outcomes for any intervention group compared to our sample. Second, we analyzed whether significant changes in Frontiers in Aging Neuroscience | www.frontiersin.org 8 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT secondary outcomes mediated the intervention-related changes health. In this proof-of-concept trial, we conclude that AE applied in cognition. We found that AE- and COMB-related cognitive as walking, and performed 45 h in a 12-weeks, 5-days per improvements were mediated by increase in S-PA. Interestingly, week program, may provide cognitive benefits for Executive despite significant increases in CRF in the AE and COMB groups function and Attention-Speed, and that the combination with compared to control, there were no significant mediation effects CCT may lead to similar results in healthy adults aged 50– of CRF for any of the significant intervention-related changes 70 years. in cognition mentioned above. This result is consistent with Our results open the debate of the potential different effects previous literature reporting no-significant correlations between and physiological mechanisms of these interventions on each change in cognition and change in CRF (Etnier et al., 2006; cognitive function and highlight the importance of frequency and Young et al., 2015). Moreover, previous findings suggest that dose of the activity. CRF may be a mediator of cognitive change related to AE only in samples aged ≥ 70 years but not in younger adults (Bherer et al., 2019). The remaining question is whether CRF change DATA AVAILABILITY STATEMENT is a mediator only when the physiological mechanisms (e.g., oxidative stress, immune system molecules, etc.) of reparation The raw data supporting the conclusions of this article will be are damaged by normal age-decline or pathology. In addition, made available by the authors, without undue reservation. since there are sex differences in the physiological adaptations to AE (Barha and Liu-Ambrose, 2018) and in the CRF level across lifespan (Al-Mallah et al., 2016), it would be interesting ETHICS STATEMENT to assess the mediating effect of CRF stratifying results by sex in The studies involving human participants were reviewed and larger samples. These findings suggest that several physiological approved by the Bioethics Commission of the University of molecular correlates and individual variables influenced by FITT Barcelona (IRB00003099) Clinical Research Ethics Committee of parameters, apart from CRF, may play an important role in the IDIAP Jordi Gol (P16/181). The patients/participants provided described benefits. their written informed consent to participate in this study. Our multidomain assessment allowed us to widely assess the effects of these interventions in a novel short-term high frequency design of the interventions. Moreover, we could assess AUTHOR CONTRIBUTIONS the role of individual variables as well as the potential mediating effect of CRF and energy expenditure in S-PA. Despite the MM conceptualized the study, contributed to the study design sample size allowed us to obtain results in our main aims and implementation as principal investigator, and also guided that are coherent with the literature (Colcombe and Kramer, and supervised all the statistical analysis and writing of this 2003), the number of participants in each group did not allow manuscript. PT-M and KE made substantial contributions to perform intra-group analyses by sex or age. The higher to the design and implementation of the trial. AC-S and percentage of females in our sample might influence our results FR-C contributed to the design and implementation of this as suggested in previous literature (Barha et al., 2017) as trial, recruited the participants and evaluated them before well as the wait-list control group which participants might and after interventions, also analyzed the data, and wrote have reduced treatment expectations. We also acknowledge that this manuscript. NL-V collaborated with recruitment and adherence is based on self-reported information and should did the follow-up of the intervention groups. AG-M and be objectively monitored in future studies in order to correct JT assisted in the use of GNPT program for computerized potential desirability bias. The low level of attrition and the cognitive training. GP guided and supervised the statistical stringent inclusion criteria lead to a very healthy motivated analysis. PM-A, MA, RD-A, JS-R, and CC contributed to the sample, which helped to contribute to the research field with implementation of the trial from their area of expertise. All a rigorous sample but could have promoted a ceiling effect authors reviewed the manuscript and provided final approval for in the analyses, despite the statistical corrections applied. Our publication of the content. study involved individually applied interventions. Further studies should address and compare the effect of these interventions when they are applied individually or in a group given the FUNDING recent bibliography suggesting cognitive enhancement as a result of social interaction (Kelly et al., 2017). These facts should be This work was supported by the Spanish Ministry of Economy considered when translating those results into clinical practice and Competitiveness: Neuroplasticity in the adulthood: where the population is more diverse. physical exercise and cognitive training (PSI2013-47724-P) and Integrative omics study on the neurobiological effects of physical activity and cognitive stimulation (PSI2016-77475-R). CONCLUSION This work was partially supported by ICREA under ICREA Academia program to MM. It has also been rewarded with three Projecte Moviment adds scientific support to the clinical pre-doctoral fellowships (FPU014/01460, FI-2016, and FI-2018) relevance of lifestyle interventions in the promotion of cognitive to NL-V, AC-S, and FR-C. This work was also supported by Frontiers in Aging Neuroscience | www.frontiersin.org 9 October 2020 | Volume 12 | Article 590168 Roig-Coll et al. Aerobic-Cognitive Training: Moviment RCT María de Maeztu Unit of Excellence (Institute of Neurosciences, the image design of the project. We would like to thank the University of Barcelona) MDM-2017-0729, Ministry of Science, participants for their time and dedication. Innovation and Universities. SUPPLEMENTARY MATERIAL ACKNOWLEDGMENTS The Supplementary Material for this article can be found We would like to thank the agreement with Technogym to use online at: https://www.frontiersin.org/articles/10.3389/fnagi. their treadmill and Gràfiques Llopis, S.A., for their support on 2020.590168/full#supplementary-material REFERENCES training in healthy elderly subjects. Int. J. Sports Med. 23, 415–421. doi: 10.1055/ s-2002-33735 Al-Mallah, M. H., Juraschek, S. P., Whelton, S., Dardari, Z. A., Ehrman, J. K., Golden, C. J. (2001). Stroop. Test de Colores y Palabras, 3 Edn. Madird: TEA Michos, E. D., et al. (2016). Sex differences in cardiorespiratory fitness and all- Ediciones. cause mortality: the henry ford exercise testing (FIT) project. Mayo Clin. Proc. Gomes-Osman, J., Cabral, D. F., Morris, T. P., McInerney, K., Cahalin, L. P., 91, 755–762. doi: 10.1016/j.mayocp.2016.04.002 Rundek, T., et al. (2018). Exercise for cognitive brain health in aging: a Anderson-Hanley, C., Arciero, P. 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Improving brain injury cognitive rehabilitation by personalized distribution or reproduction is permitted which does not comply with these terms. Frontiers in Aging Neuroscience | www.frontiersin.org 11 October 2020 | Volume 12 | Article 590168