TYPE Study Protocol PUBLISHED 29 September 2022 DOI 10.3389/fnagi.2022.936077 Effects and mechanisms of OPEN ACCESS mindfulness training and EDITED BY Jeannette R. Mahoney, Albert Einstein College of Medicine, physical exercise on cognition, United States REVIEWED BY emotional wellbeing, and brain Emmeline Ayers, Albert Einstein College of Medicine, United States outcomes in chronic stroke Jean Neils-Strunjas, University of South Carolina, United States patients: Study protocol of the Monika Sadlonova, Massachusetts General Hospital MindFit project randomized and Harvard Medical School, United States *CORRESPONDENCE controlled trial Maria Mataró mmataro@ub.edu Adrià Bermudo-Gallaguet1,2,3† , Mar Ariza2,4† , † These authors have contributed Rosalia Dacosta-Aguayo1,5 , Daniela Agudelo1 , equally to this work Neus Camins-Vila6 , Maria Boldó7 , Òscar Carrera1 , SPECIALTY SECTION This article was submitted to Sandra Vidal8 , Blai Ferrer-Uris6 , Albert Busquets6 , Neurocognitive Aging and Behavior, a section of the journal Marc Via1,2,3 , Guillem Pera5,8 , Cynthia Cáceres9 , Frontiers in Aging Neuroscience Meritxell Gomis9 , Alberto García-Molina10 , RECEIVED 04 May 2022 José María Tormos10 , Ana Arrabé11 , Gustavo Diez11 , ACCEPTED 31 August 2022 PUBLISHED 29 September 2022 Maria José Durà Mata7 , Pere Torán-Monserrat5,8 , CITATION Juan José Soriano-Raya1,2 , Sira Domènech12 , Bermudo-Gallaguet A, Ariza M, Dacosta-Aguayo R, Agudelo D, Alexandre Perera-Lluna3,13 , Kirk I. Erickson14,15 and Camins-Vila N, Boldó M, Carrera Ò, Vidal S, Ferrer-Uris B, Busquets A, Maria Mataró1,2,3* Via M, Pera G, Cáceres C, Gomis M, 1 Department of Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain, García-Molina A, Tormos JM, Arrabé A, 2 Institut de Neurociències, University of Barcelona, Barcelona, Spain, 3 Institut de Recerca Sant Joan Diez G, Durà Mata MJ, de Déu, Esplugues de Llobregat, Spain, 4 Department of Medicine, University of Barcelona, Torán-Monserrat P, Soriano-Raya JJ, Barcelona, Spain, 5 Unitat de Suport a la Recerca Metropolitana Nord, Fundació Institut Universitari Domènech S, Perera-Lluna A, per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina, Mataró, Spain, 6 Institut Nacional Erickson KI and Mataró M (2022) d’Educació Física de Catalunya, University of Barcelona, Barcelona, Spain, 7 Department of Physical Effects and mechanisms Medicine and Rehabilitation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 8 Germans of mindfulness training and physical Trias i Pujol Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, exercise on cognition, emotional 9 Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, wellbeing, and brain outcomes 10 Institut Guttmann, Institut Universitari de Neurorehabilitació, Universitat Autònoma de Barcelona, in chronic stroke patients: Study Badalona, Spain, 11 Nirakara Lab, Mindfulness and Cognitive Science Extraordinary Chair, Universidad protocol of the MindFit project Complutense de Madrid, Madrid, Spain, 12 Institut de Diagnòstic per la Imatge, Hospital Universitari randomized controlled trial. Germans Trias i Pujol, Badalona, Spain, 13 B2SLab, Departament d’Enginyeria de Sistemes, Front. Aging Neurosci. 14:936077. Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya, Barcelona, Spain, doi: 10.3389/fnagi.2022.936077 14 Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States, 15 PROFITH “PROmoting FITness and Health Through Physical Activity” Research Group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada, Spain Background: Post-stroke cognitive and emotional complications are frequent in the chronic stages of stroke and have important implications for the functionality and quality of life of those affected and their caregivers. Frontiers in Aging Neuroscience 01 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 Strategies such as mindfulness meditation, physical exercise (PE), or computerized cognitive training (CCT) may benefit stroke patients by impacting neuroplasticity and brain health. Materials and methods: One hundred and forty-one chronic stroke patients are randomly allocated to receive mindfulness-based stress reduction + CCT (n = 47), multicomponent PE program + CCT (n = 47), or CCT alone (n = 47). Interventions consist of 12-week home-based programs five days per week. Before and after the interventions, we collect data from cognitive, psychological, and physical tests, blood and stool samples, and structural and functional brain scans. Results: The effects of the interventions on cognitive and emotional outcomes will be described in intention-to-treat and per-protocol analyses. We will also explore potential mediators and moderators, such as genetic, molecular, brain, demographic, and clinical factors in our per- protocol sample. Discussion: The MindFit Project is a randomized clinical trial that aims to assess the impact of mindfulness and PE combined with CCT on chronic stroke patients’ cognitive and emotional wellbeing. Furthermore, our design takes a multimodal biopsychosocial approach that will generate new knowledge at multiple levels of evidence, from molecular bases to behavioral changes. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT04759950. KEYWORDS stroke, mindfulness, physical exercise, computerized cognitive training, neuroimaging, biomarkers Introduction Post-stroke cognitive and emotional complications are frequent consequences in the chronic stages of the disease. Stroke is a leading cause of disability worldwide (Feigin The prevalence of cognitive deficits one year after stroke et al., 2017). Advances in acute treatment have increased the ranges from 30 to 60%, depending on the study (Sexton number of people surviving a stroke which, in turn, has led to a et al., 2019). Furthermore, stroke significantly increases growth in the number of patients with long-term consequences. the risk of dementia in the long term (Pendlebury and It is estimated that up to 50% of stroke survivors experience Rothwell, 2009). Regarding emotional wellbeing, post-stroke some degree of disability at chronic stages of the disease, which depression and anxiety are common, being present in jeopardizes functionality and quality of life (Donkor, 2018). This approximately one-third of the patients at any point in burden affects the daily life of survivors and their families and time (Ayerbe et al., 2013). Both cognitive and emotional implies high health costs for governments (Rigby et al., 2009; disturbances are related to poor rehabilitation outcomes, Donkor, 2018). morbidity, and mortality (Ayerbe et al., 2013; Obaid et al., 2020). Consequently, it is fundamental to explore and test Abbreviations: APOE, apolipoprotein E; BDNF, brain-derived new health-behavior strategies to improve cognition and neurotrophic factor; CCT, computerized cognitive training; emotional wellbeing and prevent progressive cognitive decline CRP, C-reactive protein; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent and neurodegeneration after stroke. These strategies must be assay; IGF-I, insulin-like growth factor I; IL-6, interleukin-6; MBSR, mindfulness-based stress reduction; MRI, magnetic resonance imaging; PE, physical exercise; SCFA, short-chain fatty acids; SPIRIT, standard protocol items: recommendations for interventional trials; SPSS, intervention description and replication; VEGF, vascular endothelial statistical package for the social sciences; TIDieR, template for growth factor. Frontiers in Aging Neuroscience 02 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 high-impact, low-cost, and easily accessible and implemented. Biological mechanisms underlying cognitive and emotional Mindfulness, physical exercise (PE), and computerized cognitive benefits of PE include increased production of growth training (CCT) have promising therapeutic potential in this factors (e.g., BDNF, IGF-1), and decreased synthesis of pro- scenario. These may benefit stroke patients by impacting inflammatory molecules (e.g., CRP, IL-6), and accumulation of neuroplasticity and brain health (Su and Xu, 2020). markers of neurodegeneration (Kandola et al., 2019; Stillman Mindfulness is defined as “paying attention in a et al., 2020; Erickson et al., 2022). At a brain level, the particular way: on purpose, in the present moment, and positive influence of PE on the hippocampus and prefrontal non-judgmentally” (Kabat-Zinn, 2003). Standardized gray matter volume (Erickson et al., 2014), global white interventions based on this concept [e.g., mindfulness- matter volume (Sexton et al., 2016), and increased cross- based stress reduction (MBSR)] have grown substantially network specificity across various functional networks (Stillman in recent decades and have been successfully applied in et al., 2019) have been described. Nevertheless, it should be healthy and clinical human populations, with benefits noted that most of this evidence comes from studies with reported in a broad range of variables: mental health, healthy older adults. In stroke, knowledge is still scarce, cognition, pain, fatigue, physical health, and quality of with preliminary findings in animal models and clinical life (Goldberg et al., 2022). In stroke, previous systematic studies focusing mainly on motor recovery (Xing and Bai, reviews emphasize the potential utility of mindfulness in 2020). treating emotional disturbances (Lawrence et al., 2013), Computerized cognitive training consists of repeated fatigue (Ulrichsen et al., 2016), and sensorimotor functions practice of standardized cognitive exercises that can be (Zou et al., 2018), while its benefits to cognition are still performed through the computer or mobile technology (Gates understudied. and Valenzuela, 2010). CCT has rapidly evolved in the The effects of mindfulness-based interventions may be last decade because of its potential to systematically apply explained by multiple biological pathways involving the personalized cognitive rehabilitation and its straightforward cardiovascular, metabolic, inflammatory, and neuroendocrine implementation in at-home use (Solana et al., 2015). In systems (Reive, 2019). In healthy and clinical populations, the stroke care, multiple systematic reviews and meta-analyses have most frequently reported findings (not always in a consistent addressed the potential benefits of CCT in cognitive functioning way) include reductions in circulating C-reactive protein (CRP), (Mingming et al., 2022). However, although promising, interleukin-6 (IL-6), and cortisol, and increases in brain- results remain inconclusive due to study heterogeneity and derived neurotrophic factor (BDNF) and insulin-like growth methodological limitations. Some authors have further analyzed factor I (IGF-I) (Sanada et al., 2017; Reive, 2019). Meanwhile, the additive gains of combining CCT with PE in stroke neuroimaging studies have described structural and functional patients, with preliminary positive results (Amorós-Aguilar brain correlates of mindfulness in areas and networks related et al., 2021). to attentional control, emotional regulation, and self-awareness From a molecular and brain perspective, applying CCT (e.g., prefrontal and anterior cingulate cortex, amygdala, insula) following a stroke is based on the idea that repetitive cognitive (Tang et al., 2015). However, neither blood biomarkers nor tasks might promote neuroplasticity mechanisms and restore brain data correlates of mindfulness have been addressed yet in impaired cognitive function (Sigmundsdottir et al., 2016). Based stroke. on animal models using enriched environments, some authors Physical exercise is considered a “planned, structured, hypothesize that cognitive stimulation promotes the release of and repetitive subtype of physical activity that aims to growth factors (e.g., BDNF and nerve growth factor) which, improve physical fitness” (Caspersen et al., 1985). Multiple in turn, enhances cell survival and proliferation in human systematic reviews and meta-analyses have shown the brains (Valenzuela et al., 2007). Few studies have shown benefits of PE on cognition and emotional wellbeing across structural and functional brain changes after applying CCT different age groups and health states (Rebar et al., 2015; to stroke (van de Ven et al., 2016), while others have fallen Stillman et al., 2020). In stroke patients, contrarily to the to prove any changes in neuroimaging data (Nyberg et al., effects of mindfulness, the gains of PE on cognition and 2018). emotional wellbeing have been more thoroughly studied. To conclude, cumulative evidence indicates that Some meta-analyses of randomized controlled trials have mindfulness, PE, and CCT could be effective strategies against shown small-to-moderate effects of PE on cognition (Oberlin post-stroke cognitive impairment and emotional disturbances. et al., 2017), depressive symptoms (Eng and Reime, 2014), Nonetheless, it is necessary to conduct new randomized and post-stroke health-related quality of life (Ali et al., controlled trials to confirm and deepen these benefits and 2021). elucidate the biological mechanisms (i.e., metabolic, immune, There might be a variety of processes behind the benefits cardiovascular, neuroendocrine) by which they occur. As a step of PE, including cellular and molecular, brain structure and forward, the inclusion of gut microbiome data, which seems function, and psychosocial mechanisms (Stillman et al., 2020). to be affected in stroke patients (Lee et al., 2021) and might be Frontiers in Aging Neuroscience 03 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 modified by lifestyle behaviors (Manor et al., 2020), will offer Materials and methods new and valuable insights into stroke pathophysiology and rehabilitation. Study oversight and schedule The MindFit Project is a prospective, parallel, three-arm, Aims of the study single-blinded randomized controlled trial. The trial consists of three groups in total, of which two are intervention groups, The primary objective of the MindFit Project is to examine and one is the active control group. One hundred forty-one the effects of MBSR and PE on cognitive and emotional participants at three to 60 months after stroke are randomly outcomes in chronic stroke patients by comparing three groups allocated to one of three arms (1:1:1 allocation ratio). The first of participants who receive: MBSR + CCT, PE + CCT, or CCT intervention group receives an MBSR program combined with alone. The primary hypotheses sustaining our main objective CCT; the second intervention group receives a multicomponent are: PE program combined with CCT; and the third group, as an active control group, receives only CCT. The interventions last 12 weeks, with assessments at baseline and within two weeks (1) All three groups will experience gains at 3 months after completion of the trial (see Figure 2). This study is led compared to baseline in cognitive functions and by the Faculty of Psychology of the University of Barcelona in emotional status. collaboration with Hospital Universitari Germans Trias i Pujol (2) Given the study design (i.e., all three groups receive the and Institute Guttmann. The responsible ethics committees same CCT treatment, with the only difference being the approved it following the Declaration of Helsinki. This protocol addition of either MBSR or PE), these improvements in follows the SPIRIT recommendations (Chan et al., 2013). cognition and emotion will be greater in the combined treatment groups than in the only CCT group (either to a greater extent in the same outcomes or different cognitive and emotional measures). Deviation from the initial protocol (3) The add-on effects of MBSR and PE will differ from each other (i.e., they will have a specific profile of The MindFit Project was initially planned to be entirely cognitive and emotional gains). Although there is a lack of onsite. However, all interventions and most assessments (i.e., all studies comparing mindfulness and PE, we expect greater of them except for biological sample collection and brain scans) emotional gains after MBSR than PE, while PE will produce had to be converted to online versions because of the COVID- more cognitive benefits than MBSR. 19 pandemic. The biological sample collection laboratory and the MRI center remained open with extra protective measures The secondary objectives of the MindFit Project are: during the pandemic. We followed international recommendations to adapt (a) To study intervention-related changes in the molecular- assessments and interventions to the virtual context. cellular level (e.g., cardiometabolic, inflammatory, Furthermore, we ran several pilot groups to practice and neurotrophic factors, gut microbiome species), the brain improve our protocols according to participants’ feedback. level [i.e., structural and functional magnetic resonance Finally, the project started in November 2020, and data imaging (MRI)], and the behavioral level (e.g., physical collection was completed in December 2021 (see NCT04759950 activity and fitness status, mindful thinking, sleep quality, in www.ClinicalTrials.gov for the entire study version history; fatigue, quality of life). first posted on February 18, 2021). (b) To examine whether changes in the molecular-cellular, brain and behavioral levels mediate cognitive and emotional intervention-related changes. Participants (c) To determine the genetic [i.e., apolipoprotein E (APOE) genotype], clinical (e.g., comorbidities, level of brain Inclusion and exclusion criteria are detailed in Table 1. atrophy), sociodemographic (e.g., sex, age, educational Based on stroke epidemiology (Feigin et al., 2017), we level), and individual factors (e.g., cognitive reserve, general anticipated approximately 60% of the sample to be men and 80% intelligence, personality), that moderate cognitive and of cases to be ischemic strokes. emotional intervention-related changes. After the recruitment phase, we achieved our desired sample size. One hundred forty-one stroke patients from Catalonia A graphical representation of our objectives is presented in and other regions in Spain had a baseline assessment and were Figure 1. randomized to one of the three study arms. We will report the Frontiers in Aging Neuroscience 04 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 FIGURE 1 MindFit project graphical objectives. APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; CCT, computerized cognitive training; CRP, C-reactive protein; IGF-I, insulin-like growth factor I; IL-6, interleukin-6; MBSR, mindfulness-based stress reduction; PE, physical exercise; VEGF, vascular endothelial growth factor. FIGURE 2 MindFit project study design. CCT, computer-based cognitive training; MBSR, mindfulness-based stress reduction; PE, physical exercise. final numbers and the flow diagram of study recruitment in our This change in strategy accelerated the recruitment process first paper with the primary outcome results. and allowed for a larger sample with a more extensive geographic representation. Interested people contacted the study investigators by Recruitment and screening telephone, email, or social networks. Patients interested in participating received oral and written detailed information We recruited stroke patients through advertising on about the study and were asked to fulfill a screening social media, publicity, and contacting hospitals and stroke questionnaire to determine if they met the admission and acquired brain damage patient associations. Before criteria. Subsequently, we invited potential participants to the COVID-19 pandemic, we adopted a local strategy a teleconference visit where an evaluator administered the based on publication in the local press and obtaining Mini-Mental State Examination (Blesa et al., 2001) and participants from patient lists of general physicians in the exhaustively reviewed the rest of the study criteria. If candidates Metropolitan Area of Barcelona. After the pandemic’s start, were eligible, the information about the study was provided the recruitment process focused mainly on social networks, again, and any questions were answered. The informed consent expanding the target population to the entire Catalan territory. form was signed if the participant agreed to engage in the Frontiers in Aging Neuroscience 05 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 project. Afterward, an alphanumeric code in the order of arrival The mindfulness group received an MBSR program combined was assigned to the participant. with CCT; the PE group received a multicomponent PE program combined with CCT, and the control group only received CCT. The duration of the combined interventions was Assessments approximately twice that of the active control group. In the two combined therapy groups, participants did not receive any Within two weeks before the interventions started and specific instructions regarding the order in which to perform within two weeks after completing the interventions, we the interventions. performed medical, cognitive, and physical assessments, Mindfulness-based stress reduction and PE interventions neuroimaging, and biological samples collection. When included (a) online synchronous sessions guided by expert possible, we evaluated patients who dropped out of the caregivers and done in groups of 8–12 participants and (b) study in the follow-up assessment to comply with the individual autonomous sessions. In contrast, the control group intention-to-treat principle. performed all sessions independently through a computerized All the assessments were online except for brain scans, blood telerehabilitation platform. To minimize the confounder effect tests, and stool sample collection, which were done with extra of benefits from peer interaction and social support in the safety measures at the Hospital Universitari Germans Trias combined interventions, we invited participants from the i Pujol (Barcelona, Spain). We conducted online assessments same intervention arm to communicate and share experiences through the Zoom platform (except for medical and physical through WhatsApp groups. visits, which were done using a hospital-specific platform). Before starting the interventions, participants were A few days before the assessment, we communicated to the instructed to use the electronic platforms. Furthermore, participants the electronic platform which would be used, the they were provided with a manual that collected the main link to access the virtual room, and any material they needed to instructions, safety measures to perform the assigned have ready for the visit (e.g., printed documents or objects to do therapies, and a compendium of doubts and frequently the physical tests). asked questions resolved. The assessment timeline is presented in Table 2. Assessors received specific training and a written protocol of the Mindfulness-based stress reduction program assessment schedule and instructions. The same evaluators The intervention followed the scheme and instructions of carried out the baseline and post-intervention measurements to the official MBSR program designed by Kabat-Zinn (2003). minimize bias from inter-rater variability. Specifically, within the 12 weeks, there was an introduction session, followed by eight intervention sessions and an intensive practice session interspersed between sessions six and seven. Randomization and blinding The MBSR intervention took place daily, five days a week. Prototypical weeks had one day with a 150-min online session, After baseline assessments, an independent biostatistician while participants performed formal and informal practice for randomized the participants into the three groups through a simple randomizing procedure with an equal allocation ratio TABLE 1 Eligibility criteria. (i.e., 1:1:1; 47 individuals per arm) created with a random sequence generator software. We did not use any stratification Inclusion criteria Exclusion criteria method due to practical reasons. The randomization sequence was stored on an institutional server and was password • Women and men aged 18–80 years • Cognitive impairment defined as a old score in Mini-Mental State protected. Only the person in charge of the randomization, • Diagnosis of ischemic or Examination ≤23 (Blesa et al., 2001) who was not involved in either evaluation or intervention tasks, hemorrhagic stroke • Severe aphasia defined as a score had access to it. • Stroke diagnosis between 3 and ≥2 in item 9 of the National Institute Group allocation remained blind for all outcome assessors 60 months ago Health Stroke Scale (Montaner and • To have consent from a physician Alvarez-Sabín, 2006) and data analysts, while participants and care providers could to engage in an exercise intervention • Severe sensory problems not be masked due to the nature of the interventions. • Fluency in Catalan or Spanish (i.e., • Diagnoses of transient ischemic Participants received instructions not to discuss any activities able to understand and speak) attack without evidence of brain related to the intervention with the outcome assessors during • Accept to participate in the study lesion and sign the informed consent • Other neurological conditions apart the follow-up assessments. according to the Declaration of from stroke (e.g., traumatic brain Helsinki injury, brain tumors) • Severe pre-stroke psychiatric Interventions disorders (e.g., bipolar disorder, schizophrenia) • History of alcohol or other The interventions consisted of five daily sessions per substance abuse week for 12 weeks and were performed entirely remotely. Frontiers in Aging Neuroscience 06 frontiersin.org Frontiers in Aging Neuroscience Bermudo-Gallaguet et al. TABLE 2 Assessments schedule. Enrollment and Baseline assessments (within 2 weeks prior to the Intervention Post-intervention assessments (within 2 weeks screening start of the intervention) (12 weeks) after the end of the intervention) Screening Visit 0 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 (telematic) (telematic) (telematic) (telematic) (telematic) (in- (in- (telematic) (telematic) (in- (in- (telematic) person) person) person) person) Information of study 3 3 First review of criteria 3 Exhaustive review of 3 criteria Informed consent 3 form Medical story 3 General health status 3 3 Neuropsychological 3 3 07 tests Cognitive scales 3 3 Psychological scales 3 3 Anthropometric 3 3 measures Physical fitness tests 3 3 Lifestyle behaviors 3 3 scales Blood extraction 3 3 Stool sample collection 3 3 Magnetic resonance 3 3 imaging Intervention follow-up 3 10.3389/fnagi.2022.936077 diary Exercise bracelet 3 Qualitative interviews 3 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 TABLE 3 Neuropsychological assessment and proposed cognitive composites. Composite Test-subtest Attention–Speed Attention Wechsler Adult Intelligence Scale III–Digits Forward (Wechsler, 2001) Trail Making Test–A (Tombaugh, 2004) Speed Wechsler Adult Intelligence Scale III–Digit symbol coding (Wechsler, 2001) Executive functions Inhibition Stroop Color and Word Test–Interference (Golden, 2001) Flexibility Trail Making Test–B (Tombaugh, 2004) Fluency PMR phonological verbal fluency (Peña-Casanova et al., 2009) Semantic verbal fluency of animals (Peña-Casanova et al., 2009) Working Wechsler Adult Intelligence Scale III–Digits Backward (Wechsler, 2001) memory Language Boston Naming Test (15-items) (Goodglass et al., 2001) Memory Verbal memory Rey Auditory Verbal Learning Test–Total learning (Schmidt, 1996) Rey Auditory Verbal Learning Test–Delayed recall (Schmidt, 1996) Visual memory Rey-Osterrieth Complex Figure–Memory accuracy (Rey, 2009) Visuospatial functions Rey-Osterrieth Complex Figure–Copy accuracy (Rey, 2009) 20–40 min the remaining four days. An accredited mindfulness therapeutic range (i.e., a percentage of correct answers between instructor led the program. Participants were provided with 65 and 85%). The training was done individually five days a a program dossier that included theoretical explanations and week, and the duration was 45 min per session. instructions for daily practice and audio recorded by the instructor to guide the meditations. A detailed description of the mindfulness intervention following the template for Intervention adherence intervention description and replication (TIDieR) guidelines (Hoffmann et al., 2014) is given in the appendices (see Intervention adherence was counted as the total number Supplementary Material 1). of sessions performed (i.e., the summation of face-to-face and autonomous sessions). Instructors recorded attendance at face- Multicomponent physical exercise program to-face classes, while participants filled in a diary whether The PE intervention was designed following Billinger’s they had done the independent sessions and any difficulties recommendations for stroke survivors (Billinger et al., 2014). It or inconveniences they may have experienced. Instructors consisted of a 12-week program in which five weekly sessions of reviewed the diaries weekly and discussed with participants any 45–60 min were done. Three of these sessions were conducted incidents or questions that may have arised. In addition, in the in groups through video-conferencing technology and led by a case of the PE group, participants were provided with a physical physiotherapist and a strength and conditioning specialist. The activity bracelet (Fitbit Inspire HR ) that they wore the whole R other two sessions were individualized, and participants were intervention. asked to walk. A detailed description of the PE intervention Furthermore, we controlled whether the participant had following the TIDieR guidelines (Hoffmann et al., 2014) is given already taken any of these interventions before entering the in the appendices (see Supplementary Material 2). study and any other therapy he/she had followed concomitantly Computerized cognitive training program with our interventions. For this reason, we created a Computerized cognitive training was carried out using questionnaire that participants answered at the end of the trial. the Guttmann Neuropersonal Trainer (Solana et al., 2015), a computerized telerehabilitation platform. The intervention consisted of a multi-domain task program in which different Safety considerations cognitive processes such as executive function, memory, speed, and attention were included. The platform created Our health professional team reviewed each participant’s personalized training based on the scores obtained in the baseline assessment before randomization to ensure baseline neuropsychological evaluation, age, and educational intervention safety (e.g., all candidates must have a physician’s level. From the cognitive profile established, it was possible to approval to perform PE before enrollment). If any medical detect the deficits presented by the participant and thus provide incidence was found in baseline assessments (e.g., in the brain specific rehabilitation exercises. The difficulty of the tasks was scan or blood test), the participant was informed and redirected adjusted according to the participant’s performance and the to the appropriate health service. In these cases, we decided Frontiers in Aging Neuroscience 08 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 TABLE 4 Questionnaires. Name No. of items Domain or domains assessed Beck Depression Inventory-II (Sanz et al., 2003) 21 Depressive symptoms Childhood Adverse Experience International 36 Adverse childhood experiences Questionnaire (World Health Organization, 2020) (baseline only) Clinical Outcome in Routine Evaluation-Outcome Measure 34 Psychological distress with four domains: subjective wellbeing, problems/symptoms, (Feixas et al., 2012) general functioning, and risk Cognitive Reserve Questionnaire (Rami et al., 2011) 8 Cognitive reserve estimation based on proxies (baseline only) Concomitant Therapies Questionnaire (post-intervention 15 Registry of other therapies that the participants follow concomitantly with the study only) interventions Demographics and Health History (baseline only) 50 Demographics, medical story, consumption of alcohol and tobacco, COVID-19 data (infection and vaccination), female reproductive health (only in women), data important for microbiome analysis Depression Anxiety Stress Scale (Bados et al., 2005) 21 Depressive, anxiety, and stress symptoms Dysexecutive Questionnaire (Pedrero Pérez et al., 2009) 20 Dysexecutive symptoms Expectancy Questionnaire (baseline only) 10 Expectations about treatment improvements in cognition, emotional wellbeing, physical fitness, and quality of life due to study interventions Fatigue Assessment Scale (Cano-Climent et al., 2017) 10 Physical and psychological aspects of fatigue Five Facet Mindfulness Questionnaire (Aguado et al., 2015) 39 Five factors of mindfulness: observing, describing, acting with awareness, non-judging of inner experience, and non-reactivity to inner experience Food Frequency Questionnaire (Vioque and Quiles, 2003) 93 Frequency consumption of specific foods Mediterranean Diet Adherence screener 14 Adherence to the Mediterranean diet (Martínez-González et al., 2012) Memory Failures in Everyday Questionnaire (Montejo 28 Memory failures in daily life Carrasco et al., 2012) Mindfulness Attention Awareness Scale (Soler et al., 2012) 15 Mindfulness (especially the "acting with awareness" component) NEO Five-Factor Inventory (Costa and McCrae, 2008) 60 Five factors of personality: openness to experience, conscientiousness, extraversion, (baseline only) agreeableness, and neuroticism Perceived Changes Questionnaire (post-intervention only) 10 Participants’ subjective experienced changes in cognition, emotional wellbeing, physical fitness, and quality of life due to interventions Pittsburgh Sleep Quality Index (Royuela Rico and Macías 19 Seven components of sleep quality: subjective sleep quality, sleep latency, sleep Fernández, 1997) duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction Profile of Mood States-fatigue subscale (Andrade et al., 7 Mood states related to physical and psychological aspects of fatigue 2013) Psychological Wellbeing Scales (Díaz et al., 2006) 29 Six factors of psychological wellbeing: self-acceptance, positive relations, autonomy, environmental mastery, purpose in life, and personal growth Rating Scale for Attentional Behavior (Ponsford and 14 Attentional behavior in daily life Kinsella, 1991) Reduced Minnesota Leisure-Time Physical Activity 6 Physical activity Questionnaire (Ruiz Comellas et al., 2012) Stroke-specific Quality of Life Scale 38 Eight dimensions of stroke-related quality of life: physical state, communication, (Fernández-Concepción et al., 2008) cognition, emotions, feelings, basic activities of daily living, ordinary activities of daily living, and family functions World Health Organization Quality of Life (Abbreviated 26 Four dimensions of quality of life: physical health, psychological health, social form) (Lucas-Carrasco, 2012) relationships, environment whether the patient should be excluded from participation throughout the study and to fill in a diary with any difficulties based on medical recommendations. or inconveniences they experienced during or after the sessions. Once assigned to a group and before beginning the Instructors reviewed the diaries weekly and regularly informed interventions, participants received an information session and the project manager. Any severe event (e.g., fall, fracture) had a written manual with the safety measures they should take to be reported immediately to the Principal Investigator and the to avoid injuries or other potential adverse experiences. They Institution’s Research Ethics Committee. Adverse effects will be were also instructed to spontaneously report any adverse events reported in future manuscripts following official guidelines. Frontiers in Aging Neuroscience 09 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 Tailoring participants’ individual needs TABLE 5 Physical fitness components of the Senior Fitness Test (Rikli and Jones, 1999). Given the breadth of the eligibility criteria, it was anticipated Component Test that the sample would have a wide range of ages and varying Aerobic endurance 2-min step test degrees of physical and cognitive disability. For this reason, Agility/dynamic balance 8-foot up-and-go test before starting any evaluation or intervention, we determined Flexibility the individual needs of each participant. Based on these, we Lower body Chair sit-and-reach test decided on the necessary accommodations, which could involve Upper body Back scratch test a more comprehensive initial training in digital technologies Strength or specific physical, linguistic, and cognitive adaptations. Lower body 30-s chair stand test For example, in the case of people with mild to moderate Upper body 30-s arm curl test aphasia who had impaired reading ability, self-administered questionnaires were applied orally by an expert interviewer. Supplementary Materials 1, 2 provide complete information medication taken by each participant, and smoking and alcohol about the adaptations made during interventions. consumption habits. Moreover, the physician assessed the different neurological symptoms present through the National Institute of Health Stroke Scale (Montaner and Alvarez-Sabín, Data management and results 2006) and the functionality with the Barthel index (González et al., 2018) and the modified Rankin Scale (Fernández Sanz Confidentiality and access to data et al., 2021). Each participant was identified with a dissociated alphanumeric code assigned according to the order of Outcome variables inclusion (i.e., when the patient signed the informed consent). The principal investigator and the project manager kept a Primary outcomes confidential record of the participant’s personal information Cognitive functioning and their assigned identification codes. All trial data was All participants completed a comprehensive incorporated anonymously in a database stored in an neuropsychological assessment. We will create z-score institutional server that requires a password to be accessed composites for each cognitive domain from normalized (i.e., a strong password consisting of aleatory numbers, upper raw data, as well as a global cognitive function score based on and lowercase letters, and symbols). Once the database is the sum of all domains (see Table 3). Domains will be created completed, a double-check process and an assessment of its following a theoretical-driven approach based on the literature quality will be carried out. After results publication, data will be (Lezak et al., 2012). We will consider the changes in cognitive shared in anonymized form upon reasonable request. domains and global cognition as primary outcome measures. Emotional wellbeing Baseline variables Depression, anxiety, and stress levels were measured through the Beck Depression Inventory (Sanz et al., 2003) and Demographic data (i.e., age, gender, marital status, the Depression Anxiety Stress Scale (Bados et al., 2005). Detailed education, race/ethnicity, employment status, family income) information on these questionnaires is provided in Table 4. We was obtained at baseline through an online questionnaire will consider the changes in these questionnaires’ total scores as answered by the participants. Further questionnaires were primary outcome measures. administered to ascertain cognitive reserve (Rami et al., 2011), personality (Costa and McCrae, 2008), adverse childhood Secondary outcomes events (World Health Organization, 2020), and expectations Psychosocial and lifestyle measurements about treatment improvements. The Vocabulary and Matrix We applied a broad range of online questionnaires (see Reasoning subtests of the Wechsler Adult Intelligence Table 4) to assess changes in subjective cognitive functioning Scale-III (Wechsler, 2001) were administered during the (i.e., dysexecutive symptoms, attention and memory failures baseline neuropsychological assessment to estimate premorbid in everyday life), additional emotional wellbeing variables, intelligence. mindfulness, fatigue, functioning, quality of life, and lifestyle The physician in charge of the medical evaluations recorded behaviors. Furthermore, at the end of the interventions, the existence of current or previous diagnoses apart from stroke, all participants completed a questionnaire about whether stroke characteristics (e.g., type, evolution time), the specific they had experienced changes in cognition, emotional Frontiers in Aging Neuroscience 10 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 TABLE 6 Magnetic resonance imaging (MRI) and biological samples protocols. MRI protocol Sequence Parameters T1-weighted multiplanar reformat sequence Resolution: 0.9 × 0.9 × 0.9 mm, TR/TE: 1900/2.73 ms, slices: 192 T2-weighted turbo spin-echo sequence Resolution: 0.7 × 0.5 × 3 mm, TR/TE: 6000/74 ms, slices: 35 T2-weighted turbo inversion recovery magnitude Resolution: 1 × 0.8 × 3 mm, TR/TE: 9000/99 ms, slices: 44 Susceptible-weighted imaging with T2–fl3d sequence Resolution: 1.1 × 0.8 × 2 mm, TR/TE: 28/20 ms, slices: 88 Resting state with a gradient echo planar imaging sequence Resolution: 3.1 × 3.1 × 3 mm, TR/TE: 2000/25 ms, slices: 39, measurements = 240 Diffusion tensor imaging, echo planar imaging Resolution: 2 × 2 × 2 mm, TR/TE: 10200/89 ms, directions: 64, inverse b0 pulse was added to obtain PA acquisition Blood sample protocol Process Brief explanation Collection method Blood samples were collected in vacutainer tubes containing EDTA disodium (anticoagulant) and were further processed to obtain plasma or frozen at −20◦ C Plasma extraction and preparation Platelet-poor plasma was separated by double centrifugation. Aliquots were frozen at −80◦ C for following analysis Plasma analyses Plasma parameters were measured by ELISA: IL-6, BDNF, IGF-1, Cortisol and VEGF values were obtained using kits from R&D Systems (Minneapolis, MN, USA), and CRP was analyzed by a turbidimetric method using reagents from RAL (Sant Joan Despí, Spain) DNA extraction DNA extraction was performed from 3 ml of frozen blood using the Chemagic DNA Blood Kit special [Chemagic MSMI (PerkinElmer, Waltham, MA, USA)] DNA analyses Polymorphisms in the APOE gene (single-nucleotide polymorphism rs429358 and rs7412) were determined using TaqMan methodologies Stool sample protocol Process Brief explanation Collection method Fresh stool samples were collected in plastic containers that were immediately put on ice Preparation and storage Aliquots were frozen at −80◦ C for subsequent analysis DNA extraction DNA extraction was performed from 200 mg of stool sample in the InviGenius Plus Instrument using the InviMag Universal Kit (Invitek, Berlin, Deutschland) DNA analyses The quantitative and qualitative analyses from the DNA was performed by spectrophotometry (Epoch, BioTek, Santa Clara, CA, USA) SCFA determination The determination of SCFA was carried out by gas chromatography combined with mass spectrometry APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; IGF-I, insulin-like growth factor I; IL-6, interleukin-6; MRI, magnetic resonance imaging; SCFA, short-chain fatty acids; VEGF, vascular endothelial growth factor. wellbeing, physical fitness, and quality of life, and, if so, Brain magnetic resonance imaging they must rate the magnitude of either the improvement All images were obtained with a 3 Tesla scanner (Siemens or deterioration. In the same questionnaire, we added Magnetom Verio Symo MR B17). Structural, functional, and some questions about the feasibility and acceptability of diffusion sequences were acquired with the parameters the interventions. described in Table 6. The participants who presented contraindications to performing MRI (e.g., pacemaker, valves, metals in the body, claustrophobia) were not evaluated. Anthropometric measures and physical fitness Participants self-reported the values corresponding to height, weight, waist, and hip perimeters. Physical status and Blood-sample and stool-sample data functioning (i.e., aerobic capacity, strength, flexibility, and We used a standard blood test to quantify hemograms, balance) were evaluated with an adaptation of the Senior Fitness biochemical parameters, and lipid profiles. BDNF, IGF-I, Test (Rikli and Jones, 1999). Detailed information on fitness vascular endothelial growth factor (VEGF), CRP, IL-6, and tests is provided in Table 5. cortisol were analyzed in plasma, and genetic biomarkers on Frontiers in Aging Neuroscience 11 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 APOE were determined in the buffy coat fraction. Stool samples and an appropriate multiple comparisons correction method were collected to quantify species and subspecies of the intestinal will be implemented. microbiota, as well as the determination of short-chain fatty Baseline demographic and clinical characteristics of acids (SCFA). Specific details of the collection, storage, and participants in the different intervention groups will be analysis of the biological samples are included in Table 6. described with central tendency, dispersion, and position measures and compared between the three groups using parametric or non-parametric tests. To address our primary Exit qualitative interviews hypotheses, we will use multiple regression models, which will include: (a) the difference between the follow-up and We performed a qualitative study on a subset of participants baseline values in the primary outcome measures as the (those with the highest adherence to interventions and explained variable; (b) the 3-arms intervention as the explaining willingness to participate) to know their experiences and variable, and (c) other confounding factors as covariates. We evaluate the clinical significance of potential changes. will consider sex, age, years of education, time since stroke, We used standard guidelines (O’Brien et al., 2014) to and the baseline score as fixed covariates. Moreover, we develop the interview script and the data collection and will contemplate the need to adjust for further unbalanced analysis protocol. factors between groups that appear to correlate strongly with the outcomes. In case of violating the linear regression assumptions, transformations of the variables or methods Analysis of robust regression will be adopted. We will examine the secondary outcomes with the same pipeline in the per-protocol Power analysis sample. Although the sample size was not calculated to allow Sample size calculations were conducted using the Granmo interaction effects, we will examine potential mediator and v7.12 software. Accepting an alpha risk of 0.05 and a beta risk moderator effects in this sample. of less than 0.20 in a bilateral contrast, 47 participants in each group are required to detect a minimum difference of 0.75 standard deviations between each pair of groups (assuming that Discussion there are three) after standardization of the variables to have mean 0 and standard deviation 1. This sample size supports a The MindFit Project is a randomized controlled clinical 20% tracking loss rate. We established a minimum effect size trial that aims to assess the impact of mindfulness and PE of 0.75 standard deviations by considering the results of meta- combined with CCT on chronic stroke patients’ cognitive and analyses studying the effects of mindfulness or PE on cognition emotional wellbeing. We predict that the three intervention or emotional wellbeing in stroke patients (e.g., Abbott et al., groups will show improvements at the end of the trial, 2014; Oberlin et al., 2017; Ali et al., 2021; Sun et al., 2021). The but we expect that these changes will be quantitatively effect sizes reported in these papers range from small-moderate and qualitatively different between groups. We expect that (between d = 0.30 and d = 0.50) to moderate-large (between groups that have completed a combination of therapies will d = 0.50 and d = 1), depending on the intervention and the show more significant changes than those who have only outcome studied. We used an intermediate effect size that was done CCT. In addition, we hypothesize that there will be a realistic to the literature and satisfied our trial’s practical and different impact of mindfulness and PE on the cognitive and economic possibilities. emotional domains. Secondly, we plan to study the physiological mechanisms Statistical analysis underlying the changes produced by mindfulness and PE Statistical analysis will be carried out with IBM statistical through biomarkers to obtain evidence on the biological package for the social sciences (SPSS) Statistics 27 and pathways affected by each intervention and the final effect R environment. The same statistical pipeline will be run on the structure and functioning of the brain. A final step twice, in two sequential phases: (1) intention-to-treat analysis in understanding the possible effects of our interventions will considering data from all randomized participants, including be to analyze which personal and clinical variables moderate those that complete and drop out of the study (in case of their impact. In this regard, we will be able to determine missing values, an adequate method of imputation will be which strategies are most suitable for each patient profile executed whenever appropriate, depending on the proportion and thus lead stroke rehabilitation toward a personalized of missing data and the missingness mechanisms); (2) per- treatment model. protocol analysis including only those who have had a As a limitation of our study, we highlight the lack of treatment adherence equal to or higher than 80%. The a passive control group that prevents us from determining significant threshold will be set at a two-tailed p-value of 0.05, the efficacy of CCT alone. On the other hand, 3 months Frontiers in Aging Neuroscience 12 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 of intervention may not be enough to obtain robust and their area of expertise. AB-G, MA, DA, NC-V, MB, OC, and clinically meaningful results. There is a possibility that we SV collaborated to implement specific procedures. AB-G and will observe changes in biomarkers that are not reflected in MA contributed to the protocol’s design, implementation, and behavior. Instead, there may be changes in cognition and writing. All authors contributed to the article and approved the emotional wellbeing that are not yet sufficiently established submitted version. to see their molecular and brain correlates. Despite these limitations, the MindFit Project has the potential and ability to generate new knowledge at multiple levels of evidence, Funding from molecular bases to behavioral changes associated with mindfulness and exercise therapies in chronic stroke patients. In The project described in these pages was funded by addition, the integration of a qualitative perspective will help us Fundació La Marató de TV3 (201717.30.31.32). It was supported understand the significance of these possible changes and their by the ICREA Academia Program to MM and María de Maeztu clinical relevance. Unit of Excellence (Institute of Neurosciences, University of Barcelona) MDM-2017-0729, Ministry of Science and Innovation. Finally, it was rewarded with AB-G pre-doctoral Dissemination fellowship (FPU18/04344). The results of the MindFit project will be presented in numerous peer-reviewed publications. We will also publish secondary analyses of the clinical trial, and cross-sectional Acknowledgments studies will be developed with the participants’ baseline data. The results will also be presented at national and international We want to acknowledge all participants and their families, conferences. Our research group will strive to publish the the Stroke Associations, and the IGTP-HUGTP Biobank, results regardless of their nature or direction concerning the integrated into the Spanish National Biobanks and Biomodels initial hypotheses. Network of Instituto de Salud Carlos III (PT17/0015/0045, We will also promote the divulgation of the knowledge PT20/00050) and Tumour Bank Network of Catalonia for obtained: we will organize a closing day for our participants its collaboration. where we will present the main results; we will provide participants with published articles translated into Catalan and Spanish; we will create infographics with the results and publish Conflict of interest them through our newsletter and social networks. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could Ethics statement be construed as a potential conflict of interest. All participants gave written informed consent following the Declaration of Helsinki. The Bioethics Commission approved the protocol of the University of Barcelona (IRB00003099), Publisher’s note the Germans Trias i Pujol University Hospital Research Ethics All claims expressed in this article are solely those of the Committee (PI-17-110), the Healthcare Ethics Committee authors and do not necessarily represent those of their affiliated from the Institut Guttmann, and the Clinical Research Ethics organizations, or those of the publisher, the editors and the Committee of IDIAP Jordi Gol (19/056-P). reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Author contributions MM, MD, and AG-M conceptualized the study and contributed to the study design and implementation as Supplementary material principal investigators. AB-G, MA, and RD-A made substantial contributions to the design and content of the trial. NC-V, MB, The Supplementary Material for this article can be OC, BF-U, AB, MV, GP, CC, MG, JT, AA, GD, PT-M, JS-R, found online at: https://www.frontiersin.org/articles/10.3389/ SD, AP-L, and KE contributed to the design of the trial from fnagi.2022.936077/full#supplementary-material Frontiers in Aging Neuroscience 13 frontiersin.org Bermudo-Gallaguet et al. 10.3389/fnagi.2022.936077 References Abbott, R. A., Whear, R., Rodgers, L. R., Bethel, A., Coon, J. T., Kuyken, W., Fernández Sanz, A., Ruiz Serrano, J., Tejada Meza, H., and Marta Moreno, et al. (2014). Effectiveness of mindfulness-based stress reduction and mindfulness J. (2021). Validation of the Spanish-language version of the simplified modified based cognitive therapy in vascular disease: A systematic review and meta-analysis Rankin Scale telephone questionnaire. Neurologia 37, 271–276. doi: 10.1016/j.nrl. of randomised controlled trials. J. Psychosom. 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