The BrainHealth Project Study Protocol: A Longitudinal Study in Generally Healthy Adults

The BrainHealth Project Study Protocol: A Longitudinal Study in Generally Healthy Adults | 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 Study protocol The BrainHealth Project Study Protocol: A Longitudinal Study in Generally Healthy Adults Lori G. Cook, Jeffrey S. Spence, Erin E. Venza, Aaron Tate, Ian H. Robertson, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4855477/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Optimization of brain health is a focal point in medical science, yet data regarding measuring, preserving, and improving lifelong brain health are lacking. This void demands an objective, change-sensitive measure of brain health and proven strategies to strengthen brain performance. The BrainHealth Project addresses these key issues, drawing upon neuroplasticity evidence of persistent modifiability of brain function across the lifespan. This landmark study aims to definitively (i) evaluate and refine holistic change indices of brain health, (ii) evaluate the impact of evidenced-based cognitive strategies and lifestyle interventions on improving/maintaining brain health, and (iii) elucidate the mechanisms associated with brain health gains/losses. Methods : This prospective, longitudinal, interventional, open-label, single-arm clinical trial aims to recruit 100,000 generally healthy adults over 10 years. Assessments, coaching, and training are conducted online through the secure BrainHealth Platform, allowing utilization tracking. The BrainHealth Index (BHI)—a multidimensional assessment—is offered at baseline and every six months. Participants have access to coaching every three months and continual access to self-paced trainings and resources. The primary outcome is the further validation of a novel composite BHI score and its sub-scores: Clarity (cognitive health), Connectedness (social health), and Emotional Balance (well-being). The BHI includes measures sensitive to change, including gains from behavior change and integration of cognitive strategies into daily life. These contrast with traditional assessments focused on detecting cognitive decline or diagnosing pathological conditions. The primary online training, SMART (Strategic Memory Advanced Reasoning Tactics), is a strategy-based program validated with 25+ years of research. SMART promotes improvements in neural health, cognition, well-being, connectedness, and real-life function, previously reported in randomized controlled trials (RCTs). Statistical approaches focus on individual prediction using nonlinear models trained with large samples and on assessing mechanisms influencing gains or losses on brain health metrics. Discussion: This research extends RCT evidence to a longitudinal, epidemiologic approach, leveraging digital health and machine learning tools to deliver a generalizable measure of longitudinal brain health and to achieve precision brain health. By integrating advanced statistical methods and large-scale data, the BrainHealth Project should provide medicine and society with accurate and actionable ways to optimize brain health practices across the lifespan. ClinicalTrials.gov Identifier : NCT04869111 (registered April 27, 2021) brain health cognitive training executive function digital health healthy aging lifespan lifestyle neuroplasticity prevention precision health Figures Figure 1 Figure 2 BACKGROUND Improving brain health is one of the most critical health challenges facing global society. The brain, as the command center for all our actions, feelings, and thoughts, influences every aspect of our life. Yet, the importance of optimizing brain health has been historically overlooked, in part due to outdated beliefs that intellect is fixed and that the brain cannot improve after young adulthood. However, neuroscientific discoveries over the past few decades have demonstrated that the brain retains neuroplasticity across the lifespan, meaning it can be modified by experience and use at every age [ 1 , 2 ]. This understanding drives the need for objective ways to (1) measure changes in brain performance, whatever one’s starting point, and (2) examine the array of habits and practices that can strengthen brain systems and performance at an individual level. Like the preventative measures for heart health that are now well-established, we hypothesize that brain health care practices must similarly be initiated well before a person experiences losses in cognitive, psychological, social, or motor function. A healthier brain could provide protective benefits against a range of neurological, psychiatric, age-related and behavioral challenges. Moreover, such benefits would provide tremendous personal, social and economic benefit, extending peak brain performance well beyond the documented losses known to start in the late twenties to early thirties. While multiple definitions for brain health exist, a consensus is emerging. We have adapted the World Health Organization’s (WHO) definition, which promotes optimal development of neural health, cognitive health, and well-being [ 3 ], to which we added the critical element of connectedness to people and purpose, allowing a person to realize their full potential over the life course. This adaptation guides the BrainHealth Project , which aims to measure and optimize brain health. Enhancing brain health across all segments of society could drive tremendous economic and social advancement [ 4 ], a concept we term Brainomics [ 5 ]. Historically, accurate measurement of brain health has been challenging due to a focus on disease driven metrics rather than a holistic view of lifelong brain wellness. Traditional measures often highlight focus on a specific brain health skill/domain rather than being holistic or utilizing a composite approach. Additionally, they often emphasize documenting decline rather than capturing both positive and negative changes in brain health over the lifespan, as the indices used in this study allow. Recent clinical trials report converging evidence that individuals can enhance both neural and behavioral aspects of brain health and performance, regardless of their starting point [ 6 – 9 ]. These studies identified significant gains in brain function through functional magnetic resonance imaging (fMRI), and converging gains in measures of cognition, well-being, and real-life responsibilities. These early yet consistent results drive the hypothesis that generally healthy individuals without identified brain disease can improve their brain health and performance across the adult lifespan, when provided tools to establish healthy brain habits. However, to definitively address this question requires (1) validated ways to measure and monitor brain health changes and (2) easy access to training protocols and refinement of tools that promote healthy brain habits, empowering individuals to maximize their executive functioning and ability to manage stress, connect with people in meaningful ways, and make healthy lifestyle choices [ 10 ]. The BrainHealth Project aims to inform effective ways to provide a personalized, proactive approach to monitoring and enhancing brain health at any age, encouraging people to maximize their cognitive potential and thrive. Through better understanding of factors that optimize brain health across the lifespan, the potential for improved health, work, and economic-related outcomes would provide considerable value to both the individual and society at large [ 3 ]. The BrainHealth Project was inspired by the paradigm-shifting Framingham Heart Study, which since 1948 has transformed the world’s understanding of cardiovascular disease by identifying modifiable risk factors and providing crucial insights into the prevention, diagnosis and management of heart disease and stroke [ 11 , 12 ]. Its longitudinal design and comprehensive data collection have laid the foundation for decades of cardiovascular research and public health initiatives aimed at reducing the global burden of cardiovascular disease. Drawing parallels, our research endeavors to elucidate similar findings within the realm of brain health, thereby identifying actionable strategies aimed at enhancing brain vitality and mitigating and preventing age-related decline. The Framingham study shattered the myth that cardiovascular disease is an inevitable part of aging by revealing critical links between risk factors and disease development. This large-scale effort paved the way for preventive interventions, diagnostic measures, and lifelong heart health-promoting behaviors. In a similar vein, the BrainHealth Project aims to uncover factors and mechanisms that maintain brain health across the lifespan, with the goal to even enhance brain performance. We seek to build a comprehensive framework for understanding brain health maintenance and improvement across the lifespan by examining the intricate interplay between lifestyle choices, environmental influences, and biological markers. At the University of Texas at Dallas’ Center for BrainHealth, led by cognitive neuroscientist Dr. Sandra Chapman, PhD (Principal Investigator), we have conducted numerous research projects examining (i) novel assessments of brain health and (ii) top-down, executive function strategies that support cognitive, emotional, functional, and neural metrics. By bringing together our core measures of complex cognition, along with both novel and established measures of well-being, social connection, lifestyle, and purpose, the BrainHealth Index allows for both independent analysis of individual measures of brain health as well as a holistic view of how they interact with and impact overall function. Our strategy-based training protocol, known as SMART (Strategic Memory Advanced Reasoning Tactics), engages an executive function, top-down framework focusing on three core cognitive processes: Strategic Attention, Integrated Reasoning, and Innovation, described below [ 10 ]. SMART has shown efficacy in promoting gains in these cognitive areas and strengthening key brain networks that support planning, reasoning, decision-making, judgment, and emotional regulation [ 13 ]. The efficacy of SMART has been evaluated in a range of healthy and clinical populations across the lifespan. These previous clinical studies of SMART demonstrated (i) cognitive improvement in aspects of executive function and memory [ 9 , 14 – 17 ], enhanced processing speed [ 18 ], and academic achievement [ 19 , 20 ]; (ii) improved psychological well-being including reduction of depressive, stress, and anxiety symptoms[ 9 ]; and (iii) corresponding changes between behavioral and neural network gains post-SMART, including increased brain blood flow and brain network connectivity in the Central Executive and Default Mode Networks [ 6 , 9 ] and enhanced white matter integrity [ 6 ]. Prior studies of SMART relied on in-person engagement with trained study personnel, with assessment of changes assessed over a limited time period. This study aims to translate prior in-person brain health assessment and training protocols to an online, widely accessible format via the BrainHealth Platform. This secure portal allows scientists and participants to continuously track engagement and the impact of habits aimed at brain health strategies, coaching, and education over time. Therefore, the primary objectives of the BrainHealth Project are to: Evaluate and further inform whether the multidimensional BrainHealth Index can measure change - whether gains, losses, or maintained abilities - in healthy adults. Examine the impact of evidence-based cognitive strategies and lifestyle interventions on brain health using machine learning. Elucidate the mechanisms associated with brain health gains or losses. By integrating large-scale data across multiple domains and time intervals, we aim to evaluate, interpret, and predict how various factors interact to contribute to brain health at both group and individual levels. We assess this through an epidemiological approach, utilizing interventions previously shown beneficial in prior randomized trials [ 6 – 9 ]. Due to the open-label design of the study, all participants have access to interventions found previously to promote benefit, without harm. Participants were free to choose their own level of engagement in training (e.g., engaging with the habit utilization but not the learning modules). Such utilization is tracked to evaluate the impact of engagement on measured brain change from baseline over time. The data from this large, diverse population study will provide granular insights into factors such as involvement, health, and lifestyle, enabling the development of prediction models at the individual level. We anticipate that participants who consistently engage in the micro-learning modules from the online BrainHealth Platform training over time will show improved and sustained brain health outcomes compared to those who do not. A portion of the third objective will be addressed in a BrainHealth imaging sub-study protocol (currently in press). The goal of this sub-study is to assess the neural and biological mechanisms associated with, or predictive of, improved or maintained brain health through changes observed in fMRI brain scans collected at baseline, 6 months, and annually thereafter for the duration of the study. The neural data from this sub-study will be analyzed alongside the BrainHealth Index behavioral data to help develop a reliable set of biomarkers for assessing brain health longitudinally. METHODS Study Design The BrainHealth Project is a prospective, longitudinal, interventional, open-label, single-arm clinical trial. A pilot study was conducted from March to August 2020 to assess the feasibility of the online study platform and to develop a data-driven index of brain health [ 21 ]. Recruitment for the longitudinal study commenced in September 2020, following the conclusion of the pilot phase. The study aims to enroll 100,000 adults over a 10-year period, with ongoing recruitment and enrollment throughout the study duration. As the study progresses, data analysis and findings will inform the addition of more targeted data collection, and both interventional and observational sub-studies are planned. All core procedures for the Project are conducted online via the BrainHealth Platform, accessible through a desktop computer or a full-function mobile app (launched in February 2024). Participants complete an initial online baseline assessment of their BrainHealth Index, followed by personalized online coaching every three months, with continuous access to online training, exercises, and educational resources aimed at optimizing brain health and overall well-being. Participants are encouraged to reassess their BrainHealth Index every six months for the duration of their involvement. For a subset of participants who choose to link data from their personal fitness devices, metrics such as physiological markers related to sleep, physical fitness, and overall health will be collected. To assess the impact of cognitive interventions and the use of digital health and educational tools, we will also analyze participant engagement with the features and content available on the BrainHealth Platform. All activities involving the BrainHealth Project and BrainHealth Platform were approved by the University of Texas at Dallas’ Institutional Review Board prior to the initiation of research activities. Participants The study targets generally healthy adults aged 18 years and older. Inclusion criteria focus on participants' ability to access and engage with the online platform and content, as determined by self-report. These criteria include: fluency in English, access to an internet connection and device, and the ability to hear and read information on the computer or device. Exclusion criteria are based on specific health conditions. Individuals are excluded if they have a diagnosed neurodegenerative disease; a history of stroke, concussion, or brain injury that currently impairs their ability to function at their reported prior level (e.g., inability to carry out daily responsibilities); or a diagnosis of autism spectrum disorder with non-independent functioning. Participants are not excluded for other diagnoses, such as learning disorders or psychiatric or medical conditions, in order to maintain the diversity of the generally brain-healthy population and to ensure the generalizability of the results. These characteristics will be captured through self-report, along with changes in demographic data collected at each assessment timepoint, to inform potential clinical subgroup analyses as appropriate. Recruitment Participants are recruited through word of mouth, online postings, social media and advertisements, such as through the Center for BrainHealth website and e-newsletter and registries such as the Alzheimer’s Prevention Registry as well as posts on social media platforms such as Facebook, Instagram, and LinkedIn. Study flyers or recruitment information are also shared through in-person and virtual events by the Center for BrainHealth. Two healthcare system partners of the Center for BrainHealth, one in the local Dallas area and one in the eastern United States, also share the study recruitment information through flyers and social media posts. Participants do not receive any payment or reimbursement for participation in this online study. Data Collected and Instruments Used BrainHealth Index (BHI) assessment (60–90 mins. total, avg. 70 mins.). The study’s primary outcome measure is the composite BrainHealth Index (BHI) score. The BHI is scored from a multidimensional assessment of brain health and performance, comprised of an online battery of cognitive performance measures and self-report questionnaires completed by participants through the BrainHealth Platform. The BHI is unique in that it is designed to measure change over time without the presumption of decline or a specified ceiling – i.e., characterizing the development and upward improvement of brain health rather than serving as a decline-oriented, adjusted normative, or diagnostic cognitive measure. Cognitive assessment includes tasks of complex thinking capacities such as reasoning, abstraction, mental flexibility, and strategy – each with alternate-stimuli versions randomized across timepoints. The self-report questionnaires measure other aspects of daily life that relate to brain health, such as emotional well-being, quality of life, purpose, happiness, resilience, social support systems, and sleep – utilizing tools that have been empirically validated in their respective literatures where possible. In these sections of the online assessment battery, participants self-report through rating aspects of their daily life within the prior 6 months. At each testing time point (baseline and every 6 months thereafter), participants have the opportunity to divide the assessments into shorter segments over time while saving their progress to date (up to two weeks duration) to complete the overall assessment. See Table 1 for a full list of measures. Table 1 Measures included in the holistic BrainHealth Index assessment Measure Assessment Instrument Strategic Attention Visual Selective Learning Task [22] Abstraction Proverb Interpretation Task (developed at the Center for BrainHealth) Reasoning Synthesis Interpretation Memory Test of Strategic Learning (TOSL) [23] Condensed synopsis of complex text (~ 550-word narrative) Fluency of take-home messages/interpretations from text Memory for text details (free and cued/elaborated recall) Innovation Fluency of high-level Interpretations from Picture Interpretation Task (developed at the Center for BrainHealth, modeled after semantic verbal fluency task, adapted from Lezak et al. [24]) Processing Speed Coding/Digit Symbol Task (developed at the Center for BrainHealth) Sleep Pittsburgh Sleep Quality Index (PSQI) [25] Compassion Questionnaire adapted from the Light Triad Scale [26,27] Mood Depression Anxiety Stress Depression Anxiety Stress Scale (DASS-21) [28] Meaningful Activities/Purpose Engagement in Meaningful Activities Survey (EMAS) [29] Happiness Oxford Happiness Questionnaire (OHQ) [30] Social Support Social Support Survey Index [31] Resilience Connor-Davidson Resilience Scale [32] Life Satisfaction Quality of Life Scale [33] Social Engagement Social BrainHealth Scale (developed at the Center for BrainHealth) Growth Mindset BrainHealth Appraisal Questionnaire (developed at the Center for BrainHealth) Fitness Metabolic Equivalents: Cardiorespiratory Fitness (CFEQ) [34] The BrainHealth Index yields four separate scores which are shared with participants through their BrainHealth Platform study dashboard, including a composite/global BHI score as well as scores for its three validated factors: (1) Clarity (readiness to reason through complex situations and create new opportunities or solutions, i.e., cognitive health), (2) Connectedness (to people and purpose, i.e., social health), and (3) Emotional Balance (steadiness in the face of difficult situations, ability to handle adversity while remaining productive and capable). These are based on a factor analysis of change scores from measures shown in Table 1 [ 21 ]. The University of Texas at Dallas’ Center for BrainHealth investigator team designed the BHI’s composite/holistic score to capture the multiple dimensions of brain health and the interdependency amongst these dimensions, based on machine learning analytics, rather than presupposed components. For each individual, the four scores are graphed to visually track progress over time. This data visualization allows participants to realize their brain health as a whole (composite BHI score) while also reflecting the multiple paths they have to support their brain health and performance over time (factor scores). The BHI uses the individual’s own performance against which to measure growth over time rather than being compared to a group norm, allowing for a more personalized approach that is independent of starting point. See Fig. 1 , which displays the three validated factor areas and their contributing measures. Demographic information . For each participant, at baseline we collect self-report data on age, gender identity, biological sex assigned at birth, race/ethnicity, country/U.S. zip code, household income, level of education, and occupation as well as any currently diagnosed medical or psychiatric conditions. At every subsequent online assessment timepoint (offered every 6 months), any changes in these data points are collected. Training Materials The online training materials included in this study protocol consist of the following: BrainHealth Platform Training Modules, Habits, and Resources: Training Modules. Participants access the training modules through the study’s online BrainHealth Platform which includes micro-learning videos, animations to motivate learning, activities, and learning/strategy application opportunities [ 21 ]. The training protocol is comprised primarily of evidence-based cognitive strategy learning, previously shown to improve aspects of neurocognitive and real-life function in clinical trials [ 6 , 13 ]. The strategy-based cognitive training protocol, Strategic Memory Advanced Reasoning Tactics (SMART), was developed by Center for BrainHealth neuroscientists and clinicians to promote improvement in executive functioning and self-agency. The executive function/top-down SMART protocol trains three core strategies, specifically (1) strategic attention to reduce information intake, single-task to focus and make progress on daily goals, and brain down time, (2) integrated reasoning to quickly synthesize information/facts into succinct abstracted ideas and interpretations and apply to real life application, and (3) innovation to flexibly generate a multitude of ways to improve tasks, communications, meetings, relationships and missteps/mistakes. The strategies can be applied in the context of everyday-life activities and responsibilities. Based on more than 25 years of intensive research, SMART has been shown to positively impact areas of cognition (e.g., improved executive function, strategic attention, integrated reasoning, innovation, decision-making, and memory), well-being (e.g., reduced symptoms of stress, depression and anxiety), and real-life function (e.g., improved quality of life, initiation and prioritization of social engagement/relationships, and complexity of life work responsibilities). Gains in these areas were found to correspond with significant neural changes, including aspects of neural connectivity, cerebral blood flow, and neural efficiency [ 6 – 8 , 18 , 35 – 38 ]. All BrainHealth Platform SMART sessions are designed to be self-paced, consisting of 5–10-minute daily units. These sessions are reinforced with habit training and integration, encouraging participants to consistently apply tactical brain strategies to various everyday responsibilities and situations. Although training is available daily, participants can determine their own frequency of engagement. The training units combine education on brain strategies, explanations of the rationale to promote brain health literacy, and prompts for personal reflection and practical application. After completing the four SMART modules, training continues with online learning about solutions to minimize stress. These SMART strategies associated with stress management techniques are designed to build a more resilient mindset by integrating stress management techniques with healthy lifestyle choices such as physical exercise, diet, and mindful meditation—practices that have been empirically shown to reduce stress [ 39 – 43 ]. The sleep module provides information on not only the science of sleep and aspects such as sleep cycles, but also walks participants through sleep hygiene tips to help improve their quality and quantity of sleep. For detailed descriptions of these self-paced BrainHealth Platform training modules, see Table 2 . Table 2 Description of self-paced online training modules Training module Description No. of units/ Total time 1. SMART 01* Provides strategies and interactive activities teaching how to block irrelevant information and focus on key priorities and critical information (strategic attention). Example: Organize your day to accomplish significant tasks – each day prioritize the top two tasks that require deeper-level thinking. 6 units/ 55 min 2. SMART 02* Provides strategies and interactive activities on how to abstract big-picture concepts from information to better inform understanding and real-life decisions (integrated reasoning). Example: Extract key concepts from incoming information vs. trying to process and remember everything. 4 units/ 35 min 3. SMART 03* Provides strategies and interactive activities on how to generate multiple and diverse solutions/perspectives/ questions to strengthen mental flexibility (innovation). Example: Identify multiple alternative perspectives/ideas on discordant issues. 6 units/ 35 min 4. SMART 04* Provides real-life application scenarios where participants can practice dynamic implementation of the strategies from SMART 01–03 (strategic attention, integrated reasoning, innovation) in a synergistic manner. Example: Think about and prepare to ask your boss for a raise ( considering your accomplishments, impact those accomplishments have had or could have on the organization , etc.). 6 units/ 45 min 5. Stress solutions 01 Presents information about physiological and neurological response to stress, as well as cognitive strategies linked with SMART to manage and reframe stressors. Example: Reframe your perception of your response to a difficult situation from anxiety to excitement. 5 units/ 40 min 6. Stress solutions 02 Provides accessible techniques to help “recharge your mental battery” in terms of stress or fatigue, as well as education on lifestyle factors that can positively impact overall health. Example: Take several short breaks throughout your day. 4 units/ 30 min 7. Stress solutions 03 Provides research on the benefits of mindfulness, meditation, and healthy sleep habits, as well as practical tips on how to practice each one (linking with SMART strategies). Example: Participate in a mindfulness exercise. 5 units/ 45 min 8. Sleep Presents research on the science behind sleep over the lifespan, the brain impacts of poor sleep, and practical tips for improving one’s sleep habits. 16 units/ 75 min Total time 350 min *Modules 1–4 provide the foundational cognitive strategies (SMART). Habits . Each training module is paired with a set of brain-healthy "Habits" that participants can access once they complete the module. These habits allow participants to integrate specific training concepts or strategies into their daily routines. Participants can choose a habit, opt to receive daily reminders, and track their progress over time, earning levels and digital "badges" on the BrainHealth Platform. Examples of habits include minimizing distractions, taking regular breaks, completing two important big tasks each day, maintaining a consistent and healthy sleep routine, and exploring multiple possibilities to reapproach a challenge, perceived failure, dilemma or mistake. Additionally, habits can be focused on lifestyle improvements such as exercise, nutrition, and mindfulness. Challenges . After completing the primary training modules, participants advance to a continuing series of "Challenge" units designed for reinforcement and extended application of the strategies and practices. These challenges are also delivered in 5-10-minute increments and feature diverse content, such as article readings and educational video clips. Each provides insights into the relevant brain science and includes reflection questions or practical application opportunities. Monthly challenge topics are organized into four weekly segments centered around a shared theme. Examples of these themes include memory habits, managing news consumption, navigating tough conversations, the science of confidence, breathing techniques, gratitude practices, etc. Resources . Participants have access to a continually curated collection of educational resources on the broad topic of brain health, including media articles, published research studies, online lectures, etc. Additional training and resource content will be added throughout the study to offer ongoing learning opportunities and maintain participant engagement. Online coaching: Participants can engage in individual 20-minute videoconference coaching sessions every 3 months, conducted within the study platform. These sessions are led by a study brain health coach and can be self-scheduled by participants. Coaches are assigned based on availability and consist of study personnel with degrees spanning fields such as speech-language pathology, psychology, occupational therapy, education, or other areas of human performance. All coaches have experience administering and interpreting cognitive and human performance assessments, with a minimum of 2 years of post-graduate work experience in their respective field of practice. During these sessions, brain health coaches offer individualized feedback on participants' BrainHealth Index results, guide them on engaging with the online training content, assist in setting personal brain health goals, and discuss how to apply the training strategies and practices to their specific goals or context. Following the session, coaches provide summary notes on the participant's BrainHealth Platform profile, articulating the key points discussed for easy access at any time. Participants can choose to utilize this quarterly personalized coaching as much or as little as they prefer. BrainHQ training : After completing their third BrainHealth Index assessment (typically one year post-baseline), participants have the opportunity to access BrainHQ [ 44 ] training for a limited time. Through the BrainHealth Platform, participants can engage in 14 BrainHQ training exercises over a period of up to 16 weeks. In contrast to SMART, which is strategy-based, BrainHQ is a computer exercise-based approach to cognitive training, with multiple studies supporting its effectiveness in enhancing cognitive performance [ 45 ]. Each exercise adapts in difficulty according to the participant's performance, using a specialized algorithm. The exercises made available to participants in the BrainHealth Project include those addressing attention, processing speed, memory, and decision-making. During the 16 weeks of BrainHQ access, participants are encouraged to engage with BrainHQ exercises four times a week for 30 minutes each session. Retention of participants Recognizing the importance of engagement and retention in a longitudinal study, we have developed and implemented solutions to address participant engagement and retention through three avenues: (1) technology platform enhancements, (2) improved communications, and (3) opportunities for community building among participants. Initially, the BrainHealth Platform was accessible only via a web browser-based interface. However, to enhance accessibility and user experience, it has evolved to include a dedicated mobile application, launched in February 2024. This mobile app introduces advanced notification capabilities such as push notifications, sounds, and banners, which not only prompt participants to re-engage after periods of disengagement, but also remind them to complete essential study tasks, like the BrainHealth Index assessments. Furthermore, we have introduced gamification elements, such as earning “coins” for task completion and achieving higher ranks with each BrainHealth Index completed, to increase participant utilization and motivation. We have continuously improved our study communications by making messaging clearer and more concise, ensuring participants are well-informed about their progress throughout the study procedures. The improved BrainHealth Platform now includes an onboarding navigation process that clearly outlines each study step, accompanied by visual tutorial elements. These tutorials help orient participants to their online study dashboard and explain or highlight key features to enhance ease of use. For a visual representation of the study participation elements, see Fig. 2. Additionally, we have expanded communication methods beyond email, incorporating the use of text messaging for participants who opt-in. This allows for more regular and continuing study engagement, such as facilitating daily habit completion and other study interactions. The BrainHealth Project team also works to enhance participant engagement by offering monthly virtual group coaching sessions via Zoom. These 45-minute sessions are conducted live (not recorded) and are open to all study participants, providing social motivation and community-building opportunities. Additionally, in response to early participant requests for more information on the brain science behind the study, we host periodic virtual town hall webinars. These webinars, generally held annually or semi-annually, allow participants to deepen their understanding of the research they contribute to and foster a sense of involvement in a greater mission as citizen scientists. The town hall webinars are lecture-style, recorded, and subsequently made available in the BrainHealth Platform Resources section for all participants to access. In evaluating the impact of these offerings, we will assess whether these additional resources contribute to increased training utilization and improved study retention over time. Data Management and Security within the BrainHealth Platform. The online BrainHealth Platform, which hosts assessments and training tools, automatically uploads data to a secure cloud-based data management system. This system uses a relational database architecture, adheres to de-identification best practices, and implements stringent security protocols. Day-to-day study administration occurs via the platform’s secure administrative dashboard. For research analysis, additional data levels can be queried and integrated from various datasets stored in a cloud-based data lake. Access to data is strictly controlled, available only to authorized study personnel through secure access points, reinforced by strong password policies and multi-factor authentication. Assessment Scoring and Quality Control. The majority of the assessments included in the online BHI are automatically scored, except for three language-based cognitive performance measures (Abstraction, Reasoning, Innovation), which are manually scored by trained study personnel. To ensure data integrity and inter-rater reliability, quality control practices are in place. These include procedures for scoring review and consensus-building, as well as procedures for identifying and filtering invalid responses. This might involve noting any difficulties or interruptions that participants report encountering during the tasks or detecting the use of external aids. Statistical Considerations A key objective of the BrainHealth Project is to achieve precision brain health, recognizing that lifestyle interventions, cognitive training, exercise, and sleep impact individuals differently. The ultimate goal is to improve brain health for all participants, yet this improvement requires a tailored approach to meet each individual's specific needs. Consequently, the statistical approaches employed in this study prioritize individual prediction over population-wide inference. As such, formal power analyses are not relevant to sample size determination; however, see below for some population-based sub-studies that do require power justification. In the machine learning literature, it is necessary to utilize tens of thousands of samples to train, validate and test complex, nonlinear prediction models such as neural networks (including deep learning networks), support vector machines and unsupervised tree or clustering methods. To determine the factors that influence and improve brain health in individual participants, we will utilize these nonlinear models and train them using large samples. Large samples will accommodate not only the training of the models, but also the validation and testing of them on independent samples such that estimates of generalization error can be obtained with low variance. For these purposes, we plan to recruit a baseline sample that will eventually yield an expected 15,000–20,000 individuals at the end of 10 years. These sample sizes are also comparable to those in the well-publicized Framingham Heart Study, which continues to determine factors related to heart health [ 11 , 12 ]. Increased attrition and lack of adherence have been longstanding barriers to successful health-behavior interventions [ 46 ]. Given the online nature of the study and precedent from previous longitudinal, population-based studies involving internet-based/eHealth platforms [ 47 ], we similarly anticipate as much as 80%-85% attrition over the full 10-year study period. Therefore, to reach our goal we plan to recruit a baseline sample of 100,000 participants. In addition to the sample requirements of neural network prediction models, a sample of 15,000–20,000 will allow population-based sub-studies as secondary aims in the BrainHealth Project. For example, within our workplace, mental illness, and caregiver sub-studies, we focus on analyzing the mean longitudinal changes in brain health. Additionally, we aim to document potential declines in brain health that may occur due to unexpected health events as reported by participants, such as undergoing chemotherapy, experiencing a concussion, contracting COVID-19, encountering significant grief, and other impactful life events. Importantly, we also examine participants' capacity to recover, facilitated by access to brain health training supports, as they continue their participation in the longitudinal study. As the specificity of particular cohorts increases (e.g., males between 20–30 with less than a bachelor’s degree and a self-reported mental illness), the samples decrease markedly. However, having a total sample between 15,000 and 20,000 will allow rare cohorts to maintain at least samples of 100, which is required to detect effect sizes of at least 0.5 with 80% statistical power, adjusted for false positive control due to multiple testing. DISCUSSION This manuscript details the study protocol, background, and significance of the BrainHealth Project, a prospective, single-arm, open-label, longitudinal interventional clinical trial. While significant research has historically been focused on improving cardiovascular health—thereby greatly enhancing life expectancy and quality—to date, comparatively limited efforts have been made to comprehensively assess and strengthen brain health in healthy individuals across all ages and life stages. The BrainHealth Project aims to address this critical gap by focusing on measuring, monitoring, and enhancing brain health in healthy adults, from late teens through late life. The study utilizes an online portal accessible via computers or mobile devices, to allow wide accessibility and to ensure scalability. This effort builds on prior shorter-term, randomized control trials that demonstrated significant benefits from an in-person brain health intervention, known as Strategic Memory Advanced Reasoning Tactics (SMART). SMART, a manualized protocol focusing on executive functions and top-down strategies, showed gains from pre-to post-training across neural, cognitive, emotional, and social health domains, with improvements persisting at least three months post-training [ 6 – 9 ]. The current ongoing trial integrates SMART with technology and coach-facilitated lifestyle changes—including sleep, stress management, social connections, and physical exercise—to create a comprehensive and scalable extension of the previously evaluated program. This trial aims to explore the long-term impacts of these brain health interventions. A central aspect of this approach is the regular measurement of wide-spectrum brain health using regular BrainHealth Index assessments, validated in a subset of participants against comprehensive brain imaging measures over time. Major strengths of the BrainHealth Project include a focus on the following seven issues that will inform ways to motivate behavioral change to improve brain health on a population-wide basis: Utility of the BrainHealth Index : Evaluating the BrainHealth Index's ability to measure changes in holistic brain performance , where each participant serves as their own control. This approach charts individual changes over years, regardless of their starting level, independent of education, economic status, cultural background, or gender, contrasting with conventional siloed approach using normed assessments that focus on domains developed to detect decline and deliver diagnosis, and are adjusted for expected losses with age. (2) Potential gains across all ages : Assessing the potential for adults of all ages, not just older adults, to make gains when provided simple top-down cognitive strategies of executive function. This helps maintain a sense of self-agency across other health habits and other aspects of life. (3) Long-term impact : Characterizing the long-term effects of brain health strategy and lifestyle interventions over years through a longitudinal, epidemiologic-type approach. (4) Digital health accessibility : Measuring the utility of leveraging digital health technology to enhance accessibility, reaching from urban to rural areas and extending far beyond major research centers or clinical specialists and providers. (5) Precision with machine learning : Utilizing machine learning tools to rapidly develop precision brain health at an individual analysis level. (6) Mechanisms of brain health changes : Elucidating significant mechanisms underlying changes in brain health, including gains or losses, by enrolling large-sample, diverse cohorts. (7) Neural changes and neurobiological markers : Setting the stage for identifying neural changes through the BrainHealth Project’s subset imaging protocol (detailed in a separate manuscript) that correspond to gains and also future potential losses, serving to provide neurobiological markers of brain health changes and to validate the behavioral Index’s efficacy. While MRI scans are unlikely to become the standard of care for brain health monitoring on a population-level basis worldwide due to cost and accessibility, this study aims to provide validated proxy measures derived from the BrainHealth Index to accurately, reliably, and reproducibly reflect changes in individual brain health across the lifespan. In summary, the BrainHealth Project represents a concerted single-arm research study designed to test the feasibility and effectiveness of measuring and enhancing brain health using a previously validated assessment tool and interventions in an augmented and scalable manner. Brain health encompasses the optimization of neural health, cognition, connectedness to people and purpose, and emotional well-being across the lifespan—aligning with the World Health Organization’s definition of brain health [ 3 ]. All of these domains are measured repeatedly using an appropriately holistic measure - the BrainHealth Index. The study also aims to elucidate the potential neural and other physiological mechanisms that contribute to changes in brain health. By analyzing brain and physiological data, the research will inform how various aspects of brain function—such as neuronal activity, blood supply, and metabolism—are influenced by interventions and captured by changes in the BrainHealth Index over time, presumably reflecting improved brain health. The ultimate goal of this project is to provide a validated, clinically meaningful, widely accepted, generalizable measure of the brain that supports the development and testing of precision, preventive, and personalized brain health interventions, making them widely available globally. The centrality of brain health to overall health underscores the potential of scalable interventions like the one described in this project to broadly impact public health more generally. Given that some brain health aspects of neural health and cognitive performance, such as global cerebral blood flow [ 48 ] and processing speed [ 49 ], often begin to decline in early adulthood, this current project is relevant across the entire adult lifespan. It is applicable even in the absence of disease or injury and should be employed starting in early adulthood to foster and reinforce healthier brain habits across whole populations. Limitations As with any longitudinal study, particularly one conducted entirely online, participant dropout is inevitable. Another limitation is the potential for selective attrition, in that those who continue to participate beyond the baseline assessment to complete later assessment timepoints may also likely be those most highly motivated to succeed, particularly given possible gains after the initial training instruction period. Efforts will be made to recruit and retain more diverse populations (racial, level of education, socioeconomic status and others) over the course of the study to enhance study sample representativeness and support the generalizability of study findings. This study lacks a randomized control group; however, the large sample size and extended duration allow for the use of quasi-experimental designs and machine learning methods to monitor changes in brain health based on the extent of usage of the brain health interventions offered. The decision to adopt a single-arm study design was also informed by findings from our prior pilot trials demonstrating benefit of SMART in those participants. Given the significant time commitment required from participants, it was deemed more ethically appropriate to use a scientifically valid design where each participant serves as their own control and stands to benefit from engagement in the study. This approach not only aligns with the goal of precision brain health but also allows for the consideration of individual differences such as genetics and lifestyle habits. These personal factors are systematically analyzed using machine learning models, which further enhance the ability to tailor interventions based on unique participant profiles and to more accurately predict outcomes based on diverse personal data inputs. We are also testing the feasibility of integrating machine learning and artificial intelligence tools to support manual scoring components and live, virtual coaching. Finally, web-measured changes in brain health will be correlated with and validated against brain imaging-derived neural measures in a subset of participants. This correlation aims to strengthen the hypothesis that adopting healthy brain habits can yield long-term benefits to brain health, as behavioral changes over extended time periods that align with desirable neural changes are observed. Future Directions The BrainHealth Project aims to address critical clinical questions surrounding brain wellness and the potential for cognitive gains across the lifespan. As other online brain health interventions are validated through clinical trials, the BrainHealth Platform and the BrainHealth Index present opportunities for collaboration with researchers and medical experts who have evidence-based brain health protocols suitable for online implementation. By incorporating and testing these additional protocols, whether nonpharmacological or pharmacological, we can further evaluate the efficacy of the BrainHealth Index in measuring the benefits of various interventions over time. Currently, there is no widely accepted "gold standard" for a holistic measure of normal brain health. The BrainHealth Index serves to fill this void by offering an urgently needed standard that is sensitive to both meaningful positive and negative changes across key dimensions of brain health, including neural function, clarity of cognition, emotional well-being, and connectedness to people and purpose. By enhancing our understanding of the factors that optimize brain health throughout the lifespan, the BrainHealth Index has the potential to significantly impact health, work, and economic outcomes, benefiting individuals and society as a whole. Conclusion In summary, this groundbreaking study aims to decode the determinants of brain wellness and cognitive resilience throughout the lifespan. By leveraging the insights gleaned from the paradigm-shifting Framingham study and adopting a similar initial primarily observational approach, we aim to build a comprehensive repository expected to gain a novel and improved understanding of brain health maintenance and improvement that transcends traditional boundaries of the aging brain. By conducting rigorous observational analyses and integrating diverse datasets, we seek to uncover actionable strategies that promote brain wellness and cognitive enhancements across diverse populations. Ultimately, this effort is poised to reshape the landscape of brain health research and clinical practice, paving the way for future innovations and interventions. Trial Status At the time of the submission of this manuscript, enrollment was ongoing. Abbreviations BHI: BrainHealth Index; CFEQ: Metabolic Equivalents: Cardiorespiratory Fitness; COVID-19: Coronavirus Disease 2019; DASS-21: Depression Anxiety Stress Scale-21; EMAS: Engagement in Meaningful Activities Survey; fMRI: functional magnetic resonance imaging; MRI: magnetic resonance imaging; OHQ: Oxford Happiness Questionnaire; PSQI: Pittsburgh Sleep Quality Index; RCT: randomized controlled trial; SMART: Strategic Memory Advanced Reasoning Tactics; TOSL: Test of Strategic Learning; WHO: World Health Organization Declarations Ethics approval and consent to participate This study has been approved for research with human subjects by the Institutional Review Board of the University of Texas at Dallas (IRB# 23-745) and is being conducted in accordance with the Declaration of Helsinki. All participants complete the study informed consent online through the BrainHealth Platform. Consent for publication All authors have read and approved the final manuscript for publication. This manuscript does not contain any individual person’s data or image. All figures are original graphics. Availability of data and materials The datasets used and/or analyzed during the current study are available from the authors on reasonable request. Competing interests Due to prior evidence of the efficacy of the SMART program, The University of Texas at Dallas Center for BrainHealth is actively engaged in providing SMART to a variety of groups, including in the enterprise. The Center has also applied for a process patent for SMART. In addition, the system and method for precision brain health assessment is patent pending. Funding The BrainHealth Project is currently funded by private philanthropy: Jean Ann Brock, Teresa and David Disiere, Marlane Miller, Jennifer and Peter Roberts, Sammons Enterprises, Inc., as well as several anonymous donors. Authors’ contributions All authors listed have made a substantial, direct, and intellectual contribution to the work. Acknowledgements We express sincere gratitude to the coaches of the BrainHealth Project for guiding and encouraging participants with exceptional care and skill: Tandra Allen, Katie Hinds, Janet Koslovsky, Sarah Laane, Marco Lopez, Kalyn Potter, Audette Rackley, Colleen Ryan, Stacy Vernon, Jennifer Zientz. Additionally, we must thank our skilled technology, data management, and support team, including Zhengsi Chang, Margaret Chaplin, Sonal Jain, Samuel Ballard, Kamin Bouguyon, Bryan Vosburg, Haider Naeem, Sameena Shaik, Dinesh Sharma, Mahanaz Attila, Radi Tawfiq, Choe Chu, and the team at Dialexa for their tremendous work on the online platform. Finally, we are extremely grateful for the participants who choose to be pioneers in brain health and invest their time in this research. References Merzenich MM, De Charms CR. Neural representations, experience and change. In: Llinas R, Churchland P, editors. The mind-brain continuum: sensory processes. Cambridge (MA): MIT Press; 1996. p. 61–81. Merzenich MM, Van Vleet TM, Nahum M. Brain plasticity-based therapeutics. Front Hum Neurosci. 2014;(8):385. Optimizing brain health across the life course: WHO position paper. Geneva: World Health Organization; 2022. License: CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo/. Greene M. Boosting brain health is key to a thriving economy. Financial Times [Internet]. 2021 Aug 12 [cited 2023 Oct 26]. Available from https://www.ft.com/content/d202b1f3-0a69-4acd-bb1b-e2fa06b21df3. Chapman SB. Make your brain smarter: increase your brain’s creativity, energy, and focus. New York: Simon and Shuster; 2014. Chapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, et al. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015;25:396-405. doi:10.1093/cercor/bht234. Chapman SB, Aslan S, Spence JS, Keebler MW, DeFina LF, Didehbani N, et al. Distinct brain and behavioral benefits from cognitive vs. physical training: a randomized trial in aging adults. Front Hum Neurosci. 2016;10:338. doi:10.3389/fnhum.2016.00338. Chapman SB, Spence JS, Aslan S, Keebler MW. Enhancing innovation and underlying neural mechanisms via cognitive training in healthy older adults. Front Aging Neurosci. 2017;9:314. doi:10.3389/fnagi.2017.00314. Vas A, Chapman S, Aslan S, Spence J, Keebler M, Rodriguez-Larrain G, et al. Reasoning training in veteran and civilian traumatic brain injury with persistent mild impairment. Neuropsychol Rehabil. 2016;26:502–31. doi:10.1080/09602011.2015.1044013. Chapman SB, Cook LG, Vas AK, Robertson IH. Enhancing human cognitive capital by harnessing the brain’s inherent neuroplasticity. In: Matthews MD, Schnyer DM, editors. Human performance optimization. New York: Oxford University Press; 2019. p. 260-86. Andersson C, Johnson AD, Benjamin EJ, Levy D, Vasan RS. 70-year legacy of the Framingham heart study. Nat Rev Cardiol. 2019;16:687-98. doi:10.1038/s41569-019-0202-5. Bitton A, Gaziano TA. The Framingham heart study's impact on global risk assessment. Prog Cardiovasc Dis. 2010;53:68-78. doi:10.1016/j.pcad.2010.04.001. Chapman SB, Mudar RA. Enhancement of cognitive and neural functions through complex reasoning training: evidence from normal and clinical populations. Front Syst Neurosci. 2014;8:69. doi:10.3389/fnsys.2014.00069. Cook LG, Chapman SB, Elliott AC, Evenson NN, Vinton K. Cognitive gains from gist reasoning training in adolescents with chronic-stage traumatic brain injury. Front Neurol. 2014;5. doi:10.3389/fneur.2014.00087. Mudar RA, Chapman SB, Rackley A, Eroh J, Chiang H-S, Perez A, et al. Enhancing latent cognitive capacity in mild cognitive impairment with gist reasoning training: a pilot study. Int J Geriatr Psychiatry. 2017;32(5):548-555. doi:10.1002/gps.4492. Vas AK, Chapman SB, Cook LG, Elliott AC, Keebler M. Higher-order reasoning training years after traumatic brain injury in adults. J Head Trauma Rehabil. 2011;26(3):224-39. doi:10.1097/HTR.0b013e318218dd3d. Venza EE, Chapman SB, Aslan S, Zientz JE, Tyler DC, Spence JS. Enhancing executive function and neural health in bipolar disorder through reasoning training. Front Psychol. 2016;7:1676. doi:10.3389/fpsyg.2016.01676. Motes MA, Yezhuvath US, Aslan S, Spence JS, Rypma B, Chapman SB. Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial. Neurobiol Aging. 2018;62:72-81. doi:10.1016/j.neurobiolaging.2017.10.003. Gamino JF, Motes MM, Riddle R, Lyon GR, Spence JS, Chapman SB. Enhancing inferential abilities in adolescence: new hope for students in poverty. Front Hum Neurosci. 2014;8:924. doi:10.3389/fnhum.2014.00924. Gamino JF, Frost C, Riddle R, Koslovsky J, Chapman SB. Higher-order executive function in middle school: training teachers to enhance cognition in young adolescents. Front Psychol. 2022;13:867264. doi:10.3389/fpsyg.2022.867264. Chapman SB, Fratantoni JM, Robertson IH, D'Esposito M, Ling GSF, Zientz J, et al. A novel brain health index prototype improved by telehealth-delivered training during COVID-19. Front Public Health. 2021;9:641754. doi:10.3389/fpubh.2021.641754. Hanten G, Li X, Chapman SB, Swank P, Gamino J, Roberson G, et al. Development of verbal selective learning. Dev Neuropsychol. 2007;32:585-96. doi: 10.1080/87565640701361112. Vas AK, Chapman SB, Cook LG. Language impairments in traumatic brain injury: a window into complex cognitive performance. In: Salazar A, Grafman J, editors. Handbook of clinical neurology: Traumatic Brain Injury Part II. Amsterdam: Elsevier; 2015. p. 497-510. Lezak MD, Howieson DB, Loring DW, Fischer JS. Neuropsychological assessment. New York: Oxford University Press; 2004. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index (PSQI): a new instrument for psychiatric research and practice. Psychiatr Res. 1989; 28:193-213. doi:10.1016/0165-1781(89)90047-4. Johnson LKD. The Light Triad Scale: developing and validating a preliminary measure of prosocial orientation, Master’s [thesis]. London, ON, Canada: The University of Western Ontario; 2018. Available from: https://ir.lib.uwo.ca/etd/5515. Strauss C, Lever Taylor B, Gu J, Kuyken W, Baer R, Jones F, et al. What is compassion and how can we measure it? A review of definitions and measures. Clin Psychol Rev. 2016;47:15-27. doi:10.1016/j.cpr.2016.05.004. Lovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck depression and anxiety inventories. Behav Res Ther. 1995;33:335-43. doi:10.1016/0005-7967(94)00075-u. Eakman AM. Convergent validity of the engagement in meaningful activities survey in a college sample. OTJR. 2011;30:23-32. doi:10.3928/15394492-20100122-02. Hills P, Argyle M. The Oxford Happiness Questionnaire: a compact scale for the measurement of psychological well-being. Pers Indiv Differ. 2002;33:1073-82. doi:10.1016/S0191-8869(01)00213-6. Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32:705-14. doi:10.1016/0277-9536(91)90150-b. Connor KM, Davidson JRT. Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety. 2003;18:76-82. doi:10.1002/da.10113. Burckhardt CS, Anderson KL. The quality of life scale (QOLS): reliability, validity, and utilization. Health Qual Life Outcomes. 2003;1:60. doi:10.1186/1477-7525-1-60. Jurca R, Jackson AS, LaMonte MJ, Morrow JR, Blair SN, Wareham NJ, et al. Assessing cardiorespiratory fitness without performing exercise testing. Am J Prev Med. 2005; 29:185–93. doi:10.1016/j.amepre.2005.06.004. Gallen CL, Baniqued PL, Chapman SB, Aslan S, Keebler M, Didehbani N, et al. Modular brain network organization predicts response to cognitive training in older adults. PLoS One. 2016;11(12):e0169015. doi:10.1371/journal.pone.0169015. Han K, Davis RA, Chapman SB, Krawczyk DC. Strategy-based reasoning training modulates cortical thickness and resting-state functional connectivity in adults with chronic traumatic brain injury. Brain Behav. 2017;7:e00687. doi:10.1002/brb3.687/full. Han K, Martinez D, Chapman SB, Krawczyk DC. Neural correlates of reduced depressive symptoms following cognitive training for chronic traumatic brain injury. Hum Brain Mapp. 2018;00:1-17. doi: 10.1002/hbm.24052. Yang YJD, Allen T, Abdullahi SM, Pelphrey KA, Volkmar FR, Chapman SB. Neural mechanisms of behavioral change in young adults with high-functioning autism receiving virtual reality social cognition training: a pilot study. Autism Res. 2018;11(5):713-25. doi:10.1002/aur.1941. Chow CM. Sleep and wellbeing, now and in the future. Int J Environ Res Public Health. 2020;17(8):2883. Owen L, Corfe B. The role of diet and nutrition on mental health and wellbeing. Proc Nutr Soc. 2017;76(4):425-426. Esgunoglu L, Jennings A, Connole ES, Murphy KJ, Minihane AM. Short-term effects of a Mediterranean-style dietary pattern on cognition and mental wellbeing: a systematic review of clinical trials. Pro Nutr Soc. 2021;8:1-10. Penedo FJ, Dahn JR. Exercise and well-being: a review of mental and physical health benefits associated with physical activity. Curr Opin Psychiatry. 2005;18(2):189-193. Khoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, et al. Mindfulness-based therapy: a comprehensive meta-analysis. Clin Psychol Rev. 2013;33:763-71. BrainHQ: Official Site. https://www.brainhq.com. Accessed 28 June 2024. Smith GE, Housen P, Yaffe K, Ruff R, Kennison RF, Mahncke HW, et al. A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study. J Am Geriatr Soc. 2009;57(4):594-603. doi: 10.1111/j.1532-5415.2008.02167.x. Middleton KR, Anton SD, Perri MG. Long-term adherence to health behavior change. Am J Lifestyle Med. 2013;7(6):395-404. Eysenbach G. The law of attrition. J Med Internet Res. 2005;7(1):e11. doi:10.2196/jmir.7.1.e11 Lu H, Xu F, Rodrigue KM, Kennedy KM, Cheng Y, Flicker B, et al. Alterations in cerebral metabolic rate and blood supply across the adult lifespan. Cereb Cortex. 2011;21:1426-34. Hartshorne JK, Germine LT. When does cognitive functioning peak? The asynchronous rise and fall of different cognitive abilities across the life span. Psychol Sci. 2015;26(4):433-43. Additional Declarations Competing interest reported. Due to prior evidence of the efficacy of the SMART program, The University of Texas at Dallas Center for BrainHealth is actively engaged in providing SMART to a variety of groups, including in the enterprise. The Center has also applied for a process patent for SMART. In addition, the system and method for precision brain health assessment is patent pending. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4855477","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":342998461,"identity":"984c9c25-3772-45f7-a28f-76b6a50f1d0c","order_by":0,"name":"Lori G. Cook","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3QuwrCMBSA4VMK7XLU9ZRKfQWLgw4+TFw6ubg4OVQKnbzM4uUZfIRIoS6ia0fdK3RyEcRjB8HB2tEhP4S0IR8kAVCp/rAqD/n6INMHQOjU82UsIMaboNR85KkUySMSZYk5vUgYdR1rkbbP6YiwNpfa+RoWENw3JcRey7b77ngVE1IidHddRMgDvkTU2zAJ0OCDJWDYlVLEOjB5EDZO0ryXIktCN6iEhE0pDL2QYAxS8F2siTdYrGcMk15grY7fSc0M9SzjF6N9tM3SW9dxTtEuS4ffSZ74/NX8H/tVKpVK9asnSqZI99GGq5sAAAAASUVORK5CYII=","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":true,"prefix":"","firstName":"Lori","middleName":"G.","lastName":"Cook","suffix":""},{"id":342998464,"identity":"288773d6-12c8-4f63-a040-ebd8cdb8752c","order_by":1,"name":"Jeffrey S. Spence","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"S.","lastName":"Spence","suffix":""},{"id":342998465,"identity":"74bca791-852c-408d-9683-e11d1ae6c8a6","order_by":2,"name":"Erin E. Venza","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Erin","middleName":"E.","lastName":"Venza","suffix":""},{"id":342998467,"identity":"ee1a4d61-c893-4bbe-ab5c-fa473ddc827f","order_by":3,"name":"Aaron Tate","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Aaron","middleName":"","lastName":"Tate","suffix":""},{"id":342998469,"identity":"f459496f-c29d-42b8-a1fd-bf92234853d4","order_by":4,"name":"Ian H. Robertson","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"H.","lastName":"Robertson","suffix":""},{"id":342998472,"identity":"2c1e5371-7f96-447f-91c3-3852e97f7c4f","order_by":5,"name":"Mark D'Esposito","email":"","orcid":"","institution":"University of California, Berkeley","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"D'Esposito","suffix":""},{"id":342998475,"identity":"e809d6d4-bc66-42d5-bc1a-6a5324103c00","order_by":6,"name":"Geoffrey S.F. Ling","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Geoffrey","middleName":"S.F.","lastName":"Ling","suffix":""},{"id":342998477,"identity":"3b46bb90-8acc-412d-b41b-55f1b931d694","order_by":7,"name":"Jane Wigginton","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Jane","middleName":"","lastName":"Wigginton","suffix":""},{"id":342998478,"identity":"c004347b-4606-4bfc-b4b8-bf1e92d201da","order_by":8,"name":"Sandra Bond Chapman","email":"","orcid":"","institution":"The University of Texas at Dallas","correspondingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"Bond","lastName":"Chapman","suffix":""}],"badges":[],"createdAt":"2024-08-04 05:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4855477/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4855477/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66329179,"identity":"7fa1023d-fd95-4240-9d29-0226a2414c43","added_by":"auto","created_at":"2024-10-10 13:11:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87963,"visible":true,"origin":"","legend":"\u003cp\u003eBrainHealth Factor areas and corresponding measures (including neural metrics to be collected as part of a separate phase/subset of the BrainHealth Project protocol)\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855477/v1/e6068eb632d86446aa198b49.jpg"},{"id":66329180,"identity":"b6633d41-7b6c-4c4c-bab2-409abcc8724e","added_by":"auto","created_at":"2024-10-10 13:11:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":205266,"visible":true,"origin":"","legend":"\u003cp\u003eVisual outline of participant study procedures\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4855477/v1/52419afbf64d51ea4dfcd380.png"},{"id":84361367,"identity":"dc30ae2b-d4e0-40f2-a448-06ca63c4317b","added_by":"auto","created_at":"2025-06-11 04:38:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1085101,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4855477/v1/2ccda350-e697-4fc7-8cc7-8a1ab1cb6b89.pdf"}],"financialInterests":"Competing interest reported. Due to prior evidence of the efficacy of the SMART program, The University of Texas at Dallas Center for BrainHealth is actively engaged in providing SMART to a variety of groups, including in the enterprise. The Center has also applied for a process patent for SMART. In addition, the system and method for precision brain health assessment is patent pending.","formattedTitle":"The BrainHealth Project Study Protocol: A Longitudinal Study in Generally Healthy Adults","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eImproving brain health is one of the most critical health challenges facing global society. The brain, as the command center for all our actions, feelings, and thoughts, influences every aspect of our life. Yet, the importance of optimizing brain health has been historically overlooked, in part due to outdated beliefs that intellect is fixed and that the brain cannot improve after young adulthood. However, neuroscientific discoveries over the past few decades have demonstrated that the brain retains neuroplasticity across the lifespan, meaning it can be modified by experience and use at every age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis understanding drives the need for objective ways to (1) measure changes in brain performance, whatever one\u0026rsquo;s starting point, and (2) examine the array of habits and practices that can strengthen brain systems and performance at an individual level. Like the preventative measures for heart health that are now well-established, we hypothesize that brain health care practices must similarly be initiated well before a person experiences losses in cognitive, psychological, social, or motor function. A healthier brain could provide protective benefits against a range of neurological, psychiatric, age-related and behavioral challenges. Moreover, such benefits would provide tremendous personal, social and economic benefit, extending peak brain performance well beyond the documented losses known to start in the late twenties to early thirties.\u003c/p\u003e \u003cp\u003eWhile multiple definitions for brain health exist, a consensus is emerging. We have adapted the World Health Organization\u0026rsquo;s (WHO) definition, which promotes optimal development of neural health, cognitive health, and well-being [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], to which we added the critical element of connectedness to people and purpose, allowing a person to realize their full potential over the life course. This adaptation guides the \u003cb\u003eBrainHealth Project\u003c/b\u003e, which aims to measure and optimize brain health. Enhancing brain health across all segments of society could drive tremendous economic and social advancement [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], a concept we term \u003cem\u003eBrainomics\u003c/em\u003e [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHistorically, accurate measurement of brain health has been challenging due to a focus on disease driven metrics rather than a holistic view of lifelong brain wellness. Traditional measures often highlight focus on a specific brain health skill/domain rather than being holistic or utilizing a composite approach. Additionally, they often emphasize documenting decline rather than capturing both positive and negative changes in brain health over the lifespan, as the indices used in this study allow.\u003c/p\u003e \u003cp\u003eRecent clinical trials report converging evidence that individuals can enhance both neural and behavioral aspects of brain health and performance, regardless of their starting point [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These studies identified significant gains in brain function through functional magnetic resonance imaging (fMRI), and converging gains in measures of cognition, well-being, and real-life responsibilities. These early yet consistent results drive the hypothesis that generally healthy individuals without identified brain disease can improve their brain health and performance across the adult lifespan, when provided tools to establish healthy brain habits. However, to definitively address this question requires (1) validated ways to measure and monitor brain health changes and (2) easy access to training protocols and refinement of tools that promote healthy brain habits, empowering individuals to maximize their executive functioning and ability to manage stress, connect with people in meaningful ways, and make healthy lifestyle choices [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe \u003cb\u003eBrainHealth Project\u003c/b\u003e aims to inform effective ways to provide a personalized, proactive approach to monitoring and enhancing brain health at any age, encouraging people to maximize their cognitive potential and thrive. Through better understanding of factors that optimize brain health across the lifespan, the potential for improved health, work, and economic-related outcomes would provide considerable value to both the individual and society at large [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe BrainHealth Project was inspired by the paradigm-shifting Framingham Heart Study, which since 1948 has transformed the world\u0026rsquo;s understanding of cardiovascular disease by identifying modifiable risk factors and providing crucial insights into the prevention, diagnosis and management of heart disease and stroke [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Its longitudinal design and comprehensive data collection have laid the foundation for decades of cardiovascular research and public health initiatives aimed at reducing the global burden of cardiovascular disease. Drawing parallels, our research endeavors to elucidate similar findings within the realm of brain health, thereby identifying actionable strategies aimed at enhancing brain vitality and mitigating and preventing age-related decline. The Framingham study shattered the myth that cardiovascular disease is an inevitable part of aging by revealing critical links between risk factors and disease development. This large-scale effort paved the way for preventive interventions, diagnostic measures, and lifelong heart health-promoting behaviors. In a similar vein, the BrainHealth Project aims to uncover factors and mechanisms that maintain brain health across the lifespan, with the goal to even enhance brain performance. We seek to build a comprehensive framework for understanding brain health maintenance and improvement across the lifespan by examining the intricate interplay between lifestyle choices, environmental influences, and biological markers.\u003c/p\u003e \u003cp\u003eAt the University of Texas at Dallas\u0026rsquo; Center for BrainHealth, led by cognitive neuroscientist Dr. Sandra Chapman, PhD (Principal Investigator), we have conducted numerous research projects examining (i) novel assessments of brain health and (ii) top-down, executive function strategies that support cognitive, emotional, functional, and neural metrics. By bringing together our core measures of complex cognition, along with both novel and established measures of well-being, social connection, lifestyle, and purpose, the BrainHealth Index allows for both independent analysis of individual measures of brain health as well as a holistic view of how they interact with and impact overall function. Our strategy-based training protocol, known as SMART (Strategic Memory Advanced Reasoning Tactics), engages an executive function, top-down framework focusing on three core cognitive processes: Strategic Attention, Integrated Reasoning, and Innovation, described below [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. SMART has shown efficacy in promoting gains in these cognitive areas and strengthening key brain networks that support planning, reasoning, decision-making, judgment, and emotional regulation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The efficacy of SMART has been evaluated in a range of healthy and clinical populations across the lifespan. These previous clinical studies of SMART demonstrated (i) cognitive improvement in aspects of executive function and memory [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], enhanced processing speed [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and academic achievement [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; (ii) improved psychological well-being including reduction of depressive, stress, and anxiety symptoms[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]; and (iii) corresponding changes between behavioral and neural network gains post-SMART, including increased brain blood flow and brain network connectivity in the Central Executive and Default Mode Networks [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and enhanced white matter integrity [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Prior studies of SMART relied on in-person engagement with trained study personnel, with assessment of changes assessed over a limited time period.\u003c/p\u003e \u003cp\u003eThis study aims to translate prior in-person brain health assessment and training protocols to an online, widely accessible format via the BrainHealth Platform. This secure portal allows scientists and participants to continuously track engagement and the impact of habits aimed at brain health strategies, coaching, and education over time.\u003c/p\u003e \u003cp\u003eTherefore, the primary objectives of the BrainHealth Project are to:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEvaluate and further inform whether the multidimensional BrainHealth Index can measure change - whether gains, losses, or maintained abilities - in healthy adults.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eExamine the impact of evidence-based cognitive strategies and lifestyle interventions on brain health using machine learning.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eElucidate the mechanisms associated with brain health gains or losses.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eBy integrating large-scale data across multiple domains and time intervals, we aim to evaluate,\u003c/p\u003e \u003cp\u003einterpret, and predict how various factors interact to contribute to brain health at both group and individual levels. We assess this through an epidemiological approach, utilizing interventions previously shown beneficial in prior randomized trials [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Due to the open-label design of the study, all participants have access to interventions found previously to promote benefit, without harm. Participants were free to choose their own level of engagement in training (e.g., engaging with the habit utilization but not the learning modules). Such utilization is tracked to evaluate the impact of engagement on measured brain change from baseline over time. The data from this large, diverse population study will provide granular insights into factors such as involvement, health, and lifestyle, enabling the development of prediction models at the individual level. We anticipate that participants who consistently engage in the micro-learning modules from the online BrainHealth Platform training over time will show improved and sustained brain health outcomes compared to those who do not.\u003c/p\u003e \u003cp\u003eA portion of the third objective will be addressed in a BrainHealth imaging sub-study protocol (currently in press). The goal of this sub-study is to assess the neural and biological mechanisms associated with, or predictive of, improved or maintained brain health through changes observed in fMRI brain scans collected at baseline, 6 months, and annually thereafter for the duration of the study. The neural data from this sub-study will be analyzed alongside the BrainHealth Index behavioral data to help develop a reliable set of biomarkers for assessing brain health longitudinally.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe BrainHealth Project is a prospective, longitudinal, interventional, open-label, single-arm clinical trial. A pilot study was conducted from March to August 2020 to assess the feasibility of the online study platform and to develop a data-driven index of brain health [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Recruitment for the longitudinal study commenced in September 2020, following the conclusion of the pilot phase. The study aims to enroll 100,000 adults over a 10-year period, with ongoing recruitment and enrollment throughout the study duration. As the study progresses, data analysis and findings will inform the addition of more targeted data collection, and both interventional and observational sub-studies are planned.\u003c/p\u003e \u003cp\u003eAll core procedures for the Project are conducted online via the BrainHealth Platform, accessible through a desktop computer or a full-function mobile app (launched in February 2024). Participants complete an initial online baseline assessment of their BrainHealth Index, followed by personalized online coaching every three months, with continuous access to online training, exercises, and educational resources aimed at optimizing brain health and overall well-being. Participants are encouraged to reassess their BrainHealth Index every six months for the duration of their involvement.\u003c/p\u003e \u003cp\u003eFor a subset of participants who choose to link data from their personal fitness devices, metrics such as physiological markers related to sleep, physical fitness, and overall health will be collected. To assess the impact of cognitive interventions and the use of digital health and educational tools, we will also analyze participant engagement with the features and content available on the BrainHealth Platform. All activities involving the BrainHealth Project and BrainHealth Platform were approved by the University of Texas at Dallas\u0026rsquo; \u003cem\u003eInstitutional Review Board\u003c/em\u003e prior to the initiation of research activities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe study targets generally healthy adults aged 18 years and older. Inclusion criteria focus on participants' ability to access and engage with the online platform and content, as determined by self-report. These criteria include: fluency in English, access to an internet connection and device, and the ability to hear and read information on the computer or device. Exclusion criteria are based on specific health conditions. Individuals are excluded if they have a diagnosed neurodegenerative disease; a history of stroke, concussion, or brain injury that currently impairs their ability to function at their reported prior level (e.g., inability to carry out daily responsibilities); or a diagnosis of autism spectrum disorder with non-independent functioning. Participants are not excluded for other diagnoses, such as learning disorders or psychiatric or medical conditions, in order to maintain the diversity of the generally brain-healthy population and to ensure the generalizability of the results. These characteristics will be captured through self-report, along with changes in demographic data collected at each assessment timepoint, to inform potential clinical subgroup analyses as appropriate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment\u003c/h2\u003e \u003cp\u003eParticipants are recruited through word of mouth, online postings, social media and advertisements, such as through the Center for BrainHealth website and e-newsletter and registries such as the Alzheimer\u0026rsquo;s Prevention Registry as well as posts on social media platforms such as Facebook, Instagram, and LinkedIn. Study flyers or recruitment information are also shared through in-person and virtual events by the Center for BrainHealth. Two healthcare system partners of the Center for BrainHealth, one in the local Dallas area and one in the eastern United States, also share the study recruitment information through flyers and social media posts. Participants do not receive any payment or reimbursement for participation in this online study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Collected and Instruments Used\u003c/h2\u003e \u003cp\u003e \u003cem\u003eBrainHealth Index (BHI)\u003c/em\u003e assessment (60\u0026ndash;90 mins. total, avg. 70 mins.). The study\u0026rsquo;s primary outcome measure is the composite BrainHealth Index (BHI) score. The BHI is scored from a multidimensional assessment of brain health and performance, comprised of an online battery of cognitive performance measures and self-report questionnaires completed by participants through the BrainHealth Platform. The BHI is unique in that it is designed to measure change over time without the presumption of decline or a specified ceiling \u0026ndash; i.e., characterizing the development and upward improvement of brain health rather than serving as a decline-oriented, adjusted normative, or diagnostic cognitive measure. Cognitive assessment includes tasks of complex thinking capacities such as reasoning, abstraction, mental flexibility, and strategy \u0026ndash; each with alternate-stimuli versions randomized across timepoints. The self-report questionnaires measure other aspects of daily life that relate to brain health, such as emotional well-being, quality of life, purpose, happiness, resilience, social support systems, and sleep \u0026ndash; utilizing tools that have been empirically validated in their respective literatures where possible. In these sections of the online assessment battery, participants self-report through rating aspects of their daily life within the prior 6 months. At each testing time point (baseline and every 6 months thereafter), participants have the opportunity to divide the assessments into shorter segments over time while saving their progress to date (up to two weeks duration) to complete the overall assessment. See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for a full list of measures.\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\u003eMeasures included in the holistic BrainHealth Index assessment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeasure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAssessment Instrument\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStrategic Attention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVisual Selective Learning Task [22]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbstraction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProverb Interpretation Task (developed at the Center for BrainHealth)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasoning\u003c/p\u003e \u003cp\u003e\u003cem\u003eSynthesis\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eInterpretation\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eMemory\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTest of Strategic Learning (TOSL) [23]\u003c/p\u003e \u003cp\u003eCondensed synopsis of complex text (~\u0026thinsp;550-word narrative)\u003c/p\u003e \u003cp\u003eFluency of take-home messages/interpretations from text\u003c/p\u003e \u003cp\u003eMemory for text details (free and cued/elaborated recall)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInnovation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFluency of high-level Interpretations from Picture Interpretation Task (developed at the Center for BrainHealth, modeled after semantic verbal fluency task, adapted from Lezak et al. [24])\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcessing Speed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoding/Digit Symbol Task (developed at the Center for BrainHealth)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePittsburgh Sleep Quality Index (PSQI) [25]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompassion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuestionnaire adapted from the Light Triad Scale [26,27]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMood\u003c/p\u003e \u003cp\u003e\u003cem\u003eDepression\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eAnxiety\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eStress\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDepression Anxiety Stress Scale (DASS-21) [28]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeaningful Activities/Purpose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEngagement in Meaningful Activities Survey (EMAS) [29]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHappiness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOxford Happiness Questionnaire (OHQ) [30]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocial Support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSocial Support Survey Index [31]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResilience\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConnor-Davidson Resilience Scale [32]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife Satisfaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuality of Life Scale [33]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocial Engagement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSocial BrainHealth Scale (developed at the Center for BrainHealth)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth Mindset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrainHealth Appraisal Questionnaire (developed at the Center for BrainHealth)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFitness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetabolic Equivalents: Cardiorespiratory Fitness (CFEQ) [34]\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\u003eThe BrainHealth Index yields four separate scores which are shared with participants through their BrainHealth Platform study dashboard, including a composite/global BHI score as well as scores for its three validated factors: (1) Clarity (readiness to reason through complex situations and create new opportunities or solutions, i.e., cognitive health), (2) Connectedness (to people and purpose, i.e., social health), and (3) Emotional Balance (steadiness in the face of difficult situations, ability to handle adversity while remaining productive and capable). These are based on a factor analysis of change scores from measures shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The University of Texas at Dallas\u0026rsquo; Center for BrainHealth investigator team designed the BHI\u0026rsquo;s composite/holistic score to capture the multiple dimensions of brain health and the interdependency amongst these dimensions, based on machine learning analytics, rather than presupposed components. For each individual, the four scores are graphed to visually track progress over time. This data visualization allows participants to realize their brain health as a whole (composite BHI score) while also reflecting the multiple paths they have to support their brain health and performance over time (factor scores). The BHI uses the individual\u0026rsquo;s own performance against which to measure growth over time rather than being compared to a group norm, allowing for a more personalized approach that is independent of starting point. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, which displays the three validated factor areas and their contributing measures.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eDemographic information\u003c/em\u003e. For each participant, at baseline we collect self-report data on age, gender identity, biological sex assigned at birth, race/ethnicity, country/U.S. zip code, household income, level of education, and occupation as well as any currently diagnosed medical or psychiatric conditions. At every subsequent online assessment timepoint (offered every 6 months), any changes in these data points are collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eTraining Materials\u003c/h2\u003e \u003cp\u003eThe online training materials included in this study protocol consist of the following:\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBrainHealth Platform Training Modules, Habits, and Resources:\u003c/h2\u003e \u003cp\u003e \u003cem\u003eTraining Modules.\u003c/em\u003e Participants access the training modules through the study\u0026rsquo;s online BrainHealth Platform which includes micro-learning videos, animations to motivate learning, activities, and learning/strategy application opportunities [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The training protocol is comprised primarily of evidence-based cognitive strategy learning, previously shown to improve aspects of neurocognitive and real-life function in clinical trials [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The strategy-based cognitive training protocol, Strategic Memory Advanced Reasoning Tactics (SMART), was developed by Center for BrainHealth neuroscientists and clinicians to promote improvement in executive functioning and self-agency. The executive function/top-down SMART protocol trains three core strategies, specifically (1) \u003cem\u003estrategic attention\u003c/em\u003e to reduce information intake, single-task to focus and make progress on daily goals, and brain down time, (2) \u003cem\u003eintegrated reasoning\u003c/em\u003e to quickly synthesize information/facts into succinct abstracted ideas and interpretations and apply to real life application, and (3) \u003cem\u003einnovation\u003c/em\u003e to flexibly generate a multitude of ways to improve tasks, communications, meetings, relationships and missteps/mistakes. The strategies can be applied in the context of everyday-life activities and responsibilities. Based on more than 25 years of intensive research, SMART has been shown to positively impact areas of cognition (e.g., improved executive function, strategic attention, integrated reasoning, innovation, decision-making, and memory), well-being (e.g., reduced symptoms of stress, depression and anxiety), and real-life function (e.g., improved quality of life, initiation and prioritization of social engagement/relationships, and complexity of life work responsibilities). Gains in these areas were found to correspond with significant neural changes, including aspects of neural connectivity, cerebral blood flow, and neural efficiency [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll BrainHealth Platform SMART sessions are designed to be self-paced, consisting of 5\u0026ndash;10-minute daily units. These sessions are reinforced with habit training and integration, encouraging participants to consistently apply tactical brain strategies to various everyday responsibilities and situations. Although training is available daily, participants can determine their own frequency of engagement. The training units combine education on brain strategies, explanations of the rationale to promote brain health literacy, and prompts for personal reflection and practical application. After completing the four SMART modules, training continues with online learning about solutions to minimize stress. These SMART strategies associated with stress management techniques are designed to build a more resilient mindset by integrating stress management techniques with healthy lifestyle choices such as physical exercise, diet, and mindful meditation\u0026mdash;practices that have been empirically shown to reduce stress [\u003cspan additionalcitationids=\"CR40 CR41 CR42\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. The sleep module provides information on not only the science of sleep and aspects such as sleep cycles, but also walks participants through sleep hygiene tips to help improve their quality and quantity of sleep. For detailed descriptions of these self-paced BrainHealth Platform training modules, see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\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\u003eDescription of self-paced online training modules\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\u003eTraining module\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo. of units/ Total time\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. SMART 01*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides strategies and interactive activities teaching how to block irrelevant information and focus on key priorities and critical information (strategic attention). \u003cem\u003eExample: Organize your day to accomplish significant tasks \u0026ndash; each day prioritize the top two tasks that require deeper-level thinking.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 units/ 55 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. SMART 02*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides strategies and interactive activities on how to abstract big-picture concepts from information to better inform understanding and real-life decisions (integrated reasoning). \u003cem\u003eExample: Extract key concepts from incoming information\u003c/em\u003e vs. \u003cem\u003etrying to process and remember everything.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 units/ 35 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. SMART 03*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides strategies and interactive activities on how to generate multiple and diverse solutions/perspectives/ questions to strengthen mental flexibility (innovation). \u003cem\u003eExample: Identify multiple alternative perspectives/ideas on discordant issues.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 units/ 35 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. SMART 04*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides real-life application scenarios where participants can practice dynamic implementation of the strategies from SMART 01\u0026ndash;03 (strategic attention, integrated reasoning, innovation) in a synergistic manner. \u003cem\u003eExample: Think about and prepare to ask your boss for a raise\u003c/em\u003e (\u003cem\u003econsidering your accomplishments, impact those accomplishments have had or could have on the organization\u003c/em\u003e, etc.).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 units/ 45 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Stress solutions 01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresents information about physiological and neurological response to stress, as well as cognitive strategies linked with SMART to manage and reframe stressors. \u003cem\u003eExample: Reframe your perception of your response to a difficult situation from anxiety to excitement.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 units/ 40 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6. Stress solutions 02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides accessible techniques to help \u0026ldquo;recharge your mental battery\u0026rdquo; in terms of stress or fatigue, as well as education on lifestyle factors that can positively impact overall health. \u003cem\u003eExample: Take several short breaks throughout your day.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 units/ 30 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7. Stress solutions 03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProvides research on the benefits of mindfulness, meditation, and healthy sleep habits, as well as practical tips on how to practice each one (linking with SMART strategies). \u003cem\u003eExample: Participate in a mindfulness exercise.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 units/ 45 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8. Sleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresents research on the science behind sleep over the lifespan, the brain impacts of poor sleep, and practical tips for improving one\u0026rsquo;s sleep habits.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 units/ 75 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTotal time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350 min\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 \u003cem\u003e*Modules 1\u0026ndash;4 provide the foundational cognitive strategies (SMART).\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eHabits\u003c/em\u003e. Each training module is paired with a set of brain-healthy \"Habits\" that participants can access once they complete the module. These habits allow participants to integrate specific training concepts or strategies into their daily routines. Participants can choose a habit, opt to receive daily reminders, and track their progress over time, earning levels and digital \"badges\" on the BrainHealth Platform. Examples of habits include minimizing distractions, taking regular breaks, completing two important big tasks each day, maintaining a consistent and healthy sleep routine, and exploring multiple possibilities to reapproach a challenge, perceived failure, dilemma or mistake. Additionally, habits can be focused on lifestyle improvements such as exercise, nutrition, and mindfulness.\u003c/p\u003e \u003cp\u003e \u003cem\u003eChallenges\u003c/em\u003e. After completing the primary training modules, participants advance to a continuing series of \"Challenge\" units designed for reinforcement and extended application of the strategies and practices. These challenges are also delivered in 5-10-minute increments and feature diverse content, such as article readings and educational video clips. Each provides insights into the relevant brain science and includes reflection questions or practical application opportunities. Monthly challenge topics are organized into four weekly segments centered around a shared theme. Examples of these themes include memory habits, managing news consumption, navigating tough conversations, the science of confidence, breathing techniques, gratitude practices, etc.\u003c/p\u003e \u003cp\u003e \u003cem\u003eResources\u003c/em\u003e. Participants have access to a continually curated collection of educational resources on the broad topic of brain health, including media articles, published research studies, online lectures, etc. Additional training and resource content will be added throughout the study to offer ongoing learning opportunities and maintain participant engagement.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOnline coaching:\u003c/h2\u003e \u003cp\u003eParticipants can engage in individual 20-minute videoconference coaching sessions every 3 months, conducted within the study platform. These sessions are led by a study brain health coach and can be self-scheduled by participants. Coaches are assigned based on availability and consist of study personnel with degrees spanning fields such as speech-language pathology, psychology, occupational therapy, education, or other areas of human performance. All coaches have experience administering and interpreting cognitive and human performance assessments, with a minimum of 2 years of post-graduate work experience in their respective field of practice.\u003c/p\u003e \u003cp\u003eDuring these sessions, brain health coaches offer individualized feedback on participants' BrainHealth Index results, guide them on engaging with the online training content, assist in setting personal brain health goals, and discuss how to apply the training strategies and practices to their specific goals or context. Following the session, coaches provide summary notes on the participant's BrainHealth Platform profile, articulating the key points discussed for easy access at any time. Participants can choose to utilize this quarterly personalized coaching as much or as little as they prefer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBrainHQ training\u003c/span\u003e:\u003c/h2\u003e \u003cp\u003eAfter completing their third BrainHealth Index assessment (typically one year post-baseline), participants have the opportunity to access BrainHQ [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] training for a limited time. Through the BrainHealth Platform, participants can engage in 14 BrainHQ training exercises over a period of up to 16 weeks. In contrast to SMART, which is strategy-based, BrainHQ is a computer exercise-based approach to cognitive training, with multiple studies supporting its effectiveness in enhancing cognitive performance [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Each exercise adapts in difficulty according to the participant's performance, using a specialized algorithm. The exercises made available to participants in the BrainHealth Project include those addressing attention, processing speed, memory, and decision-making. During the 16 weeks of BrainHQ access, participants are encouraged to engage with BrainHQ exercises four times a week for 30 minutes each session.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRetention of participants\u003c/h2\u003e \u003cp\u003eRecognizing the importance of engagement and retention in a longitudinal study, we have developed and implemented solutions to address participant engagement and retention through three avenues: (1) technology platform enhancements, (2) improved communications, and (3) opportunities for community building among participants.\u003c/p\u003e \u003cp\u003eInitially, the BrainHealth Platform was accessible only via a web browser-based interface. However, to enhance accessibility and user experience, it has evolved to include a dedicated mobile application, launched in February 2024. This mobile app introduces advanced notification capabilities such as push notifications, sounds, and banners, which not only prompt participants to re-engage after periods of disengagement, but also remind them to complete essential study tasks, like the BrainHealth Index assessments. Furthermore, we have introduced gamification elements, such as earning \u0026ldquo;coins\u0026rdquo; for task completion and achieving higher ranks with each BrainHealth Index completed, to increase participant utilization and motivation.\u003c/p\u003e \u003cp\u003e We have continuously improved our study communications by making messaging clearer and more concise, ensuring participants are well-informed about their progress throughout the study procedures. The improved BrainHealth Platform now includes an onboarding navigation process that clearly outlines each study step, accompanied by visual tutorial elements. These tutorials help orient participants to their online study dashboard and explain or highlight key features to enhance ease of use. For a visual representation of the study participation elements, see Fig.\u0026nbsp;2. Additionally, we have expanded communication methods beyond email, incorporating the use of text messaging for participants who opt-in. This allows for more regular and continuing study engagement, such as facilitating daily habit completion and other study interactions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe BrainHealth Project team also works to enhance participant engagement by offering monthly virtual group coaching sessions via Zoom. These 45-minute sessions are conducted live (not recorded) and are open to all study participants, providing social motivation and community-building opportunities. Additionally, in response to early participant requests for more information on the brain science behind the study, we host periodic virtual town hall webinars. These webinars, generally held annually or semi-annually, allow participants to deepen their understanding of the research they contribute to and foster a sense of involvement in a greater mission as citizen scientists. The town hall webinars are lecture-style, recorded, and subsequently made available in the BrainHealth Platform Resources section for all participants to access. In evaluating the impact of these offerings, we will assess whether these additional resources contribute to increased training utilization and improved study retention over time.\u003c/p\u003e \u003cp\u003e \u003cb\u003eData Management and Security within the BrainHealth Platform.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe online BrainHealth Platform, which hosts assessments and training tools, automatically uploads data to a secure cloud-based data management system. This system uses a relational database architecture, adheres to de-identification best practices, and implements stringent security protocols. Day-to-day study administration occurs via the platform\u0026rsquo;s secure administrative dashboard. For research analysis, additional data levels can be queried and integrated from various datasets stored in a cloud-based data lake. Access to data is strictly controlled, available only to authorized study personnel through secure access points, reinforced by strong password policies and multi-factor authentication.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAssessment Scoring and Quality Control.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe majority of the assessments included in the online BHI are automatically scored, except for three language-based cognitive performance measures (Abstraction, Reasoning, Innovation), which are manually scored by trained study personnel. To ensure data integrity and inter-rater reliability, quality control practices are in place. These include procedures for scoring review and consensus-building, as well as procedures for identifying and filtering invalid responses. This might involve noting any difficulties or interruptions that participants report encountering during the tasks or detecting the use of external aids.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Considerations\u003c/h2\u003e \u003cp\u003eA key objective of the BrainHealth Project is to achieve precision brain health, recognizing that lifestyle interventions, cognitive training, exercise, and sleep impact individuals differently. The ultimate goal is to improve brain health for all participants, yet this improvement requires a tailored approach to meet each individual's specific needs. Consequently, the statistical approaches employed in this study prioritize individual prediction over population-wide inference. As such, formal power analyses are not relevant to sample size determination; however, see below for some population-based sub-studies that do require power justification.\u003c/p\u003e \u003cp\u003eIn the machine learning literature, it is necessary to utilize tens of thousands of samples to train, validate and test complex, nonlinear prediction models such as neural networks (including deep learning networks), support vector machines and unsupervised tree or clustering methods. To determine the factors that influence and improve brain health in individual participants, we will utilize these nonlinear models and train them using large samples. Large samples will accommodate not only the training of the models, but also the validation and testing of them on independent samples such that estimates of generalization error can be obtained with low variance. For these purposes, we plan to recruit a baseline sample that will eventually yield an expected 15,000\u0026ndash;20,000 individuals at the end of 10 years. These sample sizes are also comparable to those in the well-publicized Framingham Heart Study, which continues to determine factors related to heart health [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIncreased attrition and lack of adherence have been longstanding barriers to successful health-behavior interventions [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Given the online nature of the study and precedent from previous longitudinal, population-based studies involving internet-based/eHealth platforms [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], we similarly anticipate as much as 80%-85% attrition over the full 10-year study period. Therefore, to reach our goal we plan to recruit a baseline sample of 100,000 participants.\u003c/p\u003e \u003cp\u003eIn addition to the sample requirements of neural network prediction models, a sample of 15,000\u0026ndash;20,000 will allow population-based sub-studies as secondary aims in the BrainHealth Project. For example, within our workplace, mental illness, and caregiver sub-studies, we focus on analyzing the mean longitudinal changes in brain health. Additionally, we aim to document potential declines in brain health that may occur due to unexpected health events as reported by participants, such as undergoing chemotherapy, experiencing a concussion, contracting COVID-19, encountering significant grief, and other impactful life events. Importantly, we also examine participants' capacity to recover, facilitated by access to brain health training supports, as they continue their participation in the longitudinal study.\u003c/p\u003e \u003cp\u003eAs the specificity of particular cohorts increases (e.g., males between 20\u0026ndash;30 with less than a bachelor\u0026rsquo;s degree and a self-reported mental illness), the samples decrease markedly. However, having a total sample between 15,000 and 20,000 will allow rare cohorts to maintain at least samples of 100, which is required to detect effect sizes of at least 0.5 with 80% statistical power, adjusted for false positive control due to multiple testing.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis manuscript details the study protocol, background, and significance of the BrainHealth Project, a prospective, single-arm, open-label, longitudinal interventional clinical trial. While significant research has historically been focused on improving cardiovascular health\u0026mdash;thereby greatly enhancing life expectancy and quality\u0026mdash;to date, comparatively limited efforts have been made to comprehensively assess and strengthen brain health in healthy individuals across all ages and life stages. The BrainHealth Project aims to address this critical gap by focusing on measuring, monitoring, and enhancing brain health in healthy adults, from late teens through late life. The study utilizes an online portal accessible via computers or mobile devices, to allow wide accessibility and to ensure scalability.\u003c/p\u003e \u003cp\u003eThis effort builds on prior shorter-term, randomized control trials that demonstrated significant benefits from an in-person brain health intervention, known as Strategic Memory Advanced Reasoning Tactics (SMART). SMART, a manualized protocol focusing on executive functions and top-down strategies, showed gains from pre-to post-training across neural, cognitive, emotional, and social health domains, with improvements persisting at least three months post-training [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The current ongoing trial integrates SMART with technology and coach-facilitated lifestyle changes\u0026mdash;including sleep, stress management, social connections, and physical exercise\u0026mdash;to create a comprehensive and scalable extension of the previously evaluated program. This trial aims to explore the long-term impacts of these brain health interventions. A central aspect of this approach is the regular measurement of wide-spectrum brain health using regular BrainHealth Index assessments, validated in a subset of participants against comprehensive brain imaging measures over time.\u003c/p\u003e \u003cp\u003eMajor strengths of the BrainHealth Project include a focus on the following seven issues that will inform ways to motivate behavioral change to improve brain health on a population-wide basis:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eUtility of the BrainHealth Index\u003c/b\u003e: Evaluating the BrainHealth Index's ability to measure changes in \u003cem\u003eholistic brain performance\u003c/em\u003e, where each participant serves as their own control. This approach charts individual changes over years, regardless of their starting level, independent of education, economic status, cultural background, or gender, contrasting with conventional siloed approach using normed assessments that focus on domains developed to detect decline and deliver diagnosis, and are adjusted for expected losses with age.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e(2) \u003cb\u003ePotential gains across all ages\u003c/b\u003e: Assessing the potential for adults of all ages, not just older adults, to make gains when provided simple top-down cognitive strategies of executive function. This helps maintain a sense of self-agency across other health habits and other aspects of life.\u003c/p\u003e \u003cp\u003e(3) \u003cb\u003eLong-term impact\u003c/b\u003e: Characterizing the long-term effects of brain health strategy and lifestyle interventions over years through a longitudinal, epidemiologic-type approach.\u003c/p\u003e \u003cp\u003e(4) \u003cb\u003eDigital health accessibility\u003c/b\u003e: Measuring the utility of leveraging digital health technology to enhance accessibility, reaching from urban to rural areas and extending far beyond major research centers or clinical specialists and providers.\u003c/p\u003e \u003cp\u003e(5) \u003cb\u003ePrecision with machine learning\u003c/b\u003e: Utilizing machine learning tools to rapidly develop precision brain health at an individual analysis level.\u003c/p\u003e \u003cp\u003e(6) \u003cb\u003eMechanisms of brain health changes\u003c/b\u003e: Elucidating significant mechanisms underlying changes in brain health, including gains or losses, by enrolling large-sample, diverse cohorts.\u003c/p\u003e \u003cp\u003e(7) \u003cb\u003eNeural changes and neurobiological markers\u003c/b\u003e: Setting the stage for identifying neural changes through the BrainHealth Project\u0026rsquo;s subset imaging protocol (detailed in a separate manuscript) that correspond to gains and also future potential losses, serving to provide neurobiological markers of brain health changes and to validate the behavioral Index\u0026rsquo;s efficacy. While MRI scans are unlikely to become the standard of care for brain health monitoring on a population-level basis worldwide due to cost and accessibility, this study aims to provide validated proxy measures derived from the BrainHealth Index to accurately, reliably, and reproducibly reflect changes in individual brain health across the lifespan.\u003c/p\u003e \u003cp\u003eIn summary, the BrainHealth Project represents a concerted single-arm research study designed to test the feasibility and effectiveness of measuring and enhancing brain health using a previously validated assessment tool and interventions in an augmented and scalable manner. Brain health encompasses the optimization of neural health, cognition, connectedness to people and purpose, and emotional well-being across the lifespan\u0026mdash;aligning with the World Health Organization\u0026rsquo;s definition of brain health [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. All of these domains are measured repeatedly using an appropriately holistic measure - the BrainHealth Index.\u003c/p\u003e \u003cp\u003eThe study also aims to elucidate the potential neural and other physiological mechanisms that contribute to changes in brain health. By analyzing brain and physiological data, the research will inform how various aspects of brain function\u0026mdash;such as neuronal activity, blood supply, and metabolism\u0026mdash;are influenced by interventions and captured by changes in the BrainHealth Index over time, presumably reflecting improved brain health. The ultimate goal of this project is to provide a validated, clinically meaningful, widely accepted, generalizable measure of the brain that supports the development and testing of precision, preventive, and personalized brain health interventions, making them widely available globally.\u003c/p\u003e \u003cp\u003eThe centrality of brain health to overall health underscores the potential of scalable interventions like the one described in this project to broadly impact public health more generally. Given that some brain health aspects of neural health and cognitive performance, such as global cerebral blood flow [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] and processing speed [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], often begin to decline in early adulthood, this current project is relevant across the entire adult lifespan. It is applicable even in the absence of disease or injury and should be employed starting in early adulthood to foster and reinforce healthier brain habits across whole populations.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eAs with any longitudinal study, particularly one conducted entirely online, participant dropout is inevitable. Another limitation is the potential for selective attrition, in that those who continue to participate beyond the baseline assessment to complete later assessment timepoints may also likely be those most highly motivated to succeed, particularly given possible gains after the initial training instruction period. Efforts will be made to recruit and retain more diverse populations (racial, level of education, socioeconomic status and others) over the course of the study to enhance study sample representativeness and support the generalizability of study findings.\u003c/p\u003e \u003cp\u003eThis study lacks a randomized control group; however, the large sample size and extended duration allow for the use of quasi-experimental designs and machine learning methods to monitor changes in brain health based on the extent of usage of the brain health interventions offered. The decision to adopt a single-arm study design was also informed by findings from our prior pilot trials demonstrating benefit of SMART in those participants. Given the significant time commitment required from participants, it was deemed more ethically appropriate to use a scientifically valid design where each participant serves as their own control and stands to benefit from engagement in the study. This approach not only aligns with the goal of precision brain health but also allows for the consideration of individual differences such as genetics and lifestyle habits. These personal factors are systematically analyzed using machine learning models, which further enhance the ability to tailor interventions based on unique participant profiles and to more accurately predict outcomes based on diverse personal data inputs. We are also testing the feasibility of integrating machine learning and artificial intelligence tools to support manual scoring components and live, virtual coaching.\u003c/p\u003e \u003cp\u003eFinally, web-measured changes in brain health will be correlated with and validated against brain imaging-derived neural measures in a subset of participants. This correlation aims to strengthen the hypothesis that adopting healthy brain habits can yield long-term benefits to brain health, as behavioral changes over extended time periods that align with desirable neural changes are observed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eFuture Directions\u003c/h2\u003e \u003cp\u003eThe BrainHealth Project aims to address critical clinical questions surrounding brain wellness and the potential for cognitive gains across the lifespan. As other online brain health interventions are validated through clinical trials, the BrainHealth Platform and the BrainHealth Index present opportunities for collaboration with researchers and medical experts who have evidence-based brain health protocols suitable for online implementation. By incorporating and testing these additional protocols, whether nonpharmacological or pharmacological, we can further evaluate the efficacy of the BrainHealth Index in measuring the benefits of various interventions over time.\u003c/p\u003e \u003cp\u003eCurrently, there is no widely accepted \"gold standard\" for a holistic measure of normal brain health. The BrainHealth Index serves to fill this void by offering an urgently needed standard that is sensitive to both meaningful positive and negative changes across key dimensions of brain health, including neural function, clarity of cognition, emotional well-being, and connectedness to people and purpose. By enhancing our understanding of the factors that optimize brain health throughout the lifespan, the BrainHealth Index has the potential to significantly impact health, work, and economic outcomes, benefiting individuals and society as a whole.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this groundbreaking study aims to decode the determinants of brain wellness and cognitive resilience throughout the lifespan. By leveraging the insights gleaned from the paradigm-shifting Framingham study and adopting a similar initial primarily observational approach, we aim to build a comprehensive repository expected to gain a novel and improved understanding of brain health maintenance and improvement that transcends traditional boundaries of the aging brain. By conducting rigorous observational analyses and integrating diverse datasets, we seek to uncover actionable strategies that promote brain wellness and cognitive enhancements across diverse populations. Ultimately, this effort is poised to reshape the landscape of brain health research and clinical practice, paving the way for future innovations and interventions.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eTrial Status\u003c/h2\u003e \u003cp\u003eAt the time of the submission of this manuscript, enrollment was ongoing.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBHI: BrainHealth Index; CFEQ: Metabolic Equivalents: Cardiorespiratory Fitness; COVID-19: Coronavirus Disease 2019; DASS-21: Depression Anxiety Stress Scale-21; EMAS: Engagement in Meaningful Activities Survey; fMRI: functional magnetic resonance imaging; MRI: magnetic resonance imaging; OHQ: Oxford Happiness Questionnaire; PSQI: Pittsburgh Sleep Quality Index; RCT: randomized controlled trial; SMART: Strategic Memory Advanced Reasoning Tactics; TOSL: Test of Strategic Learning; WHO: World Health Organization\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved for research with human subjects by the Institutional Review Board of the University of Texas at Dallas (IRB# 23-745) and is being conducted in accordance with the Declaration of Helsinki. All participants complete the study informed consent online through the BrainHealth Platform.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript for publication. This manuscript does not contain any individual person\u0026rsquo;s data or image. All figures are original graphics.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and materials\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the authors on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eDue to prior evidence of the efficacy of the SMART program, The University of Texas at Dallas Center for BrainHealth is actively engaged in providing SMART to a variety of groups, including in the enterprise. The Center has also applied for a process patent for SMART. In addition, the system and method for precision brain health assessment is patent pending.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe BrainHealth Project is currently funded by private philanthropy: Jean Ann Brock, Teresa and David Disiere, Marlane Miller, Jennifer and Peter Roberts, Sammons Enterprises, Inc., as well as several anonymous donors.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors\u0026rsquo; contributions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll authors listed have made a substantial, direct, and intellectual contribution to the work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe express sincere gratitude to the coaches of the BrainHealth Project for guiding and encouraging participants with exceptional care and skill: Tandra Allen, Katie Hinds, Janet Koslovsky, Sarah Laane, Marco Lopez, Kalyn Potter, Audette Rackley, Colleen Ryan, Stacy Vernon, Jennifer Zientz. Additionally, we must thank our skilled technology, data management, and support team, including Zhengsi Chang, Margaret Chaplin, Sonal Jain, Samuel Ballard, Kamin Bouguyon, Bryan Vosburg, Haider Naeem, Sameena Shaik, Dinesh Sharma, Mahanaz Attila, Radi Tawfiq, Choe Chu, and the team at Dialexa for their tremendous work on the online platform. Finally, we are extremely grateful for the participants who choose to be pioneers in brain health and invest their time in this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMerzenich MM, De Charms CR. Neural representations, experience and change. In: Llinas R, Churchland P, editors. The mind-brain continuum: sensory processes. Cambridge (MA): MIT Press; 1996. p. 61\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003eMerzenich MM, Van Vleet TM, Nahum M. Brain plasticity-based therapeutics. Front Hum Neurosci. 2014;(8):385. \u003c/li\u003e\n\u003cli\u003eOptimizing brain health across the life course: WHO position paper. Geneva: World Health Organization; 2022. License: CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo/.\u003c/li\u003e\n\u003cli\u003eGreene M. Boosting brain health is key to a thriving economy. Financial Times [Internet]. 2021 Aug 12 [cited 2023 Oct 26]. Available from https://www.ft.com/content/d202b1f3-0a69-4acd-bb1b-e2fa06b21df3.\u003c/li\u003e\n\u003cli\u003eChapman SB. Make your brain smarter: increase your brain\u0026rsquo;s creativity, energy, and focus. New York: Simon and Shuster; 2014.\u003c/li\u003e\n\u003cli\u003eChapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, et al. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015;25:396-405. doi:10.1093/cercor/bht234.\u003c/li\u003e\n\u003cli\u003eChapman SB, Aslan S, Spence JS, Keebler MW, DeFina LF, Didehbani N, et al. Distinct brain and behavioral benefits from cognitive vs. physical training: a randomized trial in aging adults. Front Hum Neurosci. 2016;10:338. doi:10.3389/fnhum.2016.00338.\u003c/li\u003e\n\u003cli\u003eChapman SB, Spence JS, Aslan S, Keebler MW. Enhancing innovation and underlying neural mechanisms via cognitive training in healthy older adults. Front Aging Neurosci. 2017;9:314. doi:10.3389/fnagi.2017.00314.\u003c/li\u003e\n\u003cli\u003eVas A, Chapman S, Aslan S, Spence J, Keebler M, Rodriguez-Larrain G, et al. Reasoning training in veteran and civilian traumatic brain injury with persistent mild impairment. Neuropsychol Rehabil. 2016;26:502\u0026ndash;31. doi:10.1080/09602011.2015.1044013.\u003c/li\u003e\n\u003cli\u003eChapman SB, Cook LG, Vas AK, Robertson IH. Enhancing human cognitive capital by harnessing the brain\u0026rsquo;s inherent neuroplasticity. In: Matthews MD, Schnyer DM, editors. Human performance optimization. New York: Oxford University Press; 2019. p. 260-86.\u003c/li\u003e\n\u003cli\u003eAndersson C, Johnson AD, Benjamin EJ, Levy D, Vasan RS. 70-year legacy of the Framingham heart study. Nat Rev Cardiol. 2019;16:687-98. doi:10.1038/s41569-019-0202-5. \u003c/li\u003e\n\u003cli\u003eBitton A, Gaziano TA. The Framingham heart study\u0026apos;s impact on global risk assessment. Prog Cardiovasc Dis. 2010;53:68-78. doi:10.1016/j.pcad.2010.04.001.\u003c/li\u003e\n\u003cli\u003eChapman SB, Mudar RA. Enhancement of cognitive and neural functions through complex reasoning training: evidence from normal and clinical populations. Front Syst Neurosci. 2014;8:69. doi:10.3389/fnsys.2014.00069.\u003c/li\u003e\n\u003cli\u003eCook LG, Chapman SB, Elliott AC, Evenson NN, Vinton K. Cognitive gains from gist reasoning training in adolescents with chronic-stage traumatic brain injury. Front Neurol. 2014;5. doi:10.3389/fneur.2014.00087.\u003c/li\u003e\n\u003cli\u003eMudar RA, Chapman SB, Rackley A, Eroh J, Chiang H-S, Perez A, et al. Enhancing latent cognitive capacity in mild cognitive impairment with gist reasoning training: a pilot study. Int J Geriatr Psychiatry. 2017;32(5):548-555. doi:10.1002/gps.4492.\u003c/li\u003e\n\u003cli\u003eVas AK, Chapman SB, Cook LG, Elliott AC, Keebler M. Higher-order reasoning training years after traumatic brain injury in adults. J Head Trauma Rehabil. 2011;26(3):224-39. doi:10.1097/HTR.0b013e318218dd3d.\u003c/li\u003e\n\u003cli\u003eVenza EE, Chapman SB, Aslan S, Zientz JE, Tyler DC, Spence JS. Enhancing executive function and neural health in bipolar disorder through reasoning training. Front Psychol. 2016;7:1676. doi:10.3389/fpsyg.2016.01676.\u003c/li\u003e\n\u003cli\u003eMotes MA, Yezhuvath US, Aslan S, Spence JS, Rypma B, Chapman SB. Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial. Neurobiol Aging. 2018;62:72-81. doi:10.1016/j.neurobiolaging.2017.10.003.\u003c/li\u003e\n\u003cli\u003eGamino JF, Motes MM, Riddle R, Lyon GR, Spence JS, Chapman SB. Enhancing inferential abilities in adolescence: new hope for students in poverty. Front Hum Neurosci. 2014;8:924. doi:10.3389/fnhum.2014.00924.\u003c/li\u003e\n\u003cli\u003eGamino JF, Frost C, Riddle R, Koslovsky J, Chapman SB. Higher-order executive function in middle school: training teachers to enhance cognition in young adolescents. Front Psychol. 2022;13:867264. doi:10.3389/fpsyg.2022.867264.\u003c/li\u003e\n\u003cli\u003eChapman SB, Fratantoni JM, Robertson IH, D\u0026apos;Esposito M, Ling GSF, Zientz J, et al. A novel brain health index prototype improved by telehealth-delivered training during COVID-19. Front Public Health. 2021;9:641754. doi:10.3389/fpubh.2021.641754. \u003c/li\u003e\n\u003cli\u003eHanten G, Li X, Chapman SB, Swank P, Gamino J, Roberson G, et al. Development of verbal selective learning. Dev Neuropsychol. 2007;32:585-96. doi: 10.1080/87565640701361112.\u003c/li\u003e\n\u003cli\u003eVas AK, Chapman SB, Cook LG. Language impairments in traumatic brain injury: a window into complex cognitive performance. In: Salazar A, Grafman J, editors. Handbook of clinical neurology: Traumatic Brain Injury Part II. Amsterdam: Elsevier; 2015. p. 497-510.\u003c/li\u003e\n\u003cli\u003eLezak MD, Howieson DB, Loring DW, Fischer JS. Neuropsychological assessment. New York: Oxford University Press; 2004.\u003c/li\u003e\n\u003cli\u003eBuysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index (PSQI): a new instrument for psychiatric research and practice. Psychiatr Res. 1989; 28:193-213. doi:10.1016/0165-1781(89)90047-4.\u003c/li\u003e\n\u003cli\u003eJohnson LKD. The Light Triad Scale: developing and validating a preliminary measure of prosocial orientation, Master\u0026rsquo;s [thesis]. London, ON, Canada: The University of Western Ontario; 2018. Available from: https://ir.lib.uwo.ca/etd/5515.\u003c/li\u003e\n\u003cli\u003eStrauss C, Lever Taylor B, Gu J, Kuyken W, Baer R, Jones F, et al. What is compassion and how can we measure it? A review of definitions and measures. Clin Psychol Rev. 2016;47:15-27. doi:10.1016/j.cpr.2016.05.004.\u003c/li\u003e\n\u003cli\u003eLovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck depression and anxiety inventories. Behav Res Ther. 1995;33:335-43. doi:10.1016/0005-7967(94)00075-u.\u003c/li\u003e\n\u003cli\u003eEakman AM. Convergent validity of the engagement in meaningful activities survey in a college sample. OTJR. 2011;30:23-32. doi:10.3928/15394492-20100122-02.\u003c/li\u003e\n\u003cli\u003eHills P, Argyle M. The Oxford Happiness Questionnaire: a compact scale for the measurement of psychological well-being. Pers Indiv Differ. 2002;33:1073-82. doi:10.1016/S0191-8869(01)00213-6.\u003c/li\u003e\n\u003cli\u003eSherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32:705-14. doi:10.1016/0277-9536(91)90150-b.\u003c/li\u003e\n\u003cli\u003eConnor KM, Davidson JRT. Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety. 2003;18:76-82. doi:10.1002/da.10113.\u003c/li\u003e\n\u003cli\u003eBurckhardt CS, Anderson KL. The quality of life scale (QOLS): reliability, validity, and utilization. Health Qual Life Outcomes. 2003;1:60. doi:10.1186/1477-7525-1-60.\u003c/li\u003e\n\u003cli\u003eJurca R, Jackson AS, LaMonte MJ, Morrow JR, Blair SN, Wareham NJ, et al. Assessing cardiorespiratory fitness without performing exercise testing. Am J Prev Med. 2005; 29:185\u0026ndash;93. doi:10.1016/j.amepre.2005.06.004.\u003c/li\u003e\n\u003cli\u003eGallen CL, Baniqued PL, Chapman SB, Aslan S, Keebler M, Didehbani N, et al. Modular brain network organization predicts response to cognitive training in older adults. PLoS One. 2016;11(12):e0169015. doi:10.1371/journal.pone.0169015.\u003c/li\u003e\n\u003cli\u003eHan K, Davis RA, Chapman SB, Krawczyk DC. Strategy-based reasoning training modulates cortical thickness and resting-state functional connectivity in adults with chronic traumatic brain injury. Brain Behav. 2017;7:e00687. doi:10.1002/brb3.687/full.\u003c/li\u003e\n\u003cli\u003eHan K, Martinez D, Chapman SB, Krawczyk DC. Neural correlates of reduced depressive symptoms following cognitive training for chronic traumatic brain injury. Hum Brain Mapp. 2018;00:1-17. doi: 10.1002/hbm.24052.\u003c/li\u003e\n\u003cli\u003eYang YJD, Allen T, Abdullahi SM, Pelphrey KA, Volkmar FR, Chapman SB. Neural mechanisms of behavioral change in young adults with high-functioning autism receiving virtual reality social cognition training: a pilot study. Autism Res. 2018;11(5):713-25. doi:10.1002/aur.1941.\u003c/li\u003e\n\u003cli\u003eChow CM. Sleep and wellbeing, now and in the future. Int J Environ Res Public Health. 2020;17(8):2883.\u003c/li\u003e\n\u003cli\u003eOwen L, Corfe B. The role of diet and nutrition on mental health and wellbeing. Proc Nutr Soc. 2017;76(4):425-426.\u003c/li\u003e\n\u003cli\u003eEsgunoglu L, Jennings A, Connole ES, Murphy KJ, Minihane AM. Short-term effects of a Mediterranean-style dietary pattern on cognition and mental wellbeing: a systematic review of clinical trials. Pro Nutr Soc. 2021;8:1-10.\u003c/li\u003e\n\u003cli\u003ePenedo FJ, Dahn JR. Exercise and well-being: a review of mental and physical health benefits associated with physical activity. Curr Opin Psychiatry. 2005;18(2):189-193.\u003c/li\u003e\n\u003cli\u003eKhoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, et al. Mindfulness-based therapy: a comprehensive meta-analysis. Clin Psychol Rev. 2013;33:763-71. \u003c/li\u003e\n\u003cli\u003eBrainHQ: Official Site. https://www.brainhq.com. Accessed 28 June 2024.\u003c/li\u003e\n\u003cli\u003eSmith GE, Housen P, Yaffe K, Ruff R, Kennison RF, Mahncke HW, et al. A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study. J Am Geriatr Soc. 2009;57(4):594-603. doi: 10.1111/j.1532-5415.2008.02167.x.\u003c/li\u003e\n\u003cli\u003eMiddleton KR, Anton SD, Perri MG. Long-term adherence to health behavior change. Am J Lifestyle Med. 2013;7(6):395-404.\u003c/li\u003e\n\u003cli\u003eEysenbach G. The law of attrition. J Med Internet Res. 2005;7(1):e11. doi:10.2196/jmir.7.1.e11\u003c/li\u003e\n\u003cli\u003eLu H, Xu F, Rodrigue KM, Kennedy KM, Cheng Y, Flicker B, et al. Alterations in cerebral metabolic rate and blood supply across the adult lifespan. Cereb Cortex. 2011;21:1426-34.\u003c/li\u003e\n\u003cli\u003eHartshorne JK, Germine LT. When does cognitive functioning peak? The asynchronous rise and fall of different cognitive abilities across the life span. Psychol Sci. 2015;26(4):433-43.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"brain health, cognitive training, executive function, digital health, healthy aging, lifespan, lifestyle, neuroplasticity, prevention, precision health","lastPublishedDoi":"10.21203/rs.3.rs-4855477/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4855477/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e: \u003c/strong\u003eOptimization of brain health is a focal point in medical science, yet data regarding measuring, preserving, and improving lifelong brain health are lacking. This void demands an objective, change-sensitive measure of brain health and proven strategies to strengthen brain performance. The BrainHealth Project addresses these key issues, drawing upon neuroplasticity evidence of persistent modifiability of brain function across the lifespan. This landmark study aims to definitively (i) evaluate and refine holistic change indices of brain health, (ii) evaluate the impact of evidenced-based cognitive strategies and lifestyle interventions on improving/maintaining brain health, and (iii) elucidate the mechanisms associated with brain health gains/losses.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e: This prospective, longitudinal, interventional, open-label, single-arm clinical trial aims to recruit 100,000 generally healthy adults over 10 years. Assessments, coaching, and training are conducted online through the secure BrainHealth Platform, allowing utilization tracking. The BrainHealth Index (BHI)—a multidimensional assessment—is offered at baseline and every six months. Participants have access to coaching every three months and continual access to self-paced trainings and resources.\u003c/p\u003e\n\u003cp\u003eThe primary outcome is the further validation of a novel composite BHI score and its sub-scores: Clarity (cognitive health), Connectedness (social health), and Emotional Balance (well-being). The BHI includes measures sensitive to change, including gains from behavior change and integration of cognitive strategies into daily life. These contrast with traditional assessments focused on detecting cognitive decline or diagnosing pathological conditions.\u003c/p\u003e\n\u003cp\u003eThe primary online training, SMART (Strategic Memory Advanced Reasoning Tactics), is a strategy-based program validated with 25+ years of research. SMART promotes improvements in neural health, cognition, well-being, connectedness, and real-life function, previously reported in randomized controlled trials (RCTs). Statistical approaches focus on individual prediction using nonlinear models trained with large samples and on assessing mechanisms influencing gains or losses on brain health metrics.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003e\u003c/em\u003eThis research extends RCT evidence to a longitudinal, epidemiologic approach, leveraging digital health and machine learning tools to deliver a generalizable measure of longitudinal brain health and to achieve precision brain health. By integrating advanced statistical methods and large-scale data, the BrainHealth Project should provide medicine and society with accurate and actionable ways to optimize brain health practices across the lifespan.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eClinicalTrials.gov Identifier\u003c/strong\u003e\u003c/em\u003e: NCT04869111 (registered April 27, 2021)\u003c/p\u003e","manuscriptTitle":"The BrainHealth Project Study Protocol: A Longitudinal Study in Generally Healthy Adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-10 13:10:57","doi":"10.21203/rs.3.rs-4855477/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e45c84a6-2a06-4ac5-888a-4b93b25d58c1","owner":[],"postedDate":"October 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-11T04:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-10 13:10:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4855477","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4855477","identity":"rs-4855477","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}