Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity : The ActiveBrains Randomized Clinical Trial

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity : The ActiveBrains Randomized Clinical Trial © 2022 the Authors Published version Ortega, Francisco B.; Mora-Gonzalez, Jose; Cadenas-Sanchez, Cristina; EstebanCornejo, Irene; Migueles, Jairo H.; Solis-Urra, Patricio; Verdejo-Román, Juan; Rodriguez-Ayllon, María; Molina-Garcia, Pablo; Ruiz, Jonatan R.; MartinezVizcaino, Vicente; Hillman, Charles H.; Erickson, Kirk I.; Kramer, Arthur F.; Labayen, Idoia; Catena, Andrés Ortega, F. B., Mora-Gonzalez, J., Cadenas-Sanchez, C., Esteban-Cornejo, I., Migueles, J. H., SolisUrra, P., Verdejo-Román, J., Rodriguez-Ayllon, M., Molina-Garcia, P., Ruiz, J. R., MartinezVizcaino, V., Hillman, C. H., Erickson, K. I., Kramer, A. F., Labayen, I., & Catena, A. (2022). Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity : The ActiveBrains Randomized Clinical Trial. JAMA Network Open, 5(8), Article e2227893. https://doi.org/10.1001/jamanetworkopen.2022.27893 2022 Original Investigation | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity The ActiveBrains Randomized Clinical Trial Francisco B. Ortega, PhD; Jose Mora-Gonzalez, PhD; Cristina Cadenas-Sanchez, PhD; Irene Esteban-Cornejo, PhD; Jairo H. Migueles, PhD; Patricio Solis-Urra, PhD; Juan Verdejo-Román, PhD; María Rodriguez-Ayllon, PhD; Pablo Molina-Garcia, PhD; Jonatan R. Ruiz, PhD; Vicente Martinez-Vizcaino, MD, PhD; Charles H. Hillman, PhD; Kirk I. Erickson, PhD; Arthur F. Kramer, PhD; Idoia Labayen, PhD; Andrés Catena, PhD Abstract IMPORTANCE Pediatric overweight and obesity are highly prevalent across the world, with implications for poorer cognitive and brain health. Exercise might potentially attenuate these adverse consequences. OBJECTIVES To investigate the effects of an exercise program on brain health indicators, including intelligence, executive function, academic performance, and brain outcomes, among children with overweight or obesity and to explore potential mediators and moderators of the main effects of exercise. DESIGN, SETTING, AND PARTICIPANTS All preexercise and postexercise data for this 20-week randomized clinical trial of 109 children aged 8 to 11 years with overweight or obesity were collected from November 21, 2014, to June 30, 2016, with neuroimaging data processing and analyses conducted between June 1, 2017, and December 20, 2021. All 109 children were included in the intention-to-treat analyses; 90 children (82.6%) completed the postexercise evaluation and attended 70% or more of the recommended exercise sessions and were included in per-protocol analyses. INTERVENTIONS All participants received lifestyle recommendations. The control group continued their usual routines, whereas the exercise group attended a minimum of 3 supervised 90-minute sessions per week in an out-of-school setting. MAIN OUTCOMES AND MEASURES Intelligence, executive function (cognitive flexibility, inhibition, and working memory), and academic performance were assessed with standardized tests, and hippocampal volume was measured with magnetic resonance imaging. RESULTS The 109 participants included 45 girls (41.3%); participants had a mean (SD) body mass index of 26.8 (3.6) and a mean (SD) age of 10.0 (1.1) years at baseline. In per-protocol analyses, the exercise intervention improved crystallized intelligence, with the exercise group improving from before exercise to after exercise (mean zscore, 0.62 [95% CI, 0.44-0.80]) compared with the control group (mean zscore, –0.10 [95% CI, –0.28 to 0.09]; difference between groups, 0.72 SDs [95% CI, 0.46-0.97]; P< .001). Total intelligence also improved significantly more in the exercise group (mean zscore, 0.69 [95% CI, 0.48-0.89]) than in the control group (mean zscore, 0.07 [95% CI, –0.14 to 0.28]; difference between groups, 0.62 SDs [95% CI, 0.31-0.91]; P< .001). Exercise also positively affected a composite score of cognitive flexibility (mean zscore: exercise group, 0.25 [95% CI, 0.05-0.44]; control group, –0.17 [95% CI, –0.39 to 0.04]; difference between groups, 0.42 SDs [95% CI, 0.13-0.71]; P= .005). These main effects were consistent in intention-to-treat analyses and (continued) Key Points Question Can an exercise intervention of aerobic plus resistance training improve cognitive and brain health outcomes for children with overweight or obesity? Findings In this randomized clinical trial of 109 participants, exercise significantly improved intelligence and cognitive flexibility among preadolescent children with overweight or obesity. There was also a positive, smaller-magnitude significant effect of exercise on academic performance but no significant effect on inhibition and working memory or on structural and functional brain outcomes studied. Meaning This study suggests that exercise can positively affect intelligence and cognitive flexibility during a sensitive period of brain development in childhood and, to a smaller extent, academic performance, indicating that an active lifestyle before puberty may lead to more successful life trajectories. +Visual Abstract +Supplemental content Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 1/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 Abstract (continued) after multiple-testing correction. There was a positive, small-magnitude effect of exercise on total academic performance (mean zscore: exercise group, 0.31 [95% CI, 0.18-0.44]; control group, 0.10 [95% CI, –0.04 to 0.24]; difference between groups, 0.21 SDs [95% CI, 0.01-0.40]; P= .03), which was partially mediated by cognitive flexibility. Inhibition, working memory, hippocampal volume, and other brain magnetic resonance imaging outcomes studied were not affected by the exercise program. The intervention increased cardiorespiratory fitness performance as indicated by longer treadmill time to exhaustion (mean zscore: exercise group, 0.54 [95% CI, 0.27-0.82]; control group, 0.13 [95% CI, –0.16 to 0.41]; difference between groups, 0.42 SDs [95% CI, 0.01-0.82]; P= .04), and these changes in fitness mediated some of the effects (small percentage of mediation [approximately 10%-20%]). The effects of exercise were overall consistent across the moderators tested, except for larger improvements in intelligence among boys compared with girls. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, exercise positively affected intelligence and cognitive flexibility during development among children with overweight or obesity. However, the structural and functional brain changes responsible for these improvements were not identified. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02295072 JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 Introduction The prevalence of overweight and obesity among youths has more than quadrupled worldwide from 1975 to 2016 (from 4% to 18%). 1 Evidence suggests that obesity might negatively affect brain health (ie, cognitive and brain development). 2-4 It is therefore necessary to identify effective strategies to attenuate these adverse consequences. Physical exercise is a candidate to produce such positive stimuli because it provides multisystemic benefits to human organs, including the brain. 5,6 Existing exercise-based interventions have mostly targeted executive functions and other dimensions of cognition (eg, processing speed and language), 7-9 yet, to our knowledge, evidence regarding the effect of exercise on intelligence and its components (ie, crystallized intelligence and fluid intelligence) 10 is lacking. Against traditional beliefs, the notion that intelligence is “malleable” despite its high heritability is gaining support, 11 yet more research is warranted. Although most previous studies focused on behavioral outcomes (eg, executive function and other dimensions of cognition), only a few randomized clinical trials (RCTs) for children have investigated the effects of exercise on brain structure and function. 12-20 There is a need for highquality RCTs that combine behavioral and brain imaging outcomes, as well as a better characterization of the exercise dose administered in the interventions. 21,22 Moreover, previous studies of animals 23 and older adults 23-25 have pointed to hippocampal volume as a critical brain outcome affected by exercise. Although the hippocampus is not a brain region directly associated with intelligence, it is a central hub in networks that support executive function and memory. The effects of exercise on this brain region during a period of brain growth remain underinvestigated, to our knowledge. Furthermore, a comprehensive investigation, including a broader set of magnetic resonance imaging (MRI) outcomes, is needed to understand the overall effect of exercise on brain structure and function. The ActiveBrains RCT 26 included a broad set of both behavioral and brain MRI outcomes and was designed to test the effects of exercise on brain health among children with overweight or obesity. Our primary aim (a priori planned) was to investigate the effects of a 20-week exercise program on behavioral outcomes, including intelligence, executive function (ie, cognitive flexibility, JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 2/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 inhibition, and working memory), and academic performance as well as on hippocampal volume as a primary region of interest in children with overweight or obesity. In secondary analyses (a posteriori planned), we explored potential mediators and moderators of the main exercise effects observed in this intervention. First, we investigated cardiorespiratory fitness (CRF) as the main candidate mediator, 27-38 and we explored other specific brain regions of interest (eg, the prefrontal cortex because of its relationship with intelligence and cognitive flexibility 39-41 ) and broader brain structural and functional changes (hypothesis-free analyses) as potential mediators. Second, we tested potential moderators (sex, age, maturation, socioeconomic status, and baseline performance) of the intervention effects. 42 Third, we interrogated potential compensatory and contamination effects on daily activity levels, which were assessed with accelerometers. Fourth, we analyzed the exercise dose (ie, the actual volume and intensity of the intervention, assessed via heart rate monitoring) because this dose might have a direct effect on the magnitude of intervention effects. Methods A brief description of the material and methods is discussed. The trial protocol and statistical analysis plan are provided in Supplement 1. All methodological details are provided in the eMethods in Supplement 2. Study Design and Participants The ActiveBrains trial 26 is a parallel-group RCT conducted among children aged 8 to 11 years with overweight or obesity. The recruitment occurred mainly at the pediatric units of the 2 main hospitals in Granada, Spain. A total of 109 participants were randomly assigned (simple randomization conducted with SPSS, version 25.0 [IBM Corp]) to a control group or an exercise group. The flowchart of the study is presented in Figure 1. All preexercise and postexercise data were collected from November 21, 2014, to June 30, 2016. The parents or legal guardians of the children provided written informed consent to participate in the trial. The ActiveBrains project was approved by the ethics committee of the University of Granada, and it was registered on ClinicalTrials.gov (NCT02295072). This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Power and Sample Size Our study was powered to detect smallto medium-sized effects (ie, Cohen d= 0.3), with an α error of 5% and a power of 80% with the inclusion of 90 participants. After adjustement for an estimated 10% estimated dropout rate (a similar rate has been observed in previous trials 43 ), 100 participants were needed for sufficient power. Intervention and Control The participants in the control group continued their usual routines. Both the control and exercise groups were provided with information about healthy nutrition and recommendations for physical activity at the beginning of the study. The exercise group was instructed to attend at least 3 (of 5 offered) supervised exercise sessions per week. Sessions lasted 90 minutes (60 minutes of aerobic exercises plus 30 minutes of resistance exercises). To increase motivation and adherence, exercise sessions were based on games and playful activities that involved coordinative exercises. Outcome Measurements Intelligence, Executive Function, and Academic Performance All outcomes were assessed before and after the intervention. Crystallized intelligence, fluid intelligence, and total (ie, crystallized plus fluid) intelligence were assessed by the Spanish version of the Kaufman Brief Intelligence Test. 44 Cognitive flexibility was assessed using the Design Fluency JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 3/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 Test and the Trail Making Test. Inhibition was evaluated with a modified version of the Stroop ColorWord Test (paper-pencil version). 45-47 Working memory was measured by a modified version of the Delayed Non-Match-to-Sample computerized task. 48 Academic performance was assessed by the Spanish version of the Woodcock-Johnson III Tests of Achievement. 49 Brain MRI Outcomes The structural and functional MRI outcomes studied are summarized in eFigure 1 in Supplement 2. The MRI acquisition and the specific processing steps for each analysis are individually detailed in the eMethods in Supplement 2. Cardiorespiratory Fitness, Biological Maturation, and Socioeconomic Status Cardiorespiratory fitness was evaluated using a gas analyzer (General Electric Corp) while the participant was performing a maximal incremental treadmill test (ergometer; h/p/cosmos sports & medical gmbh). 43 Peak height velocity, a common indicator of maturity in children and Figure 1. CONSORT Flow Diagram 115 Participants assessed for eligibility 112 Accepted in the study 109 Included in ITT analyses 90 Included in per-protocol analyses 3Excluded 1Normal weight 1With ADHD 1Did not understand Spanish properly 19 Excluded from per-protocol analyses 13 Did not complete the postintervention assessments on intelligence, executive function, academic performance, or brain structure 6Did not meet exercise condition (ie, at least 70% of the recommended sessions) 3Chose not to continue 109 Randomized 52 In control group 9In first wave 23 In second wave 20 In third wave 57 In exercise group 10 In first wave 22 In second wave 25 In third wave 52 In control group 9In first wave 23 In second wave 20 In third wave 57 In exercise group 10 In first wave 22 In second wave 25 In third wave 43 In control group 5In first wave 19 In second wave 19 In third wave 47 In exercise group 9In first wave 17 In second wave 21 In third wave For final intention-to-treat (ITT) analyses, participants who left the study during the intervention or who did not complete the postexercise program assessments were imputed (see Statistical Analysis section). The actual number for each variable can be seen in eTables 1 to 22 in Supplement 2. ADHD indicates attention-deficit/hyperactivity disorder. JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 4/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 adolescents, 50 was calculated through the equations of Moore et al. 51 Parents self-reported their highest educational level attained and current occupation, as described elsewhere. 26,52 Overall Physical Activity Assessment Before and During the Intervention Activity patterns at baseline and during the intervention (week 10) were assessed with hipand wristworn accelerometers (GT3X+; ActiGraph LLC), as described elsewhere. 53 Statistical Analysis Neuroimaging data processing and analyses were conducted from June 1, 2017, to December 20, 2021. We report the findings from the per-protocol analyses in the main article and the intention-totreat analyses in the eAppendix and eTables 19 to 21 in Supplement 2 based on 2 reasons: (1) we aimed to study the efficacy of the program rather than its effectiveness, and (2) in neuroimaging, it is technically difficult to apply imputation methods on images, and rarely done. The analyses of the effects of the intervention were tested using analysis of covariance, with behavioral outcomes and several MRI outcomes (hippocampal volume as the primary region of interest) as dependent variables in separate models, group (exercise vs control) as a fixed factor, and the baseline of the study outcome as a covariate. The intervention effects are presented as zscores of change, indicating that the SDs of the postexercise program values changed from the baseline mean and SD values (ie, the standardized effect size of the change 54 ). This effect size can be interpreted according to the standard benchmarks (ie, approximately 0.2 SDs is considered a small effect size, approximately 0.5 SDs is considered a medium effect size, and approximately 0.8 SDs is considered a large effect size). 55 Results in the raw units of measure are also provided in eTables 1 to 22 in Supplement 2. All P values were from 2-sided tests and results were deemed statistically significant at P< .05. In addition, we applied multiple testing corrections on the primary outcomes following the false discovery rate method proposed by Benjamini and Hochberg. 56 A posteriori–planned analyses consisted of exploring potential mediators and moderators. Our mediation analyses are in line with the A Guideline for Reporting Mediation Analyses (AGReMA) statement. The statistical procedures were performed using SPSS software, version 25.0 (IBM Corporation) and R software, version 3.1.2 (R Group for Statistical Computing). Results The baseline characteristics of the participants are presented in eTable 1 in Supplement 2. Of the 109 randomized participants (45 girls [41.3%]; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared] of 26.8 [3.6] and mean [SD] age of 10.0 [1.1] years at baseline), 96 completed the trial (11.9% attrition rate), and 90 met the criteria for the per-protocol analyses (82.6% of the original sample). A graphical illustration of the a priori–planned and a posteriori–planned analyses of brain health outcomes is presented in eFigure 1 in Supplement 2. Additional details are provided in the eAppendix in Supplement 2. A Priori–Planned Analyses The a priori–planned analyses included the effects of the exercise intervention on intelligence, executive function, academic performance, and hippocampal volume. The largest effect size observed in the ActiveBrains exercise program was for crystallized intelligence, with the exercise group improving from before exercise to after exercise (mean zscore, 0.62 [95% CI, 0.44-0.80]) compared with the control group (mean zscore, –0.10 [95% CI, –0.28 to 0.09]; difference between groups, 0.72 SDs [95% CI, 0.46-0.97]; P< .001) (Figure 2;eTable2inSupplement 2). Total intelligence also improved significantly more among the exercise group (mean zscore, 0.69 [95% CI, 0.48-0.89]) than among the control group (mean zscore, 0.07 [95% CI, –0.14 to 0.28]; difference between groups, 0.62 SDs [95% CI, 0.31-0.91]; P< .001). In addition, exercise positively affected a composite score of cognitive flexibility, derived from 2 cognitive flexibility tests (mean zscore: JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 5/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 exercise group, 0.25 [95% CI, 0.05-0.44]; control group, –0.17 [95% CI, –0.39 to 0.04]; difference between groups, 0.42 SDs [95% CI, 0.13-0.71]; P= .005). Within this composite, the largest improvement was observed for performance on cognitive flexibility test 1 (ie, the Design Fluency Test) (mean zscore: exercise group, 0.65 [95% CI, 0.44-0.86]; control group, 0.18 [95% CI, –0.04 to 0.39]; difference between groups, 0.48 SDs [95% CI, 0.17-0.78]; P= .003). The exercise program had a null effect on inhibition (mean zscore: exercise group, –0.51 [95% CI, –0.72 to –0.30]; control group, –0.48 [95% CI, –0.70 to –0.25]; difference between groups, 0.04 SDs [95% CI, –0.27 to 0.34]; P= .82) and working memory (mean zscore: exercise group, 0.01 [95% CI, –0.20 to 0.22]; control group, 0.05 [95% CI, –0.17 to 0.27]; difference between groups, –0.04 SDs [95% CI, –0.35 to 0.27]; P= .80). For academic performance, exercise improved total academic performance (mean zscore: exercise group, 0.31 [95% CI, 0.18-0.44]; control group, 0.10 [95% CI, –0.04 to 0.24]; difference between groups, 0.21 SDs [95% CI, 0.01-0.40]; P= .03) and, particularly, mathematics (mean z score: exercise group, 0.35 [95% CI, 0.15-0.55]; control group, 0.04 [95% CI, –0.17 to 0.25]; difference between groups, 0.32 SDs [95% CI, 0.02-0.60]; P= .04), problem solving (mean zscore: exercise group, 0.41 [95% CI, 0.24-0.59]; control group, 0.05 [95% CI, –0.13 to 0.24]; difference between groups, 0.36 SDs [95% CI, 0.10-0.62]; P= .007), and academic skills (mean zscore: exercise group, 0.27 [95% CI, 0.11-0.43]; control group, 0.01 [95% CI, –0.16 to 0.17]; difference between groups, 0.27 SDs [95% CI, 0.03-0.49]; P= .03) (Figure 2; eTable 3 in Supplement 2). The exercise program had a small, nonsignificant effect on reading and writing skills and a null effect on Figure 2. Per-Protocol Effects of the ActiveBrains Exercise Program on the Main Brain Health Outcomes –0.4 0.2 1.00.6 0.80 0.4 z Score (95% CI) –0.2 Favors control Favors exercise Brain health outcome Intelligence z Score (95% CI) Crystallized intelligence 0.72 (0.46 to 0.97)a Fluid intelligence 0.20 (-0.15 to 0.57) Total intelligence 0.62 (0.31 to 0.91)a Executive function Cognitive flexibility test 1 0.48 (0.17 to 0.78)a Cognitive flexibility test 2 0.26 (-0.12 to 0.65) Cognitive flexibility composite 0.42 (0.13 to 0.71)a Inhibition 0.04 (-0.27 to 0.34) Working memory –0.04 (-0.35 to 0.27) Executive function composite 0.21 (-0.06 to 0.50) Academic performance Academic skills 0.27 (0.03 to 0.49)a Brain structure Hippocampal volume 0.06 (–0.12 to 0.24) Academic fluency –0.02 (–0.26 to 0.21) Problem solving 0.36 (0.10 to 0.62)a Reading 0.15 (–0.07 to 0.37) Mathematics 0.32 (0.02 to 0.60)a Writing 0.19 (–0.05 to 0.45) Total academic performance 0.21 (0.01 to 0.40)a Dots indicate the between-groups difference in zscores of change (ie, postexercise outcomes with respect to the baseline mean [SD] value). Bars indicate 95% CIs. Each analysis was adjusted for baseline outcomes. The cognitive flexibility composite zscore was calculated as the renormalized mean of the zscores for cognitive flexibility test 1 and cognitive flexibility test 2. The executive function composite zscore was calculated as the renormalized mean of the zscores for cognitive flexibility, inhibition, and working memory. Academic skills are the sum of components based on basic skills, such as reading decoding, mathematics calculation, and spelling. Academic fluency is the sum of tests based on reading, calculation, and writing fluency. Problem solving is the sum of the components based on solving academic problems in reading, mathematics, and writing. Total academic performance is the overall measure of academic performance based on reading, mathematics, and writing. Two of the cognitive tests (ie, the cognitive flexibility test 2 [Trail Making Test] and the inhibition test [Stroop Color-Word Test]) were originally expressed inversely, which means that lower scores indicate better performance. To simplify the visual interpretation of the main findings, we inverted these 2 scores so that they can be interpreted in the same fashion as the rest of the outcomes (ie, higher score indicates better performance). These cognitive tests are expressed in their original units and not inverted in eTables 2 and 19 in Supplement 2. a Significant effect at P< .05 (or by the 95% CI not including zero). JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 6/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 academic fluency. In exploratory analyses, the positive effect of exercise on total academic performance, mathematics, and academic skills was mediated (30%-39% of mediation) by exerciseinduced improvements in cognitive flexibility (eFigure 2A-C in Supplement 2). The improvements in academic problem solving were mediated (15% of mediation) by exercise-induced improvements in fluid intelligence (eFigure 2D in Supplement 2). However, the exercise program did not have an effect on overall hippocampal volume (mean zscore: exercise group, 0.19 [95% CI, 0.07-0.32]; control group, 0.13 [95% CI, 0.00-0.27]; difference between groups, 0.06 SDs [95% CI, –0.12 to 0.24]; P= .50; Figure 2; eTable 4 in Supplement 2). After correction for multiple comparisons of the primary outcomes (the 17 outcomes shown in Figure 2), the larger effects on crystallized intelligence (mean zscore, 0.72 [95% CI, 0.46-0.97]; Pⱕ.001), total intelligence (mean zscore, 0.62 [95% CI, 0.31-0.91]; Pⱕ.001), and the cognitive flexibility composite (mean zscore, 0.42 [95% CI, 0.13-0.71]; P= .02) persisted. Likewise, the effects on problem solving continued to be significant (mean zscore, 0.36 [95% CI, 0.10-0.62]; corrected P= .02), whereas the effects became nonsignificant for mathematics (mean zscore, 0.32 [95% CI, 0.02-0.60]; corrected P= .07), academic skills (mean zscore, 0.27 [95% CI, 0.03-0.49]; corrected P= .07), and total academic performance (mean zscore, 0.21 [95% CI, 0.01-0.40]; corrected P=.07). A Posteriori–Planned Analyses of Brain MRI Outcomes As shown in eFigure 1 in Supplement 2, we explored the effects of the intervention on a set of brain MRI outcomes, including volumetric analyses of hippocampus subregions and the prefrontal cortex (eTables 4-5 in Supplement 2); the cortical thickness, surface area, and subregions of the prefrontal cortex (eTables 6-7 in Supplement 2); and the functional connectivity between the hippocampus and prefrontal cortex (eTables 8-13 in Supplement 2). We also studied the effects of the intervention using a broader brain approach, including gray matter volumes of subcortical brain structures (eTable 14 in Supplement 2), morphologic (shape) analysis of subcortical brain structures (eFigure 3 in Supplement 2), total brain volumes (eTable 15 in Supplement 2), whole-brain voxelwise volumetric analysis, and whole-brain structural covariance network analysis (eFigure 4, eTable 16 in Supplement 2). Our intervention did not have a significant effect on any of these MRI outcomes. Effects of the Intervention on CRF and Its Role as Mediator The exercise program improved CRF as indicated by treadmill time to exhaustion (mean zscore: exercise group, 0.54 [95% CI, 0.27-0.82]; control group, 0.13 [95% CI, –0.16 to 0.41]; difference between groups, 0.42 SDs [95% CI, 0.01-0.82]; P= .04) (eTable 17 in Supplement 2). A consistent improvement, although smaller and nonsignificant, was observed in peak oxygen consumption, expressed in milliliters per kilogram per minute (mean zscore: exercise group, 0.39 [95% CI, 0.13-0.65]; control group, 0.10 [95% CI, –0.18 to 0.37]; difference between groups, 0.29 SDs [95% CI, –0.08 to 0.67]; P= .13). The effects of the exercise program on crystallized intelligence, problem solving, and total academic performance were significantly mediated by improvements in CRF (ie, time to exhaustion), with a mediation effect of 10% to 20% (Figure 3). Moderators of the Intervention Effects Figure 4 shows that the effect sizes of the exercise program were consistent across sex, age, and maturation for most of the primary outcomes studied, except for crystallized intelligence, for which the exercise program was more effective for boys, younger participants, and less mature participants. The sex differences observed could be partially explained by the finding that boys spent more time at high-intensity zones (ie, over their individualized anaerobic threshold monitored with heart rate) (eTable 18 in Supplement 2). We also observed that children with lower socioeconomic status showed larger improvements in fluid and total intelligence, as did children with a lower performance at baseline on the intelligence test (eFigure 5 in Supplement 2). JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 7/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 Exploratory Analyses Related to the Interpretation of the Intervention Effects Intention-to-Treat and Dropout Analyses The main effects of this intervention observed on intelligence and cognitive flexibility remained significant in intention-to-treat analyses (eTables 19-21 in Supplement 2), indicating the robustness of the main findings (further details in the eAppendix in Supplement 2). Participants who withdrew during the trial did not differ from those completing the study in any of the behavioral outcomes studied (eTable 22 in Supplement 2). Compensatory and Contamination Effects The children in the exercise group significantly increased their activity levels during the time of day in which they were participating in the exercise program, without reductions (ie, no compensation) during other times of the day (results from the hip-attached accelerometer in Figure 5; results from the wrist-attached accelerometer in eFigure 6 in Supplement 2). The children in the control group kept the same levels of daily activity (ie, no contamination). Figure 3. Cardiorespiratory Fitness Change Mediation Models of the Intervention Effects (ie, Exercise vs Control) on Crystallized Intelligence and Academic Performance Outcomes in Children With Overweight or Obesity Group (exercise vs control) Equation 2 B = 8.921 ß = 0.349 P <.001 Change in cardiorespiratory fitness Group (exercise vs control) Crystallized intelligence at postexercise program Crystallized intelligence at postexercise program Crystallized intelligence A Equation 3’ Indirect effect: B = 0.857 (95% CI, 0.111-2.212)a ß = 0.034 (95% CI, 0.004-0.087) % of the total effect = 9.6% B = 8.064 ß = 0.315 P <.001 Equation 1 B = 1.448 ß = 0.269 P =.01 Equation 3 B = 0.592 ß = 0.125 P =.07 Group (exercise vs control) Equation 2 B = 3.276 ß = 0.190 P =.007 Change in cardiorespiratory fitness Group (exercise vs control) Problem solving at postexercise program Problem solving at postexercise program Problem solving B Equation 3’ Indirect effect: B = 0.669 (95% CI, 0.081-1.494)a ß = 0.039 (95% CI, 0.005-0.086) % of the total effect = 20.4% B = 2.608 ß = 0.151 P =.03 Equation 1 B = 1.305 ß = 0.242 P =.03 Equation 3 B = 0.512 ß = 0.160 P =.02 Group (exercise vs control) Equation 2 B = 3.386 ß = 0.156 P =.04 Change in cardiorespiratory fitness Group (exercise vs control) Mathematics at postexercise program Mathematics at postexercise program Mathematics C Equation 3’ Indirect effect: B = 0.459 (95% CI, –0.215 to 2.052) ß = 0.021 (95% CI, –0.010 to 0.095) % of the total effect = 13.6% B = 2.928 ß = 0.135 P =.07 Equation 1 B = 1.256 ß = 0.233 P =.03 Equation 3 B = 0.365 ß = 0.091 P =.23 Group (exercise vs control) Equation 2 B = 2.481 ß = 0.109 P =.03 Change in cardiorespiratory fitness Group (exercise vs control) Total academic performance at postexercise program Total academic performance at postexercise program Total academic performance D Equation 3’ Indirect effect: B = 0.423 (95% CI, 0.029-1.219)a ß = 0.019 (95% CI, 0.001-0.054) % of the total effect = 17.1% B = 2.058 ß = 0.091 P =.09 Equation 1 B = 1.349 ß = 0.250 P =.02 Equation 3 B = 0.314 ß = 0.075 P =.15 Each analysis was adjusted by the respective intelligence or academic performance outcomes at baseline. Change in cardiorespiratory fitness expresses the change in total completion time (minutes) of the treadmill test at postexercise program with respect to the total completion time (minutes) at baseline because it was the main cardiorespiratory fitness outcome influenced by the exercise program. Problem solving is the sum of the components based on solving academic problems in reading, mathematics, and writing. Total academic performance is the overall measure of the academic performance based on reading, mathematics, and writing. B indicates unstandardized regression coefficient; β, standardized regression coefficient. a Significant indirect effect at P< .05. JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 8/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 13. 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Cognitive Flexibility and Fluid Intelligence Mediation Models of the Intervention Effects (ie, Exercise vs Control) on Academic Performance Outcomes in Children With Overweight or Obesity eFigure 3. An Illustration of the Shape Analysis of Subcortical Brain Structures eFigure 4. Structural Covariance Networks Delineated by Non-Negative Matrix Factorization Analysis eFigure 5. Per-Protocol Effects of the ActiveBrains Exercise Program on the Main Brain Health Outcomes by Parental Educational Levels (A), Parental Occupational Levels (B), and Baseline Levels (C) JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 17/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023 eFigure 6. Comparison of the 24 h Physical Activity Patterns Derived From Aggregated Raw Accelerations (ie, Euclidean Norm Minus One Accelerations) Measured With an Accelerometer Attached at the Nondominant Wrist at Baseline (ie, Black Line) and in the Middle of the Exercise Program (ie, Orange Line) in Exercise and Control Groups eFigure 7. Violin Plots Characterizing the Intensity of the Exercise Program as Measured by Heart Rate (HR) Monitors eFigure 8. Box Plot Showing the Distribution of the Attendance to the Exercise Program eTable 1. Descriptive Baseline Characteristics of the ActiveBrains Participants Meeting Intention-to-Treat Criteria eTable 2. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw and z-Score Post-Exercise (ie, z-Score of Change From Baseline) Intelligence and Executive Function Outcomes eTable 3. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (Standard Score) and z-Score PostExercise (z-Score of Change From Baseline) Academic Performance Outcomes (Woodcock-Muñoz Standardized Test) eTable 4. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (mm 3 ) and z-Scores of Post-Exercise Hippocampal Volume eTable 5. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (mm 3 ) and z-Scores of Post-Exercise Prefrontal Cortex Gray Matter Volume Outcomes eTable 6. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (mm) and z-Scores of Post-Exercise Prefrontal Cortex Cortical Thickness Outcomes eTable 7. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (mm 2 ) and z-Scores of Post-Exercise Prefrontal Cortex Surface Area Outcomes eTable 8. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Left Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 9. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Left Anterior Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 10. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Left Posterior Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 11. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Right Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 12. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Right Anterior Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 13. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (β Values) and z-Scores of PostExercise Right Posterior Hippocampal Functional Connectivity With Prefrontal Cortex Subregions eTable 14. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (mm 3 ) and z-Scores of Post-Exercise Subcortical Brain Volumes Other Than the Hippocampus eTable 15. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (cm 3 ) and z-Scores of Post-Exercise Total Brain Volumes eTable 16. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (Loadings) and z-Scores of PostExercise Structural Covariance Network eTable 17. Per-Protocol Effects of the ActiveBrains Exercise Program on Raw (Loadings) and z-Scores of PostExercise Cardiorespiratory Fitness eTable 18. Sex Differences in Intensity Monitored by Heart Rate During the Exercise Sessions eTable 19. Intention-to-Treat Effects of the ActiveBrains Exercise Program on Raw and z-Scores of Post-Exercise Intelligence and Executive Function Outcomes eTable 20. Intention-to-Treat Effects of the ActiveBrains Exercise Program on Raw (Standard Score) and z-Scores of Post-Exercise Academic Performance Outcomes (Woodcock-Muñoz Standardized Test) eTable 21. Intention-to-Treat Effects of the ActiveBrains Exercise Program on Raw (mm 3 ) and z-Scores of PostExercise Hippocampal Gray Matter Volume eTable 22. Descriptive Characteristics of the ActiveBrains Participants That Completed The Study (ie, Nondropouts) and Those That Did Not Complete The Study (ie, Dropouts) at Baseline SUPPLEMENT 3. Data Sharing Statement JAMA Network Open | Pediatrics Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity JAMA Network Open. 2022;5(8):e2227893. doi:10.1001/jamanetworkopen.2022.27893 (Reprinted) August 30, 2022 18/18 Downloaded From: https://jamanetwork.com/ by a Jyvaskylan Yliopisto User on 10/12/2023