Aerobic Exercise and Cognitive Function in Chronic Severe Traumatic Brain Injury Survivors: A Within-Subject A-B-A Intervention Study

Aerobic Exercise and Cognitive Function in Chronic Severe Traumatic Brain Injury Survivors: A Within-Subject A-B-A Intervention Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Aerobic Exercise and Cognitive Function in Chronic Severe Traumatic Brain Injury Survivors: A Within-Subject A-B-A Intervention Study Lidia Pérez López, Margalida Coll-Andreu, Meritxell Torras-Garcia, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4743451/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Sep, 2024 Read the published version in BMC Sports Science, Medicine and Rehabilitation → Version 1 posted 4 You are reading this latest preprint version Abstract Background Following acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations. Methods In this within-subject A-B-A study design, we incorporated 20-weeks of supervised aerobic exercise interventions delivered three times per week (Phase B) between participants typical rehabilitation schedules (Phases A). We further tested if participation in supervised aerobic exercise increased participants daily physical activity (PA) levels using waist-worn actigraphy. Results Five of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+ 1SD in normative scores). Linear mixed effects models showed a significant main effect of time at the group level with significant improvement in TMT-B pre-to-post exercise and no significant effect in other planned comparisons (pre-exercise to baseline nor follow-up to post-exercise) indicating that the addition of the intervention improved performance that was not due to practice effects. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to Phase A with three of six individuals making a significant behavior changes when analyzed at the individual level. Conclusions The addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels. Trial Registration ISRCTN17487462. Traumatic Brain Injury Cognitive function Physical Exercise Physical Activity Figures Figure 1 Figure 2 Background Sustained deficits in executive function, attention, memory, and processing speed are common following severe traumatic brain injury (TBI) and are a primary driver of poor quality of life and persistent functional disability in TBI survivors ( 1 ). Around 65% of people who suffer moderate or severe TBI develop chronic cognitive deficits( 2 ). Yet, following acute and sub-acute rehabilitation, individuals re-integrating into community settings are faced with limited resources and no accessible or efficacious interventions to treat debilitating cognitive deficits. Long-term behavioural strategies such lifestyle interventions could significantly benefit individuals with lasting TBI-related deficits( 3 ), but limited evidence of their effect exists( 4 ). In non-injured adults, aerobic physical exercise has been shown to effect broad domains of cognitive function, with the largest effect sizes being seen on executive function( 5 – 7 ). Physical activities are often used in within sub-acute rehabilitation settings, but limited high quality evidence exists of how regimented physical exercise regimes can affect cognition in the chronic stages of recovery from moderate-to-severe TBI( 4 ). Prior human studies of physical exercise on cognitive function in TBI have included both heterogenous populations and recovery stages (mix of acute and chronic), short-term interventions (four to 12 weeks), retrospective study designs and single-arm studies ( 8 – 12 ). Nevertheless, in several of these studies, improvements in cognitive function were reported, including improvements in executive function( 9 ). Additionally, alternative treatments are currently being tested and significant improvements in executive function have also been reported following invasive therapeutic interventions such as thalamic deep-brain stimulation in six individuals with chronic moderate-to-severe TBI ( 13 ). While such invasive intervention shows promise for chronic severe TBI survivors, if similar gains can be achieved with non-invasive interventions, then more individuals living with chronic cognitive deficits from injury would benefit from accessible, economic and safe interventions. An additional consideration with behavioural lifestyle interventions is the ability of individuals with cognitive deficits to voluntarily engage in the healthy behaviour outside of the prescribed intervention sessions. Executive function, cortical brain regions underpinning executive function and psychosocial constructs such as exercise self-efficacy are related to voluntary engagement in physical activity and exercise in non-injured adults( 14 – 16 ). Exercise interventions, even in sub-acute moderate-to-severe TBI have been shown to be feasible ( 10 , 17 ), but survivors of TBI report significant barriers to participation in physical exercise ( 18 , 19 ). Importantly though, if given certain resources (e.g., free access to local gymnasiums), community-dwelling individuals with moderate-to-severe TBI will adhere to physical exercise( 20 ). However, whether enrolment in a structured physical exercise intervention alone promotes adoption of physical activity outside of the intervention sessions in chronic severe TBI survivors is unknown. If individuals make a behaviour change because of participation of the structured intervention, then the long-term benefits of this intervention are increased. Compared to currently non-effective pharmacological agents or promising invasive interventions such as deep brain stimulation, aerobic physical exercise represents is an accessible, non-invasive and long-term behavioural intervention that can potentially treat cognitive deficits in individuals with chronic severe TBI. Therefore, this study had two aims; 1) to test the effect of a 20-week aerobic physical exercise intervention on cognitive function in individuals with chronic severe TBI and 2) test the effect of the intervention on voluntary engagement in daily physical activity levels outside of the intervention sessions. We tested these aims using a within-subjects A-B-A study design with phase B consisting of 20 weeks of aerobic physical exercise sessions delivered three-times per week. METHODS Participants Participants were recruited from two ambulatory neurorehabilitation centres. All patients from both centres who met the following inclusion criteria were invited to participate in the study: 1) a severe TBI, defined as a score between 3 and 8 in Glasgow comma scale at time of injury; 2) a minimum of 8 months since injury; 3) lack of medical contraindications to engage in physical exercise of moderate or vigorous intensity; 4) preserved communication abilities to perform neuropsychological assessments, and to give informed consent. Eight patients fulfilled these criteria two of whom declined to enrol in the study. The final sample consisted of 6 individuals (5 male, 1 female). This project was approved by the ethics committee for animal and human experimentation of the leading institution (CEEAH 4658). All the participants received verbal and written information about the study and signed informed consent. All measures were taken to preserve the confidentiality of the individuals’ identity. Study Design This was a single-arm within-subject study that followed an A-B-A design (Fig. 1 ). Three phases (20 weeks each) were designed as follows; Phase A1: Ongoing individually tailored outpatient neurorehabilitation (see Table 1 for a complete description); Phase B: tailored outpatient neurorehabilitation plus scheduled aerobic physical exercise (three sessions per week, 30 minutes/session); Phase A2: Tailored outpatient rehabilitation without the physical exercise intervention. The closure of the rehabilitation centres in response to the first wave of the covid-19 pandemic reduced Phase B to 17 weeks in five participants and online rehabilitation was provided to the participants in phase A2. Cognitive function was assessed at the beginning and end of each study phase. Daily physical activity levels were measured for seven consecutive days in each phase of the study. Aerobic Exercise Intervention (Phase B) The aerobic exercise intervention was delivered in-person within each rehabilitation centre using either a cycling rehabilitation trainer (MOTOmed Viva 2 leg trainer; RECK-technik GmbH & Co.KG; Betzenweiler, Germany) for two participants with motor impairment, a stationary cycle ergometer (Decathlon; Domyos Essential) or combined the use of a treadmill (Domfit F1. BH Fitness; Álava, Spain) and a MOTOmed. Each session (~ 30 minutes) consisted of a 5-minute warm up and cool down. Resting HR and blood pressure were recorded before and after each session with the use of a hand-held sphygmomanometer (Omron electronics; Barcelona; Spain). The intensity of exercise was progressively increased with a target heart rate intensity zone of 60–80% heart rate reserve (HRR). The corresponding heart rate in beats per minute was calculated suing the Karvonen equation ([220-age]-resting heart rate x intended % HRR + resting heart rate) set from the 3rd week onwards. Intensity zones were re-calculated every four weeks to account for any changes in resting heart rate. Heart rate was continuously recorded during the exercise sessions by means of a wrist pulsometer (Polar M430; Polar Electro; Kempele, Finland). Participants were asked to rate their perceived exertion and comfort/distress every five minutes using Borg’s scale ( 6 – 20 ) of perceived exertion and a visual analogue scale, respectively. Primary Outcomes: Cognitive Function We defined our primary outcome measure in this analysis as trail making test part B (TMT-B), to be able to make direct comparisons with prior exercise studies( 9 ) and alternative treatments for cognitive deficits in moderate-to-severe traumatic brain injury ( 13 ). Trail making B is thought of as an executive control measure testing working memory and set shifting abilities ( 21 – 23 ). Given the severe deficits of the participants in this study, we did not limit their response time. Raw completion time scores are used in subsequent statistical analyses, and we also present percentage change and scaled normative scores to increase interpretability. Normalized scaled scores were calculated based on the Neuronorma project for the Spanish population( 24 ) whereby the population mean is 10 and a one standard deviation change is equal to three. Additionally, to reduce the influence of slowed motor and visuomotor function on performance of the TMT-B, we also tested the difference score of TMT-B minus TMT-A (B-A). Several additional executive function assessments were collected as executive function is particularly vulnerable to injury and has been shown to be modulated by aerobic exercise in other populations. These included the Rey-Osterrieth complex figure test, including a copy phase (perceptual and motor capacity) and a memory phase (30 min later), measuring visuospatial memory( 25 ) and The Card Sorting Test (CST), using the short-form of the Berg’s CST (Psychology Experimental Building Language -PEBL) (64 cards instead of the 128 used in the long form)( 26 ), which assesses ability to change strategies based on the demands of the task as a measure of flexibility. All tests were administered by a trained neuropsychologist in-person. Primary Outcomes: Physical Activity Engagement in voluntary physical activity in daily life was recorded during three periods of seven consecutive days, in each of the study phases (see Fig. 1 for an illustration of the study design). Seven consecutive days were chosen to ensure that participants wore the accelerometer for at least ≥ 4 (week and/or weekend) days for ≥ 10 h/day of waking hours. The first recording took place on either week two or week three of the study period; the second recording was taken on either week fourteen or fifteen and the third, within one week of the end of the study period, shortly after the end of the covid-19 lockdown. To measure physical activity and sedentary behaviours, an Actigraph wT3X-BT accelerometer (Actigraph, LLC; Pensacola FL, USA) was worn on the waist during each day of the recording periods (the device was not worn at night nor during bathing or water activities and only one participant wore the device during the exercise sessions- these recordings were subsequently removed during data processing). Physical activity and sedentary behaviours were analysed with the following criteria: Raw accelerometer data were downloaded and successively converted into 10-s epochs. Six consecutive epochs were summed to obtain activity counts per minute (cpm). All data were downloaded and processed using the ActiLife software (Firmware 4.4.0, Actigraph, LLC; Pensacola FL, USA). Based on cpm, physical activities were classified into sedentary (less than 100 cpm); light (between 100 and 1951 cpm), moderate (between 1952 and 5724 cpm), vigorous (between 5725 and 9498 cpm) and very vigorous physical activity (9499 cpm and above). For our primary outcomes, percent times in light physical activity (100–1951 cpm), moderate to vigorous physical activity (MVPA; ≥ 1952 cpm) and sedentary time (< 100 cpm) were calculated based on total daily recording minutes. Statistical Analysis All statistical analyses were performed using Jamovi (The Jamovi project, 2023), a R-based software. Linear mixed effects regression models were used to test for changes in our primary outcome (TMT-B) over time (beginning of phase A1 [baseline], beginning of Phase B [pre-exercise], post-phase B [post-exercise], and post-phase A2 [follow-up]). Mixed effects models are the recommended statistical technique( 27 ) for analyzing outcomes measured at repeated timepoints as they can properly account for correlation between repeated measures within subjects. Importantly, these models are suitable for small-N studies( 28 ). Separate models included each cognitive outcome as the response variable, assessment time (four repeated measures) as a fixed effect and a participant specific random intercept. Age and years of education were included as covariates in the model. Model assumptions were checked using Q-Q plots and residual vs fitted plots. Three planned comparisons were performed to test the effect of both introducing the intervention during phase B and removing it for Phase A2. These comparisons were 1) Pre-exercise phase B compared to baseline beginning of Phase A1 (to minimize and test for practice effects), 2) post-exercise phase B compared to pre-exercise phase B (main effect of the intervention) and 3) post-phase A2 (follow-up) compared to post-exercise phase B (the effect of removing the intervention). These planned comparisons allow one to test the effect of the addition of the Phase B intervention, whereby if the intervention has an effect, significant changes in outcomes would only be observed in the pre-to-post phase B comparison. Full model effect sizes are presented as marginal R squared. Planned comparisons of the mean change in the raw scores are presented with 95% confidence intervals and Bonferroni-corrected p-values, with significance set at p < = 0.05. Effect sizes and 95% confidence intervals are presented only for secondary cognitive outcomes. To test for changes in voluntary physical activity and inactivity, data were analysed at the group level using similar linear mixed effects models as previously described with assessment times being reduced to the three (during phase A, during phase B and during phase A2) assessment time points when Actigraph data were collected. Two planned comparisons per the study design to test for changes in PA as a function of Phase B were conducted testing Phase B to Phase A1 and Phase B to Phase A2. RESULTS Table 1 provides descriptive and demographic details for each participant, including a description of their injury, major cognitive deficits, and individual tailored rehabilitation programs. The exercise intervention was well tolerated by all the participants, and no negative events were reported. A mean adherence rate to the intervention sessions during Phase B of 72.22 ± 18.70% was recorded (individual adherence data are presented in the supplementary materials 1). Heart rate response to exercise was limited in the two individuals with motor impairments (P1 and P5) where mean time spent within the heart rate training zones during intervention sessions was minimal. Three participants spent > 50% of intervention sessions within the heart rate training zones and one participant spent ~ 25% of time within the heart rate training zones (supplementary material 2). Table 1 Participant characteristics and Phase A description Patient Time since injury Sex Age Cause of TBI Injury severity Main cognitive areas impaired at baseline Other areas affected Characteristics of individually-tailored outpatient neurorehabilitation P1 16 years Male 45 Work accident. Crushed by falling wall Severe. GCS: 4/15 Processing speed, selective and divided attention, perseverative errors and WM Behavioral and motor deficits. Hemiparesis and dysarthria. He is a wheelchair user, but can stand up with the aid of crutches. The patient spends around 8hr/day (on working days) doing multiple activities in an outpatient center (social activities, physiotherapy) P2 8 months Female 24 Motorbike accident. Frontal collision with a van Severe. GCS: 3/15 Comma (2 days). Required craniotomy to alleviate intracranial pressure. 3 months hospitalization Phonological fluency, planning, categorization, processing speed, alternating attention, naming, immediate and delayed memory Emotional deficits 3 sessions/week of neuropsychological rehabilitation at an outpatient center P3 4 years Male 43 Motorbike accident Severe. GCS: 3/15. Comma state for 15 days post-TBI Planning and WM Low emotional inhibitory capacity. He has, however, a high level of social inclusion and participates in many community events 1hr of neuropsychological rehabilitation every two weeks. He also participated as a volunteer at the rehabilitation center, helping to organize social activities P4 22 years Male 42 Motorbike accident Severe. GCS: 4/15 Comma states for 15 days post-TBI Phonological fluency, planning, categorization, processing speed, alternating attention, delayed memory and WM Behavioral and motor sequelae. Hemiparesis. He is a wheelchair user, but can stand up with the aid of crutches. He showed apathy and behavioral disinhibition 3h/week of rehabilitation in an outpatient center (physiotherapy, social activities) P5 15 months Male 62 Work accident. 4 story fall. Severe. GCS: 4/15 1 month hospitalization. Comma state for 20 days post-TBI Phonological fluency, planning, alternating attention, attention span, WM, immediate and delayed memory Polytrauma. Behavioral and motor impairments. 1hr/week of neuropsychological rehabilitation in an outpatient center P6 29 months Male 56 Car accident. Truck collision. Severe. GCS: 5/15 3 months of hospitalization Alternating attention, planning, categorization, immediate and delayed memory Polytrauma. Behavioral and physical alterations. Exophthalmos, that was surgically remediated shortly after the beginning of the study 2hr of neuropsychological rehabilitation every 2 weeks at two different centers. The patient decided to discontinue the rehabilitation sessions at the middle of the exercise stage of the study, but did not discontinue the exercise intervention. GCS: Glasgow Coma Scale, ≤ 8 = severe. Cognitive Function Mean (± SD) raw scores, full model results and effect sizes for each cognitive test at each assessment time point are found in Table 2 . Five of the six participants improved TMT-B performance more than 10% pre-to-post exercise (Fig. 2 ) which equates to a 0.66 SD increase in one participant and a one SD increase in three participants (Table 3 ). At the group level, a significant main effect of time was found for TMT-B [F(3, 13.02) = 3.67; P = .041] and TMTA-B [F(3,13.07) = 3.74; P = .039]. Planned comparisons showed significant improvements in TMT-B and TMT-B-A performance from pre-to-post phase B. Table 2 Cognitive function outcomes Test Baseline Pre-phase A1 Phase A1 Pre-exercise Phase B Post-exercise Phase A2 Post-phase A2 Main effect of time A1-Baseline Mean difference (95% CI) B-A1 Mean difference (95% CI) A2-B Mean difference (95% CI) TMT-B (seconds) 302 (132.8) 344 (165.5) 244 (78.4) 208 (103.4) F(3.13.02) = 3.67 P = .041 Marginal R 2 = 0.082 42.17 (-21.8; 106.1) -100.50* (-36.6; -164.4) 13.85 (-59.9; 87.6) B-A (seconds) 207 (73.4) 272 (155.6) 166 (68.3) 139 (61.4) F(3,13.07) = 3.74 P = .039 Marginal R 2 = 0.160 65.67 (-1.13; 132.5) -106.17* (-13.01; -172.96) 9.40 (-67.55; 86.4) TMT-A (seconds) 95.7 (75.1) 72.2 (40.1) 77.8 (44.3) 73.8 (48.7) F( 3 , 15 ) = 0.51 Marginal R 2 = 0.08 -0.17 (-0574; 0.232) 0.045 (-0.357; 0.449) -0.12 (-0.526; 0.28) ROCF-copy 35.2 (1.33) 34.3 (0.82) 34.3 (0.82) 36 (0) F( 3 , 15 ) = 5.56 Marginal R 2 = 0.425 -0.83 (-1.77;0.104) 0 (-0.937; 0.937) 1.66 (0.729; 2.60) ROCF-memory 19.1 (9.33) 21.3 (7.53) 19.2 (7.16) 21.9 (8.71) F( 3 , 15 ) = 0.92 Marginal R 2 = 0.346 2.25 (-1.97; 6.47) -2.166 (-6.38; 2.05) 2.75 (-1.47; 6.971) CST Categories 3.83 (3.06) 4 (3.58) 3.50 (3.56) 4.17 (3.54) F( 3 , 15 ) = 0.49 Marginal R 2 = 0.221 0.167 (-1.031; 1.36) -0.500 (-1.697; 0.697) 0.667 (-0531; 1.86) CST total errors 46.3 (15.1) 46.7 (16.5) 51.3 ( 21 ) 39.8 (16.7) F( 3 , 15 ) = 2.18 Marginal R 2 = 0.299 0.333 (-8.53; 9.198) 4.667 (-4.20; 13.532) -11.50 (2.637; 20.37) CST Perseverative errors 18.2 (13.3) 26.3 (16.5) 20.3 (20.4) 19 (14.8) F( 3 , 15 ) = 0.41 Marginal R 2 = 0.148 8.167 (-7.77; 24.10) -6.00 (-21.94; 9.94) -1.33 (-17.27; 14.60) TMT: trail making test. ROCF: Rey-Osterrieth complex figure test. CST: Card sorting task. Grey shading illustrates primary outcome. Effect sizes (R 2 ) are presented only for secondary outcomes. *: statistically significant after Bonferroni-correction for multiple comparisons. Table 3 Scaled scores for pre-to-post exercise change in trail-making test part B Participant ID Pre-exercise TMT-B scaled score Post-exercise TMT-B scaled score P1 2 (2.66 SD below the mean) 5 (increase by 1 SD) P2 6 (1.66 SD below the mean) 6 (no change) P3 9 (normal range) 10 (normal range) P4 2 (2.66 SD below the mean) 5 (increase by 1 SD) P5 2 (2.66 SD below the mean) 5 (increase by 1 SD) P6 6 (1.66 SD below the mean) 7 (increase by 0.66 SD) Scaled scores were calculated using the Neuronoma project for the Spanish population whereby the population mean is equal to 10 and a one standard deviation change is equal to three. Five of six participants were below the normal range at the beginning of the exercise intervention. Physical activity and inactivity outside of the intervention sessions A significant main effect of time was found for daily percent time spent in MVPA [F( 2,10 ) = 2.43; p = 0.046, marignal R 2 = 0.06). Planned comparisons showed that daily percent time spent in MVPA significantly increased in Phase B compared to Phase A1 (mean estimate increase: 1.958%, 95% CI: 0.624; 3.29 or 14.63 minutes, 95% CI 4.76; 24.50). No other significant main effects were seen for LPA or time spent sedentary (full model results are found in Table 3 ). Individual-level analyses of physical activity change are presented in supplementary materials 3. Table 4 Daily physical activity Actigraph measure Phase A1 Pre-exercise Phase B Post-exercise Phase A2 Post-phase A2 Main effect of time B-A1 Mean difference (95% CI) A2-B Mean difference (95% CI) % sedentary time 81 (6.56) 72.5 (11.32) 78.8 (6.66) F( 2 , 10 ) = 2.43 P = .13 Marginal R 2 = 0.159 -8.45 (-16.26; -0.639) 6.30 (-1.51; 14.11) % light PA 15.6 (6.14) 22.2 (12.75) 16.5 (4.66) F( 2 , 10 ) = 1.65 P = .24 Marginal R 2 = 0.075 0.304 (-0.030; 0.639) -0.202 (-0.536; 0.132) % MVPA 3.45 (2.50) 5.44 (3.50 4.70 (3.55) F( 2 , 10 ) = 4.25 P = .046 Marginal R 2 = 0.062 1.958* (0.624; 3.29) -0.707 (-2.04; 0.627) PA: physical activity. MVPA: moderate-to-vigorous physical activity. * indicates statistical significance after Bonferroni correction. DISCUSSION In this study we found that the addition of a 20-week supervised aerobic physical exercise intervention significantly increased executive function in chronic survivors of severe TBI. In addition, we found that voluntary engagement in physical activity, specifically MVPA, was increased during the intervention phase. Our results build on a limited literature of the effect of aerobic physical exercise on cognitive function in survivors of severe TBI and provide evidence that aerobic exercise is a potential efficacious treatment for chronic deficits in executive function in this population. A rich pre-clinical literature suggests that aerobic exercise is both neuroprotective and evokes mechanisms of neuroplasticity following TBI, resulting in significant improvements in cognitive function( 29 – 36 ). Nevertheless, these promising pre-clinical models have not been completely or successfully translated into human clinical studies ( 4 ). Several studies have shown no significant effect of aerobic exercise ( 10 , 11 , 37 ) on either objective cognitive tests (trail making test included) or cognitive scales such as the cognitive sub-scale of the functional independence measure. These two studies were short-term interventions (four and eight weeks) and included heterogenous participants in terms of injury severity. As such, it is possible that engagement in physical exercise for longer durations is necessary to result in significant improvements in cognitive function, which is also been shown to be the case in older adults with and without mild cognitive impairment( 38 ). Further, two other studies( 8 , 9 ) used interventions of three and six months, respectively, and found improvements in set shifting performance and subjective cognitive complaints. Our results add to this literature with inferences based on a more robust study design (compared to single arm studies) whereby compared to our no-intervention phase A, set shifting abilities were significantly improved when including 20-weeks of aerobic exercise delivered three-times per week to the participants’ rehabilitation. Importantly, five out of six participants increased performance by more than 10%, with four showing a population-based increase of around 1SD, which reflects an effect size that has been considered clinically meaningful in other population-normed studies( 39 ). Currently, no pharmacological agent has been proven to treat cognitive deficits in TBI. As such, alternative treatments have been developed and tested with promising results. For example, Schiff and colleagues( 13 ) tested the initial feasibility of thalamic deep brain stimulation to treat chronic cognitive deficits in individuals with moderate or severe TBI and reported significant improvements in set-shifting abilities (trail-making B). Another behavioural intervention, cognitive training, is ubiquitous in in-patient rehabilitation of TBI and has shown preliminary efficacy in improving performance on cognitive performance in brain injured populations( 40 , 41 ). Our results suggest that the effects of exercise lie predominantly with executive set shifting abilities, consistent with prior studies in TBI( 9 ). Nevertheless, prior work studying the effects of physical activity (of which physical exercise is a sub-component of) have shown large effects on quality of life( 42 ) and overall morbidity and mortality( 43 , 44 ). Therefore, this behavioural intervention can potentially have broader reaching benefits than comparable behavioural or invasive interventions for survivors of severe TBI. Voluntary engagement in physical activity outside of an exercise intervention study is important for the long-term adoption of this healthy lifestyle behaviour. If individuals with TBI make a behaviour change during participation in prescribed physical exercise such that they engage in more voluntary physical activity and less sedentary behaviour, then the cumulative effect of such interventions would be increased. Barriers to participation in physical activity have been studied in TBI populations( 18 , 19 ), and specific TBI barriers exists. One barrier that is consistently reported is a lack of advice or information on where and how to exercise. In one prior study, providing free access to local gymnasiums, Devine and colleagues( 20 ) showed that TBI survivors increased their voluntary physical activity. Our results suggest that when participants were engaged in supervised physical exercise, they too increased their voluntary physical activity habits, specifically the amount of time spent performing moderate-to-vigorous physical activity. It is possible therefore that in survivors of severe TBI, simply providing access and education on physical activity could be enough to increase voluntary participation in this lifestyle habit. Nevertheless, when looking at the individual physical activity data, only three of the six participants increased their physical activity. Consequently, individual behaviour change interventions are likely required to evoke behavioural change in every participant. Our study has several limitations that should be considered when interpreting the results. The small sample size limits the generalizability of our findings, notwithstanding, the use of linear mixed effects models enhances confidence in the statistical analysis and our use of percentage change in phase B allows one to make comparisons with comparable invasive interventions. However, a properly powered randomized study with a comparator condition will provide concrete inferences on the effect of this intervention in this population. Phase A2 was confounded by the closure of the rehabilitation centres due to the lockdown imposed because of the Covid-19 pandemic which may have affected the data collected during phase A2, particularly the voluntary physical activity recordings. Notwithstanding, this confound does not limit our confidence when making inferences comparing phase B to phase A1. The use of a single primary cognitive outcome measure limits the ability to test for broad changes in cognitive function as a result of this intervention and future studies should be properly powered to detect changes across a variety of cognitive outcomes. We provide the effect sizes and mean changes for several other executive function tasks to increase future hypothesis generation but avoid making statistical inferences on these outcomes. Lastly, only three participants exercised within the heart rate training zones during the supervised intervention sessions which highlights the difficulty in thresholding exercise intensity in severe TBI patients, which is consistent with prior studies( 17 ). Notwithstanding, time spent in heart rate training zones was not reflective of the individual effect sizes on cognitive outcomes. Future exercise studies need to develop protocols to threshold the intensity of aerobic exercise in moderate and severe TBI populations. CONCLUSIONS Supervised aerobic exercise is potentially effective at improving executive function deficits in chronic survivors of severe TBI. It is likely that sustained periods of exercise training are necessary to see beneficial effects. Trained personnel are required to engage severe TBI survivors in supervised exercise sessions which limits the scalability of this intervention however the results show the importance of physical activity-based interventions in chronic survivors of TBI. Simply engaging in supervised physical exercise may however be enough to encourage those with severe TBI to become more physically active in their daily life. More research is needed to discover the mechanisms of such a behaviour change. Declarations Ethics approval and consent to participate: This project was approved by the ethics committee for animal and human experimentation of the leading institution (CEEAH 4658). All the participants received verbal and written information about the study and signed informed consent prior to engaging in any research activities. All measures were taken to preserve the confidentiality of the individuals’ identity. Consent for publication: Not applicable. Availability of data and materials: The dataset used in the analysis during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding : No funding was obtained for this research. Author’ contributions: LPL wrote the protocols, collected all the assessments and delivered the exercise interventions. MCA conceptualised the study, supervised the data collection and performed the statistical analyses. MTG helped conceptualize the study. MFF analysed the actigraph data. GRO analysed the actigraph data. MGB helped conceive the study and oversaw the data analysis of the actigraph data. IPC helped conceive the study and its protocols. LC helped conceive the study and its protocols. DCM helped conceive the study and its protocols. TPM conceptualized the study, oversaw the statistical analysis and drafted the manuscript. All authors made significant contributions to the manuscript and gave their final approval. Acknowledgements : We would like the thank the directors of the rehabilitation centres who graciously gave their space for the conduct of this study. We would like the thank the participants and their families for participating in this research study. References Ruttan L, Martin K, Liu A, Colella B, Green RE. Long-term cognitive outcome in moderate to severe traumatic brain injury: a meta-analysis examining timed and untimed tests at 1 and 4.5 or more years after injury. Arch Phys Med Rehabil. 2008 Dec;89(12 Suppl):S69-76. Rabinowitz AR, Levin HS. Cognitive sequelae of traumatic brain injury. Psychiatr Clin North Am. 2014 Mar;37(1):1–11. Malá H, Rasmussen CP. 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Getting Fit to Counteract Cognitive Aging: Evidence and Future Directions. Physiol Bethesda Md. 2022 Jul 1;37(4):0. Gordon WA, Sliwinski M, Echo J, McLoughlin M, Sheerer M, Meili TE. The benefits of exercise in individuals with traumatic brain injury: A retrospective study. J Head Trauma Rehabil. 1998 Aug;13(4):58–67. Chin LM, Keyser RE, Dsurney J, Chan L. Improved cognitive performance following aerobic exercise training in people with traumatic brain injury. Arch Phys Med Rehabil. 2015;96(4):754–9. Bateman A, Culpan FJ, Pickering AD, Powell JH, Scott OM, Greenwood RJ. The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: A randomized controlled evaluation. Arch Phys Med Rehabil. 2001 Feb 1;82(2):174–82. McMillan T, Robertson IH, Brock D, Chorlton L. Brief mindfulness training for attentional problems after traumatic brain injury: A randomised control treatment trial. Neuropsychol Rehabil. 2002;12(2):117–25. Grealy MA, Johnson DA, Rushton SK. 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Interpreting the trail making test following traumatic brain injury: comparison of traditional time scores and derived indices. J Clin Exp Neuropsychol. 2005 Oct;27(7):897–906. Llinàs-Reglà J, Vilalta-Franch J, López-Pousa S, Calvó-Perxas L, Torrents Rodas D, Garre-Olmo J. The Trail Making Test. Assessment. 2017 Mar 1;24(2):183–96. Sánchez-Cubillo I, Periáñez JA, Adrover-Roig D, Rodríguez-Sánchez JM, Ríos-Lago M, Tirapu J, et al. Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc JINS. 2009;15(3):438–50. Tamayo F, Casals-Coll M, Sánchez-Benavides G, Quintana M, Manero RM, Rognoni T, et al. [Spanish normative studies in a young adult population (NEURONORMA young adults Project): norms for the verbal span, visuospatial span, Letter-Number Sequencing, Trail Making Test and Symbol Digit Modalities Test]. Neurol Barc Spain. 2012 Jul;27(6):319–29. Peña-Casanova J, Gramunt-Fombuena N, Quiñones-Úbeda S, Sánchez-Benavides G, Aguilar M, Badenes D, et al. Spanish Multicenter Normative Studies (NEURONORMA Project): norms for the Rey-Osterrieth complex figure (copy and memory), and free and cued selective reminding test. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol. 2009 Jun;24(4):371–93. Fox CJ, Mueller ST, Gray HM, Raber J, Piper BJ. Evaluation of a short-form of the Berg Card Sorting Test. PloS One [Internet]. 2013 May 14 [cited 2022 Feb 8];8(5). Available from: https://pubmed.ncbi.nlm.nih.gov/23691107/ Gueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. Arch Gen Psychiatry. 2004 Mar;61(3):310–7. Wiley RW, Rapp B. Statistical analysis in Small-N Designs: using linear mixed-effects modeling for evaluating intervention effectiveness. Aphasiology. 2019;33(1):1–30. Amorós-Aguilar L, Portell-Cortés I, Costa-Miserachs D, Torras-Garcia M, Riubugent-Camps È, Almolda B, et al. The benefits of voluntary physical exercise after traumatic brain injury on rat’s object recognition memory: A comparison of different temporal schedules. Exp Neurol. 2020 Apr;326:113178. Griesbach GS, Gomez-Pinilla F, Hovda DA. The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res. 2004 Aug 6;1016(2):154–62. Griesbach GS, Hovda DA, Gomez-Pinilla F. Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation. Brain Res. 2009 Sep 8;1288:105–15. Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, et al. Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury. J Neural Transm Vienna Austria 1996. 2011 Sep;118(9):1263–72. Buchmann Godinho D, da Silva Fiorin F, Schneider Oliveira M, Furian AF, Rechia Fighera M, Freire Royes LF. The immunological influence of physical exercise on TBI-induced pathophysiology: Crosstalk between the spleen, gut, and brain. Neurosci Biobehav Rev. 2021 Nov 1;130:15–30. Chytrova G, Ying Z, Gomez-Pinilla F. Exercise normalizes levels of MAG and Nogo-A growth inhibitors after brain trauma. Eur J Neurosci. 2008 Jan;27(1):1–11. Jacotte-Simancas A, Costa-Miserachs D, Coll-Andreu M, Torras-Garcia M, Borlongan CV, Portell-Cortés I. Effects of voluntary physical exercise, citicoline, and combined treatment on object recognition memory, neurogenesis, and neuroprotection after traumatic brain injury in rats. J Neurotrauma. 2015 May 15;32(10):739–51. Piao CS, Stoica BA, Wu J, Sabirzhanov B, Zhao Z, Cabatbat R, et al. Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury. Neurobiol Dis. 2013 Jun;54:252–63. Lee YSC, Ashman T, Shang A, Suzuki W. Brief report: Effects of exercise and self-affirmation intervention after traumatic brain injury. NeuroRehabilitation. 2014;35(1):57–65. Gomes-Osman J, Cabral DF, Morris TP, McInerney K, Cahalin LP, Rundek T, et al. Exercise for cognitive brain health in aging: A systematic review for an evaluation of dose. Neurol Clin Pract. 2018 Jun;8(3):257–65. Heaton RK, Psychological Assessment Resources I. Revised Comprehensive Norms for an Expanded Halstead-Reitan Battery: Demographically Adjusted Neuropsychological Norms for African American and Caucasian Adults, Professional Manual [Internet]. Psychological Assessment Resources; 2004. Available from: https://books.google.com/books?id=x9sJtwAACAAJ Bogdanova Y, Yee MK, Ho VT, Cicerone KD. Computerized Cognitive Rehabilitation of Attention and Executive Function in Acquired Brain Injury: A Systematic Review. J Head Trauma Rehabil. 2016;31(6):419–33. Sigmundsdottir L, Longley WA, Tate RL. Computerised cognitive training in acquired brain injury: A systematic review of outcomes using the International Classification of Functioning (ICF). Neuropsychol Rehabil. 2016 Oct;26(5–6):673–741. Marquez DX, Aguiñaga S, Vásquez PM, Conroy DE, Erickson KI, Hillman C, et al. A systematic review of physical activity and quality of life and well-being. Transl Behav Med. 2020 Oct 12;10(5):1098–109. Lee DH, Rezende LFM, Joh HK, Keum N, Ferrari G, Rey-Lopez JP, et al. Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults. Circulation. 2022 Aug 16;146(7):523–34. Zhao M, Veeranki SP, Magnussen CG, Xi B. Recommended physical activity and all cause and cause specific mortality in US adults: prospective cohort study. BMJ. 2020 Jul 1;370:m2031. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Published Journal Publication published 27 Sep, 2024 Read the published version in BMC Sports Science, Medicine and Rehabilitation → Version 1 posted Editorial decision: Revision requested 18 Jul, 2024 Editor assigned by journal 17 Jul, 2024 Submission checks completed at journal 17 Jul, 2024 First submitted to journal 15 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Bellaterra (Cerdanyola del Vallès)","correspondingAuthor":false,"prefix":"","firstName":"Lidia","middleName":"Pérez","lastName":"López","suffix":""},{"id":328565828,"identity":"d412af55-7dae-47af-a3dd-548b58f65c69","order_by":1,"name":"Margalida Coll-Andreu","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona. Bellaterra (Cerdanyola del Vallès)","correspondingAuthor":false,"prefix":"","firstName":"Margalida","middleName":"","lastName":"Coll-Andreu","suffix":""},{"id":328565829,"identity":"c89bf0f5-d3b3-470e-b62a-b93f3c9f0973","order_by":2,"name":"Meritxell Torras-Garcia","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona. 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Bellaterra (Cerdanyola del Vallès)","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Costa-Miserachs","suffix":""},{"id":328565836,"identity":"d6d19098-aed5-4200-bd42-293f42b948aa","order_by":9,"name":"Timothy P. Morris","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYDACZlSuBAM/iEoowK2DB6LFAKFFsgGkxQCHepAWBlQtQOYBNAF0YM/OncBcUPFHzryBO/Fx5R4Le+PzqxM/PDBgkOcXO4DDYbwbmGecMTCWOcC72fDMM4nEbTfebpYAOsxw5uwE3Fp42wwSZzDwbpNsOCCRYHbj7AaQlgSD2/i0/DOoh2mxN55xdvMPwloaDBIkoFoYN/D3bsNvy2HeDYdnHDM2nMEM9AtQS+KMG7zbLBIMJHD6hb3/7MbHBTVy8hLsvRsfNhyos+fvP7v55o8KG3l+aexaQOAwmIQnAwmwSgmcylEUQwD/AbyqR8EoGAWjYOQBANqcVXRrdxIcAAAAAElFTkSuQmCC","orcid":"","institution":"Northeastern University","correspondingAuthor":true,"prefix":"","firstName":"Timothy","middleName":"P.","lastName":"Morris","suffix":""}],"badges":[],"createdAt":"2024-07-15 14:06:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4743451/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4743451/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13102-024-00993-4","type":"published","date":"2024-09-27T15:57:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62652354,"identity":"2aeb0755-0327-40f1-9c76-fa7faca86f26","added_by":"auto","created_at":"2024-08-17 01:00:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34174,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design followed an A-B-A design, whereby phase B consisted of 20-weeks of supervised aerobic exercise sessions delivered three-times per week. Wrist-worn physical activity measurements were collected for seven consecutive days during each study phase. Cognitive function assessments were completed four times before and after each phase.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4743451/v1/e07faa8375cecff07526deb5.png"},{"id":62652353,"identity":"4a099342-786f-4abd-8132-7bed46b95483","added_by":"auto","created_at":"2024-08-17 01:00:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17507,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual percentage change in trail-making test B from pre-to-post exercise (phase B). All participants improved performance, with five of six increasing by more than 10%.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4743451/v1/0de7ed547c0a97f01ca6de8a.png"},{"id":65627748,"identity":"650d33e4-179c-459d-811b-86c2c2410e13","added_by":"auto","created_at":"2024-09-30 16:16:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":841659,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4743451/v1/5e5fc54d-bdd2-4355-a090-55b64459ed54.pdf"},{"id":62652352,"identity":"6d96ced1-29e0-405b-bf0d-488ae87f2710","added_by":"auto","created_at":"2024-08-17 01:00:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19314,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-4743451/v1/3d3c0eafa52e0af35710ffeb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Aerobic Exercise and Cognitive Function in Chronic Severe Traumatic Brain Injury Survivors: A Within-Subject A-B-A Intervention Study","fulltext":[{"header":"Background","content":"\u003cp\u003eSustained deficits in executive function, attention, memory, and processing speed are common following severe traumatic brain injury (TBI) and are a primary driver of poor quality of life and persistent functional disability in TBI survivors (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Around 65% of people who suffer moderate or severe TBI develop chronic cognitive deficits(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Yet, following acute and sub-acute rehabilitation, individuals re-integrating into community settings are faced with limited resources and no accessible or efficacious interventions to treat debilitating cognitive deficits. Long-term behavioural strategies such lifestyle interventions could significantly benefit individuals with lasting TBI-related deficits(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), but limited evidence of their effect exists(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn non-injured adults, aerobic physical exercise has been shown to effect broad domains of cognitive function, with the largest effect sizes being seen on executive function(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Physical activities are often used in within sub-acute rehabilitation settings, but limited high quality evidence exists of how regimented physical exercise regimes can affect cognition in the chronic stages of recovery from moderate-to-severe TBI(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Prior human studies of physical exercise on cognitive function in TBI have included both heterogenous populations and recovery stages (mix of acute and chronic), short-term interventions (four to 12 weeks), retrospective study designs and single-arm studies (\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Nevertheless, in several of these studies, improvements in cognitive function were reported, including improvements in executive function(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Additionally, alternative treatments are currently being tested and significant improvements in executive function have also been reported following invasive therapeutic interventions such as thalamic deep-brain stimulation in six individuals with chronic moderate-to-severe TBI (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). While such invasive intervention shows promise for chronic severe TBI survivors, if similar gains can be achieved with non-invasive interventions, then more individuals living with chronic cognitive deficits from injury would benefit from accessible, economic and safe interventions.\u003c/p\u003e \u003cp\u003eAn additional consideration with behavioural lifestyle interventions is the ability of individuals with cognitive deficits to voluntarily engage in the healthy behaviour outside of the prescribed intervention sessions. Executive function, cortical brain regions underpinning executive function and psychosocial constructs such as exercise self-efficacy are related to voluntary engagement in physical activity and exercise in non-injured adults(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Exercise interventions, even in sub-acute moderate-to-severe TBI have been shown to be feasible (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), but survivors of TBI report significant barriers to participation in physical exercise (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Importantly though, if given certain resources (e.g., free access to local gymnasiums), community-dwelling individuals with moderate-to-severe TBI will adhere to physical exercise(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, whether enrolment in a structured physical exercise intervention alone promotes adoption of physical activity outside of the intervention sessions in chronic severe TBI survivors is unknown. If individuals make a behaviour change because of participation of the structured intervention, then the long-term benefits of this intervention are increased.\u003c/p\u003e \u003cp\u003eCompared to currently non-effective pharmacological agents or promising invasive interventions such as deep brain stimulation, aerobic physical exercise represents is an accessible, non-invasive and long-term behavioural intervention that can potentially treat cognitive deficits in individuals with chronic severe TBI. Therefore, this study had two aims; 1) to test the effect of a 20-week aerobic physical exercise intervention on cognitive function in individuals with chronic severe TBI and 2) test the effect of the intervention on voluntary engagement in daily physical activity levels outside of the intervention sessions. We tested these aims using a within-subjects A-B-A study design with phase B consisting of 20 weeks of aerobic physical exercise sessions delivered three-times per week.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eParticipants were recruited from two ambulatory neurorehabilitation centres. All patients from both centres who met the following inclusion criteria were invited to participate in the study: 1) a severe TBI, defined as a score between 3 and 8 in Glasgow comma scale at time of injury; 2) a minimum of 8 months since injury; 3) lack of medical contraindications to engage in physical exercise of moderate or vigorous intensity; 4) preserved communication abilities to perform neuropsychological assessments, and to give informed consent. Eight patients fulfilled these criteria two of whom declined to enrol in the study. The final sample consisted of 6 individuals (5 male, 1 female). This project was approved by the ethics committee for animal and human experimentation of the leading institution (CEEAH 4658). All the participants received verbal and written information about the study and signed informed consent. All measures were taken to preserve the confidentiality of the individuals\u0026rsquo; identity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis was a single-arm within-subject study that followed an A-B-A design (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Three phases (20 weeks each) were designed as follows; Phase A1: Ongoing individually tailored outpatient neurorehabilitation (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for a complete description); Phase B: tailored outpatient neurorehabilitation plus scheduled aerobic physical exercise (three sessions per week, 30 minutes/session); Phase A2: Tailored outpatient rehabilitation without the physical exercise intervention. The closure of the rehabilitation centres in response to the first wave of the covid-19 pandemic reduced Phase B to 17 weeks in five participants and online rehabilitation was provided to the participants in phase A2. Cognitive function was assessed at the beginning and end of each study phase. Daily physical activity levels were measured for seven consecutive days in each phase of the study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAerobic Exercise Intervention (Phase B)\u003c/h2\u003e \u003cp\u003eThe aerobic exercise intervention was delivered in-person within each rehabilitation centre using either a cycling rehabilitation trainer (MOTOmed Viva 2 leg trainer; RECK-technik GmbH \u0026amp; Co.KG; Betzenweiler, Germany) for two participants with motor impairment, a stationary cycle ergometer (Decathlon; Domyos Essential) or combined the use of a treadmill (Domfit F1. BH Fitness; \u0026Aacute;lava, Spain) and a MOTOmed. Each session (~\u0026thinsp;30 minutes) consisted of a 5-minute warm up and cool down. Resting HR and blood pressure were recorded before and after each session with the use of a hand-held sphygmomanometer (Omron electronics; Barcelona; Spain). The intensity of exercise was progressively increased with a target heart rate intensity zone of 60\u0026ndash;80% heart rate reserve (HRR). The corresponding heart rate in beats per minute was calculated suing the Karvonen equation ([220-age]-resting heart rate x intended % HRR\u0026thinsp;+\u0026thinsp;resting heart rate) set from the 3rd week onwards. Intensity zones were re-calculated every four weeks to account for any changes in resting heart rate. Heart rate was continuously recorded during the exercise sessions by means of a wrist pulsometer (Polar M430; Polar Electro; Kempele, Finland). Participants were asked to rate their perceived exertion and comfort/distress every five minutes using Borg\u0026rsquo;s scale (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) of perceived exertion and a visual analogue scale, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcomes: Cognitive Function\u003c/h2\u003e \u003cp\u003eWe defined our primary outcome measure in this analysis as trail making test part B (TMT-B), to be able to make direct comparisons with prior exercise studies(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and alternative treatments for cognitive deficits in moderate-to-severe traumatic brain injury (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Trail making B is thought of as an executive control measure testing working memory and set shifting abilities (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Given the severe deficits of the participants in this study, we did not limit their response time. Raw completion time scores are used in subsequent statistical analyses, and we also present percentage change and scaled normative scores to increase interpretability. Normalized scaled scores were calculated based on the Neuronorma project for the Spanish population(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) whereby the population mean is 10 and a one standard deviation change is equal to three. Additionally, to reduce the influence of slowed motor and visuomotor function on performance of the TMT-B, we also tested the difference score of TMT-B minus TMT-A (B-A).\u003c/p\u003e \u003cp\u003eSeveral additional executive function assessments were collected as executive function is particularly vulnerable to injury and has been shown to be modulated by aerobic exercise in other populations. These included the Rey-Osterrieth complex figure test, including a copy phase (perceptual and motor capacity) and a memory phase (30 min later), measuring visuospatial memory(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) and The Card Sorting Test (CST), using the short-form of the Berg\u0026rsquo;s CST (Psychology Experimental Building Language -PEBL) (64 cards instead of the 128 used in the long form)(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), which assesses ability to change strategies based on the demands of the task as a measure of flexibility. All tests were administered by a trained neuropsychologist in-person.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcomes: Physical Activity\u003c/h2\u003e \u003cp\u003eEngagement in voluntary physical activity in daily life was recorded during three periods of seven consecutive days, in each of the study phases (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for an illustration of the study design). Seven consecutive days were chosen to ensure that participants wore the accelerometer for at least\u0026thinsp;\u0026ge;\u0026thinsp;4 (week and/or weekend) days for \u0026ge;\u0026thinsp;10 h/day of waking hours. The first recording took place on either week two or week three of the study period; the second recording was taken on either week fourteen or fifteen and the third, within one week of the end of the study period, shortly after the end of the covid-19 lockdown. To measure physical activity and sedentary behaviours, an Actigraph wT3X-BT accelerometer (Actigraph, LLC; Pensacola FL, USA) was worn on the waist during each day of the recording periods (the device was not worn at night nor during bathing or water activities and only one participant wore the device during the exercise sessions- these recordings were subsequently removed during data processing). Physical activity and sedentary behaviours were analysed with the following criteria: Raw accelerometer data were downloaded and successively converted into 10-s epochs. Six consecutive epochs were summed to obtain activity counts per minute (cpm). All data were downloaded and processed using the ActiLife software (Firmware 4.4.0, Actigraph, LLC; Pensacola FL, USA). Based on cpm, physical activities were classified into sedentary (less than 100 cpm); light (between 100 and 1951 cpm), moderate (between 1952 and 5724 cpm), vigorous (between 5725 and 9498 cpm) and very vigorous physical activity (9499 cpm and above). For our primary outcomes, percent times in light physical activity (100\u0026ndash;1951 cpm), moderate to vigorous physical activity (MVPA; \u0026ge; 1952 cpm) and sedentary time (\u0026lt;\u0026thinsp;100 cpm) were calculated based on total daily recording minutes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using Jamovi (The Jamovi project, 2023), a R-based software. Linear mixed effects regression models were used to test for changes in our primary outcome (TMT-B) over time (beginning of phase A1 [baseline], beginning of Phase B [pre-exercise], post-phase B [post-exercise], and post-phase A2 [follow-up]). Mixed effects models are the recommended statistical technique(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) for analyzing outcomes measured at repeated timepoints as they can properly account for correlation between repeated measures within subjects. Importantly, these models are suitable for small-N studies(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Separate models included each cognitive outcome as the response variable, assessment time (four repeated measures) as a fixed effect and a participant specific random intercept. Age and years of education were included as covariates in the model. Model assumptions were checked using Q-Q plots and residual vs fitted plots. Three planned comparisons were performed to test the effect of both introducing the intervention during phase B and removing it for Phase A2. These comparisons were 1) Pre-exercise phase B compared to baseline beginning of Phase A1 (to minimize and test for practice effects), 2) post-exercise phase B compared to pre-exercise phase B (main effect of the intervention) and 3) post-phase A2 (follow-up) compared to post-exercise phase B (the effect of removing the intervention). These planned comparisons allow one to test the effect of the addition of the Phase B intervention, whereby if the intervention has an effect, significant changes in outcomes would only be observed in the pre-to-post phase B comparison. Full model effect sizes are presented as marginal R squared. Planned comparisons of the mean change in the raw scores are presented with 95% confidence intervals and Bonferroni-corrected p-values, with significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;=\u0026thinsp;0.05. Effect sizes and 95% confidence intervals are presented only for secondary cognitive outcomes. To test for changes in voluntary physical activity and inactivity, data were analysed at the group level using similar linear mixed effects models as previously described with assessment times being reduced to the three (during phase A, during phase B and during phase A2) assessment time points when Actigraph data were collected. Two planned comparisons per the study design to test for changes in PA as a function of Phase B were conducted testing Phase B to Phase A1 and Phase B to Phase A2.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides descriptive and demographic details for each participant, including a description of their injury, major cognitive deficits, and individual tailored rehabilitation programs. The exercise intervention was well tolerated by all the participants, and no negative events were reported. A mean adherence rate to the intervention sessions during Phase B of 72.22\u0026thinsp;\u0026plusmn;\u0026thinsp;18.70% was recorded (individual adherence data are presented in the supplementary materials 1). Heart rate response to exercise was limited in the two individuals with motor impairments (P1 and P5) where mean time spent within the heart rate training zones during intervention sessions was minimal. Three participants spent\u0026thinsp;\u0026gt;\u0026thinsp;50% of intervention sessions within the heart rate training zones and one participant spent\u0026thinsp;~\u0026thinsp;25% of time within the heart rate training zones (supplementary material 2).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParticipant characteristics and Phase A description\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime since injury\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCause of TBI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInjury severity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMain cognitive areas impaired at baseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOther areas affected\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCharacteristics of individually-tailored outpatient neurorehabilitation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWork accident. Crushed by falling wall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere. GCS: 4/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eProcessing speed, selective and divided attention, perseverative errors and WM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBehavioral and motor deficits. Hemiparesis and dysarthria. He is a wheelchair user, but can stand up with the aid of crutches.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eThe patient spends around 8hr/day (on working days) doing multiple activities in an outpatient center (social activities, physiotherapy)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMotorbike accident. Frontal collision with a van\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere. GCS: 3/15\u003c/p\u003e \u003cp\u003eComma (2 days). Required craniotomy to alleviate intracranial pressure. 3 months hospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePhonological fluency, planning, categorization, processing speed, alternating attention, naming, immediate and delayed memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEmotional deficits\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3 sessions/week of neuropsychological rehabilitation at an outpatient center\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMotorbike accident\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere. GCS: 3/15. Comma state for 15 days post-TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePlanning and WM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow emotional inhibitory capacity. He has, however, a high level of social inclusion and participates in many community events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1hr of neuropsychological rehabilitation every two weeks. He also participated as a volunteer at the rehabilitation center, helping to organize social activities\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMotorbike accident\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere.\u003c/p\u003e \u003cp\u003eGCS: 4/15 Comma states for 15 days post-TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePhonological fluency, planning, categorization, processing speed, alternating attention, delayed memory and WM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBehavioral and motor sequelae. Hemiparesis. He is a wheelchair user, but can stand up with the aid of crutches.\u003c/p\u003e \u003cp\u003eHe showed apathy and behavioral disinhibition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3h/week of rehabilitation in an outpatient center (physiotherapy, social activities)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWork accident. 4 story fall.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere. GCS: 4/15\u003c/p\u003e \u003cp\u003e1 month hospitalization. Comma state for 20 days post-TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePhonological fluency, planning, alternating attention, attention span, WM, immediate and delayed memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePolytrauma.\u003c/p\u003e \u003cp\u003eBehavioral and motor impairments.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1hr/week of neuropsychological rehabilitation in an outpatient center\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCar accident. Truck collision.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere. GCS: 5/15\u003c/p\u003e \u003cp\u003e3 months of hospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAlternating attention, planning, categorization, immediate and delayed memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePolytrauma. Behavioral and physical alterations. Exophthalmos, that was surgically remediated shortly after the beginning of the study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2hr of neuropsychological rehabilitation every 2 weeks at two different centers.\u003c/p\u003e \u003cp\u003eThe patient decided to discontinue the rehabilitation sessions at the middle of the exercise stage of the study, but did not discontinue the exercise intervention.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eGCS: Glasgow Coma Scale, \u0026le;\u0026nbsp;8\u0026thinsp;=\u0026thinsp;severe.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCognitive Function\u003c/h2\u003e \u003cp\u003eMean (\u0026plusmn;\u0026thinsp;SD) raw scores, full model results and effect sizes for each cognitive test at each assessment time point are found in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Five of the six participants improved TMT-B performance more than 10% pre-to-post exercise (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) which equates to a 0.66 SD increase in one participant and a one SD increase in three participants (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). At the group level, a significant main effect of time was found for TMT-B [F(3, 13.02)\u0026thinsp;=\u0026thinsp;3.67; P\u0026thinsp;=\u0026thinsp;.041] and TMTA-B [F(3,13.07)\u0026thinsp;=\u0026thinsp;3.74; P\u0026thinsp;=\u0026thinsp;.039]. Planned comparisons showed significant improvements in TMT-B and TMT-B-A performance from pre-to-post phase B.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCognitive function outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003cp\u003ePre-phase A1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhase A1\u003c/p\u003e \u003cp\u003ePre-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase B\u003c/p\u003e \u003cp\u003ePost-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePhase A2\u003c/p\u003e \u003cp\u003ePost-phase A2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMain effect of time\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eA1-Baseline\u003c/p\u003e \u003cp\u003eMean difference (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-A1\u003c/p\u003e \u003cp\u003eMean difference (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eA2-B\u003c/p\u003e \u003cp\u003eMean difference (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-B\u003c/p\u003e \u003cp\u003e(seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e302 (132.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e344 (165.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e244 (78.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e208 (103.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(3.13.02)\u0026thinsp;=\u0026thinsp;3.67\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;.041\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42.17\u003c/p\u003e \u003cp\u003e(-21.8; 106.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-100.50*\u003c/p\u003e \u003cp\u003e(-36.6; -164.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13.85\u003c/p\u003e \u003cp\u003e(-59.9; 87.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB-A\u003c/p\u003e \u003cp\u003e(seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e207 (73.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e272 (155.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e166 (68.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e139 (61.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(3,13.07)\u0026thinsp;=\u0026thinsp;3.74\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;.039\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e65.67\u003c/p\u003e \u003cp\u003e(-1.13; 132.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-106.17*\u003c/p\u003e \u003cp\u003e(-13.01; -172.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.40\u003c/p\u003e \u003cp\u003e(-67.55; 86.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-A\u003c/p\u003e \u003cp\u003e(seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95.7 (75.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.2 (40.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.8 (44.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.8 (48.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.51\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.17\u003c/p\u003e \u003cp\u003e(-0574; 0.232)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003cp\u003e(-0.357; 0.449)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.12\u003c/p\u003e \u003cp\u003e(-0.526; 0.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROCF-copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.2 (1.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.3 (0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.3 (0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;5.56\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.425\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.83\u003c/p\u003e \u003cp\u003e(-1.77;0.104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e(-0.937; 0.937)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003cp\u003e(0.729; 2.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROCF-memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.1 (9.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3 (7.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.2 (7.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.9 (8.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.92\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.346\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003cp\u003e(-1.97; 6.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-2.166\u003c/p\u003e \u003cp\u003e(-6.38; 2.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.75\u003c/p\u003e \u003cp\u003e(-1.47; 6.971)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCST Categories\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.83 (3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.50 (3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.17 (3.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.49\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003cp\u003e(-1.031; 1.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.500\u003c/p\u003e \u003cp\u003e(-1.697; 0.697)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.667\u003c/p\u003e \u003cp\u003e(-0531; 1.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCST total errors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.3 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46.7 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.3 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.8 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;2.18\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003cp\u003e(-8.53; 9.198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.667\u003c/p\u003e \u003cp\u003e(-4.20; 13.532)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-11.50\u003c/p\u003e \u003cp\u003e(2.637; 20.37)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCST Perseverative errors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.2 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.3 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.3 (20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.41\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.167\u003c/p\u003e \u003cp\u003e(-7.77; 24.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-6.00\u003c/p\u003e \u003cp\u003e(-21.94; 9.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-1.33\u003c/p\u003e \u003cp\u003e(-17.27; 14.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eTMT: trail making test. ROCF: Rey-Osterrieth complex figure test. CST: Card sorting task. Grey shading illustrates primary outcome. Effect sizes (R\u003csup\u003e2\u003c/sup\u003e) are presented only for secondary outcomes. *: statistically significant after Bonferroni-correction for multiple comparisons.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eScaled scores for pre-to-post exercise change in trail-making test part B\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipant ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-exercise TMT-B scaled score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-exercise TMT-B scaled score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.66 SD below the mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (increase by 1 SD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1.66 SD below the mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (no change)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (normal range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (normal range)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.66 SD below the mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (increase by 1 SD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.66 SD below the mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (increase by 1 SD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1.66 SD below the mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (increase by 0.66 SD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eScaled scores were calculated using the Neuronoma project for the Spanish population whereby the population mean is equal to 10 and a one standard deviation change is equal to three. Five of six participants were below the normal range at the beginning of the exercise intervention.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePhysical activity and inactivity outside of the intervention sessions\u003c/h2\u003e \u003cp\u003eA significant main effect of time was found for daily percent time spent in MVPA [F(\u003csub\u003e2,10\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;2.43; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046, \u003csub\u003emarignal\u003c/sub\u003eR\u003csup\u003e2\u003c/sup\u003e = 0.06). Planned comparisons showed that daily percent time spent in MVPA significantly increased in Phase B compared to Phase A1 (mean estimate increase: 1.958%, 95% CI: 0.624; 3.29 or 14.63 minutes, 95% CI 4.76; 24.50). No other significant main effects were seen for LPA or time spent sedentary (full model results are found in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Individual-level analyses of physical activity change are presented in supplementary materials 3.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDaily physical activity\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActigraph measure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhase A1\u003c/p\u003e \u003cp\u003ePre-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhase B\u003c/p\u003e \u003cp\u003ePost-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhase A2\u003c/p\u003e \u003cp\u003ePost-phase A2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMain effect of time\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eB-A1\u003c/p\u003e \u003cp\u003eMean difference\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eA2-B\u003c/p\u003e \u003cp\u003eMean difference (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% sedentary time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (6.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.5 (11.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78.8 (6.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;2.43\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;.13\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-8.45\u003c/p\u003e \u003cp\u003e(-16.26; -0.639)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.30\u003c/p\u003e \u003cp\u003e(-1.51; 14.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% light PA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6 (6.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2 (12.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.5 (4.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;1.65\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;.24\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003cp\u003e(-0.030; 0.639)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.202\u003c/p\u003e \u003cp\u003e(-0.536; 0.132)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% MVPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.45 (2.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.44 (3.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.70 (3.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;4.25\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;.046\u003c/p\u003e \u003cp\u003eMarginal R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.958*\u003c/p\u003e \u003cp\u003e(0.624; 3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.707\u003c/p\u003e \u003cp\u003e(-2.04; 0.627)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003ePA: physical activity. MVPA: moderate-to-vigorous physical activity. * indicates statistical significance after Bonferroni correction.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study we found that the addition of a 20-week supervised aerobic physical exercise intervention significantly increased executive function in chronic survivors of severe TBI. In addition, we found that voluntary engagement in physical activity, specifically MVPA, was increased during the intervention phase. Our results build on a limited literature of the effect of aerobic physical exercise on cognitive function in survivors of severe TBI and provide evidence that aerobic exercise is a potential efficacious treatment for chronic deficits in executive function in this population.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA rich pre-clinical literature suggests that aerobic exercise is both neuroprotective and evokes mechanisms of neuroplasticity following TBI, resulting in significant improvements in cognitive function(\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Nevertheless, these promising pre-clinical models have not been completely or successfully translated into human clinical studies (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Several studies have shown no significant effect of aerobic exercise (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) on either objective cognitive tests (trail making test included) or cognitive scales such as the cognitive sub-scale of the functional independence measure. These two studies were short-term interventions (four and eight weeks) and included heterogenous participants in terms of injury severity. As such, it is possible that engagement in physical exercise for longer durations is necessary to result in significant improvements in cognitive function, which is also been shown to be the case in older adults with and without mild cognitive impairment(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Further, two other studies(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) used interventions of three and six months, respectively, and found improvements in set shifting performance and subjective cognitive complaints. Our results add to this literature with inferences based on a more robust study design (compared to single arm studies) whereby compared to our no-intervention phase A, set shifting abilities were significantly improved when including 20-weeks of aerobic exercise delivered three-times per week to the participants\u0026rsquo; rehabilitation. Importantly, five out of six participants increased performance by more than 10%, with four showing a population-based increase of around 1SD, which reflects an effect size that has been considered clinically meaningful in other population-normed studies(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCurrently, no pharmacological agent has been proven to treat cognitive deficits in TBI. As such, alternative treatments have been developed and tested with promising results. For example, Schiff and colleagues(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) tested the initial feasibility of thalamic deep brain stimulation to treat chronic cognitive deficits in individuals with moderate or severe TBI and reported significant improvements in set-shifting abilities (trail-making B). Another behavioural intervention, cognitive training, is ubiquitous in in-patient rehabilitation of TBI and has shown preliminary efficacy in improving performance on cognitive performance in brain injured populations(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Our results suggest that the effects of exercise lie predominantly with executive set shifting abilities, consistent with prior studies in TBI(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Nevertheless, prior work studying the effects of physical activity (of which physical exercise is a sub-component of) have shown large effects on quality of life(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) and overall morbidity and mortality(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Therefore, this behavioural intervention can potentially have broader reaching benefits than comparable behavioural or invasive interventions for survivors of severe TBI.\u003c/p\u003e \u003cp\u003eVoluntary engagement in physical activity outside of an exercise intervention study is important for the long-term adoption of this healthy lifestyle behaviour. If individuals with TBI make a behaviour change during participation in prescribed physical exercise such that they engage in more voluntary physical activity and less sedentary behaviour, then the cumulative effect of such interventions would be increased. Barriers to participation in physical activity have been studied in TBI populations(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and specific TBI barriers exists. One barrier that is consistently reported is a lack of advice or information on where and how to exercise. In one prior study, providing free access to local gymnasiums, Devine and colleagues(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) showed that TBI survivors increased their voluntary physical activity. Our results suggest that when participants were engaged in supervised physical exercise, they too increased their voluntary physical activity habits, specifically the amount of time spent performing moderate-to-vigorous physical activity. It is possible therefore that in survivors of severe TBI, simply providing access and education on physical activity could be enough to increase voluntary participation in this lifestyle habit. Nevertheless, when looking at the individual physical activity data, only three of the six participants increased their physical activity. Consequently, individual behaviour change interventions are likely required to evoke behavioural change in every participant.\u003c/p\u003e \u003cp\u003eOur study has several limitations that should be considered when interpreting the results. The small sample size limits the generalizability of our findings, notwithstanding, the use of linear mixed effects models enhances confidence in the statistical analysis and our use of percentage change in phase B allows one to make comparisons with comparable invasive interventions. However, a properly powered randomized study with a comparator condition will provide concrete inferences on the effect of this intervention in this population. Phase A2 was confounded by the closure of the rehabilitation centres due to the lockdown imposed because of the Covid-19 pandemic which may have affected the data collected during phase A2, particularly the voluntary physical activity recordings. Notwithstanding, this confound does not limit our confidence when making inferences comparing phase B to phase A1. The use of a single primary cognitive outcome measure limits the ability to test for broad changes in cognitive function as a result of this intervention and future studies should be properly powered to detect changes across a variety of cognitive outcomes. We provide the effect sizes and mean changes for several other executive function tasks to increase future hypothesis generation but avoid making statistical inferences on these outcomes. Lastly, only three participants exercised within the heart rate training zones during the supervised intervention sessions which highlights the difficulty in thresholding exercise intensity in severe TBI patients, which is consistent with prior studies(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Notwithstanding, time spent in heart rate training zones was not reflective of the individual effect sizes on cognitive outcomes. Future exercise studies need to develop protocols to threshold the intensity of aerobic exercise in moderate and severe TBI populations.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eSupervised aerobic exercise is potentially effective at improving executive function deficits in chronic survivors of severe TBI. It is likely that sustained periods of exercise training are necessary to see beneficial effects. Trained personnel are required to engage severe TBI survivors in supervised exercise sessions which limits the scalability of this intervention however the results show the importance of physical activity-based interventions in chronic survivors of TBI. Simply engaging in supervised physical exercise may however be enough to encourage those with severe TBI to become more physically active in their daily life. More research is needed to discover the mechanisms of such a behaviour change.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis project was approved by the ethics committee for animal and human experimentation of the leading institution (CEEAH 4658). All the participants received verbal and written information about the study and signed informed consent prior to engaging in any research activities. All measures were taken to preserve the confidentiality of the individuals\u0026rsquo; identity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u0026nbsp;Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials: \u003c/strong\u003eThe dataset used in the analysis during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;No funding was obtained for this research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo; contributions:\u003c/strong\u003e\u0026nbsp;LPL wrote the protocols, collected all the assessments and delivered the exercise interventions. MCA conceptualised the study, supervised the data collection and performed the statistical analyses. MTG helped conceptualize the study. MFF analysed the actigraph data. GRO analysed the actigraph data. MGB helped conceive the study and oversaw the data analysis of the actigraph data. IPC helped conceive the study and its protocols. LC helped conceive the study and its protocols. DCM helped conceive the study and its protocols. TPM conceptualized the study, oversaw the statistical analysis and drafted the manuscript. All authors made significant contributions to the manuscript and gave their final approval.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We would like the thank the directors of the rehabilitation centres who graciously gave their space for the conduct of this study. We would like the thank the participants and their families for participating in this research study. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRuttan L, Martin K, Liu A, Colella B, Green RE. Long-term cognitive outcome in moderate to severe traumatic brain injury: a meta-analysis examining timed and untimed tests at 1 and 4.5 or more years after injury. Arch Phys Med Rehabil. 2008 Dec;89(12 Suppl):S69-76. \u003c/li\u003e\n\u003cli\u003eRabinowitz AR, Levin HS. Cognitive sequelae of traumatic brain injury. Psychiatr Clin North Am. 2014 Mar;37(1):1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eMal\u0026aacute; H, Rasmussen CP. The effect of combined therapies on recovery after acquired brain injury: Systematic review of preclinical studies combining enriched environment, exercise, or task-specific training with other therapies. 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Physiol Bethesda Md. 2022 Jul 1;37(4):0. \u003c/li\u003e\n\u003cli\u003eGordon WA, Sliwinski M, Echo J, McLoughlin M, Sheerer M, Meili TE. The benefits of exercise in individuals with traumatic brain injury: A retrospective study. J Head Trauma Rehabil. 1998 Aug;13(4):58\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eChin LM, Keyser RE, Dsurney J, Chan L. Improved cognitive performance following aerobic exercise training in people with traumatic brain injury. Arch Phys Med Rehabil. 2015;96(4):754\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eBateman A, Culpan FJ, Pickering AD, Powell JH, Scott OM, Greenwood RJ. The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: A randomized controlled evaluation. Arch Phys Med Rehabil. 2001 Feb 1;82(2):174\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eMcMillan T, Robertson IH, Brock D, Chorlton L. Brief mindfulness training for attentional problems after traumatic brain injury: A randomised control treatment trial. Neuropsychol Rehabil. 2002;12(2):117\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eGrealy MA, Johnson DA, Rushton SK. Improving cognitive function after brain injury: The use of exercise and virtual reality. Arch Phys Med Rehabil. 1999 Jun 1;80(6):661\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSchiff ND, Giacino JT, Butson CR, Choi EY, Baker JL, O\u0026rsquo;Sullivan KP, et al. Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. Nat Med. 2023 Dec;29(12):3162\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eG\u0026uuml;rdere C, Strobach T, Pastore M, Pfeffer I. Do executive functions predict physical activity behavior? A meta-analysis. BMC Psychol. 2023 Feb 2;11(1):33. \u003c/li\u003e\n\u003cli\u003eMorris TP, Burzynska A, Voss M, Fanning J, Salerno EA, Prakash R, et al. 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J Funct Morphol Kinesiol. 2018 Sep 14;3(3):47. \u003c/li\u003e\n\u003cli\u003ePham T, Green R, Neaves S, Hynan LS, Bell KR, Juengst SB, et al. Physical activity and perceived barriers in individuals with moderate-to-severe traumatic brain injury. PM R. 2022 May 20; \u003c/li\u003e\n\u003cli\u003eDevine JM, Wong B, Gervino E, Pascual-Leone A, Alexander MP. Independent, Community-Based Aerobic Exercise Training for People With Moderate-to-Severe Traumatic Brain Injury. Arch Phys Med Rehabil. 2016 Aug;97(8):1392\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eLange RT, Iverson GL, Zakrzewski MJ, Ethel-King PE, Franzen MD. Interpreting the trail making test following traumatic brain injury: comparison of traditional time scores and derived indices. J Clin Exp Neuropsychol. 2005 Oct;27(7):897\u0026ndash;906. \u003c/li\u003e\n\u003cli\u003eLlin\u0026agrave;s-Regl\u0026agrave; J, Vilalta-Franch J, L\u0026oacute;pez-Pousa S, Calv\u0026oacute;-Perxas L, Torrents Rodas D, Garre-Olmo J. The Trail Making Test. Assessment. 2017 Mar 1;24(2):183\u0026ndash;96. \u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Cubillo I, Peri\u0026aacute;\u0026ntilde;ez JA, Adrover-Roig D, Rodr\u0026iacute;guez-S\u0026aacute;nchez JM, R\u0026iacute;os-Lago M, Tirapu J, et al. Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc JINS. 2009;15(3):438\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eTamayo F, Casals-Coll M, S\u0026aacute;nchez-Benavides G, Quintana M, Manero RM, Rognoni T, et al. [Spanish normative studies in a young adult population (NEURONORMA young adults Project): norms for the verbal span, visuospatial span, Letter-Number Sequencing, Trail Making Test and Symbol Digit Modalities Test]. Neurol Barc Spain. 2012 Jul;27(6):319\u0026ndash;29. \u003c/li\u003e\n\u003cli\u003ePe\u0026ntilde;a-Casanova J, Gramunt-Fombuena N, Qui\u0026ntilde;ones-\u0026Uacute;beda S, S\u0026aacute;nchez-Benavides G, Aguilar M, Badenes D, et al. Spanish Multicenter Normative Studies (NEURONORMA Project): norms for the Rey-Osterrieth complex figure (copy and memory), and free and cued selective reminding test. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol. 2009 Jun;24(4):371\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eFox CJ, Mueller ST, Gray HM, Raber J, Piper BJ. Evaluation of a short-form of the Berg Card Sorting Test. PloS One [Internet]. 2013 May 14 [cited 2022 Feb 8];8(5). Available from: https://pubmed.ncbi.nlm.nih.gov/23691107/\u003c/li\u003e\n\u003cli\u003eGueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. Arch Gen Psychiatry. 2004 Mar;61(3):310\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWiley RW, Rapp B. Statistical analysis in Small-N Designs: using linear mixed-effects modeling for evaluating intervention effectiveness. Aphasiology. 2019;33(1):1\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eAmor\u0026oacute;s-Aguilar L, Portell-Cort\u0026eacute;s I, Costa-Miserachs D, Torras-Garcia M, Riubugent-Camps \u0026Egrave;, Almolda B, et al. The benefits of voluntary physical exercise after traumatic brain injury on rat\u0026rsquo;s object recognition memory: A comparison of different temporal schedules. Exp Neurol. 2020 Apr;326:113178. \u003c/li\u003e\n\u003cli\u003eGriesbach GS, Gomez-Pinilla F, Hovda DA. The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res. 2004 Aug 6;1016(2):154\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eGriesbach GS, Hovda DA, Gomez-Pinilla F. Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation. Brain Res. 2009 Sep 8;1288:105\u0026ndash;15. \u003c/li\u003e\n\u003cli\u003eItoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, et al. Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury. J Neural Transm Vienna Austria 1996. 2011 Sep;118(9):1263\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eBuchmann Godinho D, da Silva Fiorin F, Schneider Oliveira M, Furian AF, Rechia Fighera M, Freire Royes LF. The immunological influence of physical exercise on TBI-induced pathophysiology: Crosstalk between the spleen, gut, and brain. Neurosci Biobehav Rev. 2021 Nov 1;130:15\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eChytrova G, Ying Z, Gomez-Pinilla F. Exercise normalizes levels of MAG and Nogo-A growth inhibitors after brain trauma. Eur J Neurosci. 2008 Jan;27(1):1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eJacotte-Simancas A, Costa-Miserachs D, Coll-Andreu M, Torras-Garcia M, Borlongan CV, Portell-Cort\u0026eacute;s I. Effects of voluntary physical exercise, citicoline, and combined treatment on object recognition memory, neurogenesis, and neuroprotection after traumatic brain injury in rats. J Neurotrauma. 2015 May 15;32(10):739\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003ePiao CS, Stoica BA, Wu J, Sabirzhanov B, Zhao Z, Cabatbat R, et al. Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury. Neurobiol Dis. 2013 Jun;54:252\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eLee YSC, Ashman T, Shang A, Suzuki W. Brief report: Effects of exercise and self-affirmation intervention after traumatic brain injury. NeuroRehabilitation. 2014;35(1):57\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eGomes-Osman J, Cabral DF, Morris TP, McInerney K, Cahalin LP, Rundek T, et al. Exercise for cognitive brain health in aging: A systematic review for an evaluation of dose. Neurol Clin Pract. 2018 Jun;8(3):257\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eHeaton RK, Psychological Assessment Resources I. Revised Comprehensive Norms for an Expanded Halstead-Reitan Battery: Demographically Adjusted Neuropsychological Norms for African American and Caucasian Adults, Professional Manual [Internet]. Psychological Assessment Resources; 2004. Available from: https://books.google.com/books?id=x9sJtwAACAAJ\u003c/li\u003e\n\u003cli\u003eBogdanova Y, Yee MK, Ho VT, Cicerone KD. Computerized Cognitive Rehabilitation of Attention and Executive Function in Acquired Brain Injury: A Systematic Review. J Head Trauma Rehabil. 2016;31(6):419\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eSigmundsdottir L, Longley WA, Tate RL. Computerised cognitive training in acquired brain injury: A systematic review of outcomes using the International Classification of Functioning (ICF). Neuropsychol Rehabil. 2016 Oct;26(5\u0026ndash;6):673\u0026ndash;741. \u003c/li\u003e\n\u003cli\u003eMarquez DX, Agui\u0026ntilde;aga S, V\u0026aacute;squez PM, Conroy DE, Erickson KI, Hillman C, et al. A systematic review of physical activity and quality of life and well-being. Transl Behav Med. 2020 Oct 12;10(5):1098\u0026ndash;109. \u003c/li\u003e\n\u003cli\u003eLee DH, Rezende LFM, Joh HK, Keum N, Ferrari G, Rey-Lopez JP, et al. Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults. Circulation. 2022 Aug 16;146(7):523\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eZhao M, Veeranki SP, Magnussen CG, Xi B. Recommended physical activity and all cause and cause specific mortality in US adults: prospective cohort study. BMJ. 2020 Jul 1;370:m2031. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-sports-science-medicine-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssmr","sideBox":"Learn more about [BMC Sports Science, Medicine and Rehabilitation](http://bmcsportsscimedrehabil.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ssmr/default.aspx","title":"BMC Sports Science, Medicine and Rehabilitation","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Traumatic Brain Injury, Cognitive function, Physical Exercise, Physical Activity","lastPublishedDoi":"10.21203/rs.3.rs-4743451/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4743451/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFollowing acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this within-subject A-B-A study design, we incorporated 20-weeks of supervised aerobic exercise interventions delivered three times per week (Phase B) between participants typical rehabilitation schedules (Phases A). We further tested if participation in supervised aerobic exercise increased participants daily physical activity (PA) levels using waist-worn actigraphy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFive of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+\u0026thinsp;1SD in normative scores). Linear mixed effects models showed a significant main effect of time at the group level with significant improvement in TMT-B pre-to-post exercise and no significant effect in other planned comparisons (pre-exercise to baseline nor follow-up to post-exercise) indicating that the addition of the intervention improved performance that was not due to practice effects. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to Phase A with three of six individuals making a significant behavior changes when analyzed at the individual level.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e \u003cp\u003eISRCTN17487462.\u003c/p\u003e","manuscriptTitle":"Aerobic Exercise and Cognitive Function in Chronic Severe Traumatic Brain Injury Survivors: A Within-Subject A-B-A Intervention Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 00:59:55","doi":"10.21203/rs.3.rs-4743451/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-18T07:48:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-17T09:25:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-17T09:25:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Sports Science, Medicine and Rehabilitation","date":"2024-07-15T14:03:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-sports-science-medicine-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssmr","sideBox":"Learn more about [BMC Sports Science, Medicine and Rehabilitation](http://bmcsportsscimedrehabil.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ssmr/default.aspx","title":"BMC Sports Science, Medicine and Rehabilitation","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a294e9e3-8486-4ffd-b1db-1ddaee67de52","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-30T16:09:00+00:00","versionOfRecord":{"articleIdentity":"rs-4743451","link":"https://doi.org/10.1186/s13102-024-00993-4","journal":{"identity":"bmc-sports-science-medicine-and-rehabilitation","isVorOnly":false,"title":"BMC Sports Science, Medicine and Rehabilitation"},"publishedOn":"2024-09-27 15:57:16","publishedOnDateReadable":"September 27th, 2024"},"versionCreatedAt":"2024-08-17 00:59:55","video":"","vorDoi":"10.1186/s13102-024-00993-4","vorDoiUrl":"https://doi.org/10.1186/s13102-024-00993-4","workflowStages":[]},"version":"v1","identity":"rs-4743451","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4743451","identity":"rs-4743451","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}