Cardiac electrophysiology research increasingly relies on computational methods to connect experimental and clinical observations to understand underlying mechanisms. These methods process experimental data, such as optical mapping and body-surface potential mapping, and model biophysical processes, such as the behavior of electrical sources within the heart and the electrical potential fields linked to these. Signal processing from experiments and clinical recordings helps elucidate electrophysiological properties across various domains, while computational modeling offers a theoretical understanding. Patient-specific models increasingly help interpret observations and improve individual cardiac electrical behavior approximations. Consequently, advancements in computational methodologies are vital for gaining new insights into cardiac electrophysiology and arrhythmias.Computational methods in cardiac electrophysiology,” and share a perspective on the potential future impact of such technology  with BSPMs over time to predict AF recurrence. The advantage of using BSPM without performing noninvasive inverse mapping techniques  is that it avoids ECGI’s particular intricacies and pitfalls. Melgaard et al. have performed such inverse mapping but have limited it to a simplified, potentially more stable, approach. They restrict their inverse technique to the 12-lead ECG and a generic  geometry. Their method was able to noninvasively localize the latest electrically activated region in patients with LBBB, which is relevant for lead placement during CRT implantation. Although the use of generic geometries forfeits the need for imaging in patients, it likely affects the accuracy with which abnormalities can be localized in the heart. This was also studied by Molero et al., who investigated the effect of the density of personalized digitized torso meshes in patients with AF undergoing ECGI. They found that including the exact positions of the electrodes on the patient’s torso directly in the mesh (thus matching electrodes with mesh nodes) drastically reduces the need for high-density meshes. Their findings suggest that meshes primarily composed of electrode positions may contain sufficient geometric detail for accurate inverse reconstructions (if sufficient electrodes are present).Body-surface potential mapping (BSPM) may provide information beyond the 12-lead electrocardiogram (ECG), which is particularly relevant for extraction of therapy predictors in complex (chaotic) rhythms such as atrial fibrillation (AF). Meng et al. introduced a novel formulation of ECGI and then applied this method to the less-studied intracardiac approach. First, the method of fundamental solutions (MFS) was employed to map intracardiac (catheter-based) signals to the endocardium of the heart. MFS is a meshless ECGI approach that has been applied to inverse torso-heart mapping, but not yet to inverse catheter-heart (intracardiac) mapping. They studied the intracardiac MFS approach and found that it outperforms traditional (mesh-based) approaches and is theoretically simpler to set up. Subsequent application of this method in patients with AF showed that it is a feasible mapping method, but catheters must be large enough to capture features of complex rhythms .In two companion papers, Combined, these papers add important insights to the field: For some applications, BSPM or simplified ECGI approaches (based on the 12-lead ECG) may be sufficient; and for more complex applications such as intracardiac mapping, meshless approaches may be better suited than the traditional mesh-based approaches with more complex requirements. Sometimes, simpler is better.Castiglioni et al. used cepstral analysis, a method to identify the periodicity of a signal, for single-lead electrocardiograms to quantify the quality of the recording. Even if multiple electrodes are available, defining the most informative metrics remains an ongoing process, as illustrated by Kappel et al., who assessed three quantitative indices to predict whether a uniform ablation strategy resulted in AF termination .With the advent of telehealth, a robust quality assessment of input data from (wearable) sensors is essential. Uzelac et al. developed a method that allows simultaneous recording of these quantities in a single-camera optical mapping setup. This allows the quantitative characterization of their dynamic interactions that play a role in arrhythmogenesis at the tissue level. Among others, dynamics may be the result of inflammation, which was studied with computational models to begin unraveling the underlying complex interactions by Bi et al.Optical mapping plays a major role in unraveling arrhythmia mechanisms in experimental investigations. Such mechanisms may be partially based on complex interactions between transmembrane voltage and intracellular calcium. Traditionally, computational models have been indispensable in experimental studies to facilitate more accurate analysis and to infer mechanisms underlying cardiac function. Driven by recent methodological advances, cardiac modeling has also begun to appear in clinical applications as a means of aiding in diagnosis and stratification, or—by exploiting their mechanistic nature that allows to predict therapy outcomes—for the optimal planning of therapies. All of these application scenarios pose different challenges, many of which are addressed in this Research Topic.Barral et al.). It also profits from more accurate biophysical representation of mechanisms, such as electro-mechanical force generation at the cellular level  or of atrial electrophysiology in experimentally important porcine models . Models also play a pivotal role in gaining insight into the relationship between key pathological processes in cardiac diseases such as myocardial fibrosis and their reflection in the most important observable physical measurements, that is, intracardiac electrograms. The computational methodology for best representing the impact of fibrosis in models on electrograms was comprehensively reviewed by (Sánchez and Loewe).Overall, cardiac modeling benefits from methodological advances leading to improved robustness, accuracy and numerical stability . These vary considerably between individual patients and across cardiovascular diseases. They developed a multi-domain variational autoencoder network that integrates electrocardiogram and MRI-based 3D anatomy data into a unified model. Demonstrating high fidelity reconstruction and generation of realistic virtual populations, their approach enhances cardiovascular disease classification and supports the creation of accurate computational models, capturing disease and patient variability. Doste et al. proposed utilizing cardiac models for accurately and non-invasively determining the site of origin of ectopic beats in outflow tract arrhythmias prior to ablation therapy, to improve intervention outcomes. They enriched the training data with simulation-based synthetic data to train a machine-learning classification model. Their study demonstrated that simulated data are pivotal for enhancing training classification algorithms to achieve sufficiently accurate localization of the sites of origin.At the forefront of cardiac modeling research is the development of methodologies for generating anatomically accurate and physiologically detailed computational models calibrated to patient data at an individual level. Such personalized models represent data acquired from individuals with high fidelity, or are statistically representative of a group of patients. Such digital twin models or virtual cohorts are now gaining importance in clinical applications, in the medical device industry as well as in regulatory policy. Furthering these arguably most advanced models of cardiac function to deliver on these high promises relies on improving several critical aspects. Most importantly, model calibration must be achieved with high fidelity by comparing to clinically observable data. These calibration processes must be streamlined and automated to create digital twins with sufficient reliability within feasible timeframes. Personalized computational methodology is ideally positioned—and perhaps critical—to assess an individual’s true risk for arrhythmias, as it is increasingly recognized that simplified concepts such as “wave length,” “scar volume,” and “reduced ejection fraction” are insufficient to accurately assess this. This is particularly true when addressing both electrical and structural abnormalities, as can be studied using the recently introduced unifying “Circle of Reentry” , Figure Artificial intelligence (AI), although relatively unaddressed in this collection of papers, is expected to significantly change our scientific understanding . AlthougComputational methods in cardiac electrophysiology” collectively contribute to advancements in computational methods that can transform the understanding, analysis, and treatment of cardiac arrhythmias. By focusing on the development of robust and accurate models, as well as innovative approaches to personalize patient care, these methodologies pave the way for better clinical applicability and predictive outcomes. The integration of artificial intelligence and machine learning techniques, which have seen rapid growth and adoption in recent years and months, is poised to propel the field forward, enabling deeper insights and more effective treatment strategies. Overall, the synergy of computational electrophysiology, AI, and experimental and clinical data holds great promise for improved diagnostic accuracy, patient-specific therapeutic planning, and an enhanced understanding of complex cardiac interactions, ultimately contributing to better patient outcomes and quality of life.In conclusion, the papers presented in this Research Topic on “


Public involvement (often referred to as patient and public involvement or PPI) integrates the voices of the public in health and care research. However, groups such as care home residents are often excluded from involvement opportunities due to the complexities of involving people with additional care and communication needs. Despite a range of approaches being used, there is little understanding about how best to incorporate their experiences, and those of other care home stakeholders, into the design and conduct of research.A systematic review was conducted to identify PPI methods that better meet the specific needs of care home stakeholders. This was undertaken by (1) outlining effective PPI approaches used in care home research and the key stakeholders involved; (2) describing the role of PPI in different care home contexts and (3) identifying stakeholders’ experiences and attitudes towards PPI in care homes.Databases CINAHL, Embase, MEDLINE, PsycINFO and Scopus were searched for English language papers from inception to November 2021. A narrative synthesis approach was utilised to organise the extracted data into five themes.The search initially yielded 2314 articles (following de-duplication), with 27 meeting the inclusion criteria. Articles reported a range of input from stakeholders , with the impact of PPI varying according to the type of care establishment and research context. The experiences and reflections of stakeholders’ about their involvement in care home research varied, with some studies offering first-hand accounts compared with summaries from researchers. Some articles explicitly evaluated the effectiveness of the PPI approach using specific outcome measures whilst others indirectly described the impact of their approach. Five themes were identified as characterising an effective PPI approach: (1) valuing stakeholders’ perspectives, (2) awareness of the multi-faceted research context, (3) ensuring inclusivity and transparency, (4) maintaining flexibility and adaptability and (5) utilising resources and wider support.Effective PPI in care home research requires researchers to create person-centred opportunities to adequately involve groups with physical and cognitive impairments. The findings led to the creation of evidence-based practical recommendations to support future involvement opportunities and help researchers develop strategies for inclusive opportunities for involvement.Systematic Review Registration: The review was prospectively registered on PROPSERO (CRD42021293353). Public involvement actively incorporates the views and lived experiences of those affected by research and is essential to ensure that research is meaningful. However, involving some under-served groups, such as people living in care homes, can be complicated due to their additional care and communication needs. The best way to involve care home residents, families and staff in research is unclear. In this systematic review we looked at studies using different approaches to public involvement in care home research. We found that studies involved different combinations of residents, families, and staff depending on the type of study and what was involved. Some articles described what methods of public involvement had taken place, whilst others explained how effective their approach to involvement had been and why. For involvement to be effective, it was important that researchers valued differing perspectives by providing a safe forum for stakeholders to share their opinions. Researchers should also understand that successful involvement requires flexibility and adaptability to accommodate the varied needs of individuals such as time commitments and simplifying the complexities of the research terminology. Additionally, researchers should utilise the wide range of available resources and support to ensure under-served groups are appropriately included within the research team. We concluded that public involvement in care home research needs to focus on the needs of the individuals to ensure that people with physical and cognitive impairments can be involved. The findings can help care home researchers to create equal opportunities for all to be involved. The N’ ‘them” . The pub’ ‘them” , 4. The Despite this, care home residents continue to be under-represented, with minimal understanding of the benefits of utilising their first-hand experiences in research , 3. OldeAdults dependent on social care are the greatest recipients of healthcare services, with many experiencing complex multimorbidity, increasing frailty and dependency on nursing staff , 9. CareWhen designing and conducting research, it is important embed public involvement throughout which incorporates the lived experience of care home residents and caregivers , 12 alonTo address this gap, we aimed to systematically identify and synthesise published studies to identify effective PPI approaches used in care home research. The objectives were to: (1) outline what approaches were used in PPI in care home research and the key stakeholders involved; (2) describe the role of PPI in different care home contexts and (3) identify stakeholders’ experiences and attitudes towards PPI in care home research. In this review, ‘public’ refers to residents , relatives, caregivers and representative organisations. These groups can be considered key stakeholders in care home research. Approaches were considered ‘effective’ where the researchers who reported the study had viewed their experience of PPI activity as positive or having been successful in achieving its aims.The findings from this systematic review can be used to improve the standard of PPI in care home research by identifying the best approaches to create inclusive opportunities for care home stakeholders . Better This systematic review is reported in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The pro. This approach is best suited for qualitative research and enables the exploration of behaviours and individual experiences.This review was limited to English language studies without date limits on the publication year. Studies were included if they reported PPI research in care homes, residential homes, or nursing homes regardless of the care home population (older people or younger adults with disabilities), research topic or study methodology. Studies were excluded if they did not report PPI in care home research, key stakeholders were not included, or the study was conducted in other social care settings. The SPIDER framework   was utilA search of five electronic databases  was conducted in November 2021. The search strategy was developed with guidance from a subject librarian . Additional studies were retrieved from web searching and searching a topic-specific journal (Research Involvement and Engagement) by adapting the search concepts used in the electronic databases to create specific search strategies for additional literature resources.De-duplicated studies were exported into EndNote 20.2. Study selection comprised of three stages: firstly, the titles and abstracts from the initial literature search were screened by the first author. Of these studies, 10% were then double screened by another researcher to ensure consistency. Secondly, the full text of included articles (n = 94) were independently reviewed by two co-authors for eligibility, the reasons for exclusion were recorded in accordance with the PRISMA guidance . RecordsIn accordance with the published protocol, quality assessment of included studies was attempted using the Mixed Methods Appraisal Tool (MMAT) 2018 version which enables appraisal of different study designs . HoweverA data extraction tool was developed for this review with guidance from Backhouse et al. . ExtractCodes were created to capture the meaning of key underlying and recurring concepts and were organised into themes which were iteratively developed using headings from the data extraction tool. Definitions for each generated theme were developed and refined through regular discussions amongst the research team.Database searches yielded 3671 papers with an additional 15 papers identified from other sources. Following de-duplication this resulted in a total of 2314 records, of which 94 studies were retrieved for full-text assessment following identification of studies via databases (n = 79) and other methods (n = 15) , relatives, caregivers and representative organisations. However, due to power dynamics and polyvocal perspectives there were conflicts of interest resulting in the views of residents being overpowered by caregivers and representative organisations , 45. MorThe negative perceptions associated with care homes often limits residents’ engagement in research as sole participants; becoming the ‘researched’ as opposed to the ‘co-researchers’. This was highlighted in the study with younger adults  where deThe growing importance of equality, diversity and inclusivity in research offers a diverse perspective to recruitment strategies. Representation from those with varying educational attainment, gender, geography, and ethnicity provides a broader perspective on the issues affecting vulnerable adults , 10, 14.Care home residents can aid dissemination, research findings should be distributed to non-academic settings by PPI stakeholders who are sensitive to the tone of dissemination . For exaThe first-hand experiences and reflections of stakeholders’ regarding their role of PPI in care home research was not always explicitly stated. Some articles highlighted the perception of being ill-informed or unknowledgeable regarding the research concepts  whilst oThis review was prospectively reported on PROSPERO. The inclusion criteria provided a platform for care home residents who are often underrepresented in research, whilst recognising that the perspectives and experiences of a wider range of stakeholders are often valuable to include. However, challenges were encountered during the screening process as PPI is not always being reported in the title, abstract or study aims which may have led to relevant studies not being included. Additionally, the lack of clear definitions around involvement, participation, engagement, and co-production made it difficult to differentiate between the role of PPI stakeholders within the research design. Consequently, more research is required to characterise key terminology along the PPI continuum and to develop tools to appraise the quality of articles reporting PPI activities or approaches. The variable quality of PPI reporting has been widely reported elsewhere and led to the development of reporting frameworks such as GRIPP2 .Our findings are supported by a scoping review which was published following our review and which focused on mapping co-production approaches to care home research for older adults . As in oDue to resource limitations public involvement was not included in the research design, analysis or authorship of this study which, if incorporated, would have enhanced the outcomes and conduct of the study and provide opportunities to apply the research findings into practice. We were similarly limited to English language studies which impacted the representativeness of the sample. Notably, most of the studies were conducted prior to the COVID-19 pandemic during which there were seismic shifts in the nature and mode of PPI activities. Other limitations included the risk of bias, with a single reviewer of full-text eligibility and data extraction and a sample independently reviewed by a second reviewer. This may have resulted in subjective assessment and key methodological concerns remaining unidentified.These findings unify current understanding of incorporating care home residents as PPI members within research. Utilising evidence-based insights with appropriate adjustments to PPI methods Fig. , care hoWe have used the findings from this review to develop practical recommendations that will support more inclusive and effective PPI in care home research Table .Table 4PWe have used the evidence-based PPI guidelines to propose practical recommendations which can be applied in future care home research. Further exploration is needed to develop strategies for involving residents with greater support needs and time-pressured care home staff within research. Strategies are also needed which extend beyond the traditional methods of PPI to incorporate more innovative approaches within different study designs, whilst establishing appraisal tools to adequately measure and report the quality of PPI.People living in care homes often require the highest and most complex level of care, whose needs are met by a large and diverse workforce. An effective PPI approach transforms the view of residents and staff as consumers with a passive voice to owners of research with active and valuable participation in the creation of knowledge. This is achieved by careful consideration of five person-centred factors: valuing stakeholders’ perspectives, ensuring inclusivity and transparency, taking account of the multi-faceted research context, maintaining flexibility and adaptability whilst utilising resources and wider support. It is hoped that the practical recommendations given can transform the research culture and create a research environment that is representative and accessible to this under-served group regardless of age, experience, or health status.


Enjoyable group-based physical activity programmes provide an engaging opportunity for older adults to experience healthy ageing promotion. To understand the programme delivery context, we explored how exercise instructors seek to make their existing sessions enjoyable.n = 9) who were experienced in delivering group-based exercise programmes to community-dwelling older adults were interviewed. The mean interview length was 50 minutes.A semi-structured interview guide was used to qualitatively investigate how exercise instructors create the conditions to promote an enjoyable experience. Exercise instructors  Identifying individual expectations and motives for engagement. Exercise instructors recognised that safety was a foundational aspect of the exercise programme, so that older adults could enjoy exercising confidently. 2) Adopting a tailored approach to meet the needs of older adults. Exercise instructors ensured that the exercises were inclusive of all abilities so that older adults could enjoy exercising collectively. 3) Encouraging collective participation through the development of social support networks. Exercise instructors created a relaxed social atmosphere, facilitating social support, so that older adults could enjoy being part of the group and experience belonging.In summary, exercise instructors reported that tailoring sessions to meet the identified needs of older adults and encouraging the group to foster social support can create the conditions to promote an enjoyable experience. The findings can inform the promotion of enjoyment and engagement into existing programs. Findings can be used by exercise instructors, policy makers, researchers, and civil society organisations to ensure that opportunities for healthy ageing are sustainable. Longer-term group-based physical activity opportunities are required to ensure that older adults can experience belonging in a group they enjoy being active in, and which encourages the development of external social networks they may not otherwise have. For the purpose of the presentation, the primary focus is on how exercise instructors can incorporate the social elements of enjoyment in group-based physical activity programmes for older adults, across the dynamic progression of group identity.This study was funded by a Postgraduate Studentship from the Department for the Economy (DfE) in Northern Ireland.


There is converging evidence that regionally differential aging processes in the human brain exist, mainly affecting the frontal lobe and relatively sparing posterior and infratentorial areas [The morphological correlates of brain aging in neuroimaging are characterized al areas . Magnetial areas . Machineal areas . Applicaal areas , and appAlthough the performance of most brain age estimators is promising , 5, a maFor brain age estimation, artificial neural networks (ANN) have been established as very promising ML models due to their superior performance in solving complex non-linear problems. ANN are capable of grasping complex interactions of different white matter tracts which are important for assessing brain health. Although multimodal ML models perform best, single MRI modality approaches may be a better candidate to achieve widespread clinical adoption, where ease of use is important. In addition, convolutional neural networks and other deep learning algorithms applied to conventional T1w images have the potential to match DTI in its predictive power ; howeverIn a recent study on brain aging, an ANN was capable of estimating the subjects’ chronological age with high accuracy by solely relying on DTI data . In addiBeyond these developments in brain aging research, recent advances in ML have exceeded the expectations of many AI experts, with transformer-based deep learning models leading the field. In the resources-intensive field of geriatrics, automation and intelligent systems are the keys to mastering the challenges of demographic change in societies worldwide. In this environment, the application of AI to neuroimaging targeted at aging in particular is well positioned to improve and expand geriatric diagnostics in the future.


Gamification has emerged as a novel technique for improving mental health and enhancing treatment effectiveness. This paper provides an overview of gamification approaches to mental health intervention, identifies factors that may be related to variations in treatment effectiveness, and discusses possible strategies for tailoring gamified interventions to clients’ needs.Recent research has documented the potential of gamified mental health interventions for bolstering mental wellness and mitigating psychological symptoms. However, their effectiveness may vary depending on study design-related factors and gender-specific considerations. Literature reviews have also identified yet-to-be resolved issues surrounding the possible strengths and weaknesses of the personalization versus standardization of gamification, as well as the potential benefits of gamification for increasing engagement versus the potential risks of over-engagement and behavioral addiction to gamified components.This review highlights the need for careful planning and execution of gamified mental health interventions to optimize their effectiveness and suitability for meeting clients’ individual needs and preferences. Dance Dance Revolution for cardiovascular fitness and weight control [Nike + for physical activity tracking and SuperBetter for achieving personal health objectives [Gamification, a technique that integrates gaming elements into non-game contexts, has gained popularity in promoting physical and mental well-being in recent years ••, 2•. I control . Since tjectives , 5. Gamijectives –9.Gamification has emerged as a novel approach for improving mental health interventions, with two major applications in current practice. One approach involves directly developing gamified mental health interventions to create novel and more engaging treatments, whereas the other involves integrating gamification elements into existing mental health interventions to enhance their efficacy.In the cyber age, advanced digital technologies originally created for gaming and entertainment such as virtual reality (VR) and augmented reality (AR) have been repurposed as tools to bolster mental wellness –13. One Both VR and AR technologies have been shown to provide clients with highly customizable scenarios for practicing skills such as social training and phobia exposure therapy in either mixed or fully constructed environments , 14. TheAnother approach to incorporating gamification into mental health interventions is to add gaming elements as supplementary components to existing programs. For instance, a team of scholars sought to improve the effectiveness of a computerized cognitive-behavioral intervention designed for altering cognitive biases in clients diagnosed with depression. Specifically, they endeavored to alleviate the tediousness of repetitive tasks in this intervention by incorporating six key gamification components: goals, challenges, feedback, rewards, progress, and fun . Their fAnother study examined the use of gamification elements in unguided cognitive-behavioral therapy for adolescents diagnosed with depression . These eGamification components are increasingly being used in new forms of mental health interventions, including ecological momentary interventions delivered through mHealth systems such as mobile apps •. EcologAlthough gamification has shown promise as a technique for improving mental health interventions, a more nuanced analysis of its efficacy in improving psychological outcomes is needed. In particular, it is important to examine the variability in gamification effectiveness across studies and samples and to identify key gamification components and factors that play an influential role in treatment outcomes. Meta-analysis is a powerful tool that can provide valuable insights into these issues .Of note, a recent meta-analytic investigation revealed that gamified interventions generally elicit small to moderate positive effects on an array of mental health indicators, particularly on subjective well-being and quality of life indices ••. HowevThe effectiveness of gamified interventions in mitigating anxiety symptoms has been found to vary by the duration of the intervention. Specifically, interventions with shorter durations are more effective in relieving anxiety symptoms than those with longer durations. This finding may be due to the primary focus of brief or short-term psychological interventions on the specific issues faced by clients. These interventions enable therapists to target specific problems and symptoms and to help clients develop strategies and skills to address those issues , 26. FurThe efficacy of gamified interventions in reducing anxiety symptoms is influenced not only by the intervention duration but also by the duration of follow-up assessment. Among the cluster of studies that have evaluated the efficacy of gamified interventions, those with longer follow-up assessment periods generally exhibited stronger desirable treatment effects. Such variations may be related to the time required for clients to integrate the targeted behavioral changes into their daily lives, which is particularly important for complex or long-term behavioral changes involved in the treatment of psychiatric symptoms. This is often the case for gamified VR exposure and other cognitive-behavioral therapies. For instance, some gamified VR exposure therapies use the behavioral therapy technique of systematic desensitization to treat certain phobias , 30••. TAlthough longer follow-up periods for outcome assessment may allow clients additional opportunities to reinforce targeted changes through ongoing gaming experiences, it is worth considering the potential confounding effects of maturation, which are changes that occur over time independent of the intervention’s effectiveness . To compConsiderations specific to gender are important in evaluating the effectiveness of gamified interventions. A recent meta-analysis revealed that on average, gamified interventions were more effective in mitigating anxiety symptoms among male clients than among their female counterparts ••. This Gender differences in gaming motivation have also been found, with male gamers generally exhibiting greater motivation for competition and challenge than female gamers . To enhaGender differences in game genre preferences may also impact clients’ engagement with and the effectiveness of gamified interventions for anxiety reduction. Research has shown that male gamers tend to prefer fast-paced, action-oriented games such as first-person shooter and sports games, whereas female gamers tend to prefer puzzle and social games . HoweverGamified interventions involve the use of gaming elements in therapeutic settings to motivate and engage clients to foster more positive treatment outcomes. However, as discussed above, clients may have varying needs, preferences, and backgrounds that affect their involvement and participation. Hence, gamification should not be regarded as a one-size-fits-all solution. Two major approaches have been proposed for designing and delivering gamified interventions: personalization and standardization. Both approaches have their advantages and disadvantages, and mental health practitioners must carefully consider their intervention’s goals, target population, and available resources when deciding between these approaches.The personalized approach to gamification involves individualizing gamified interventions by tailoring them to the specific needs and preferences of clients, taking into account a range of factors such as their experienced problems, goals, personalities, and demographic characteristics ••. This From the user’s perspective, studies have indicated a general preference for gamified apps that offer a greater degree of customization •. EmpiriDespite the benefits associated with personalization in gamified interventions, there are also limitations to this approach. Specifically, over-personalization can restrict the generalizability of interventions across diverse populations and make it difficult to assess their effectiveness . MoreoveIt is worth noting, however, that the standardized or one-size-fits-all approach may not be suitable for all clients and may increase the risk of mismatching clients with gamified components, thus reducing engagement and increasing dropout rates. While standardized approaches may enhance the quality of the evidence obtained, it is important to recognize that the optimal degree of personalization and standardization may vary across populations and therapeutic settings. Therefore, a flexible and adaptable approach to gamification that strikes a balance between personalization and standardization is worth considering in the development and evaluation of gamified interventions.When considering whether to use personalized or standardized approaches, mental health practitioners can make an informed decision by conducting a cost–benefit analysis, which involves weighing the advantages and disadvantages of different intervention designs to determine which one offers the largest net benefit . PersonaConversely, standardization may entail costs such as potential issues related to the gamified intervention’s relevance and acceptability to a heterogeneous group of clients, as well as potential challenges in implementing the intervention consistently across clients and settings . NeverthClient engagement has been a longstanding concern in mental health interventions, as a lack of engagement can adversely impact treatment effectiveness , 62. GameQuoo is a gamified app featuring a series of mini-games that can help clients strengthen a variety of skills, including emotion regulation and interpersonal communication [Various studies have demonstrated the potential benefits of gamification for improving retention rates in mental health interventions. For instance, nication . Clientsnication ••. Similnication . The appnication •, the apAnother body of research has reported that gamification can foster cognitive engagement, which refers to the extent to which clients are actively involved in the learning or problem-solving process and are mentally invested in the task at hand . GamificDespite the effectiveness of gamification in enhancing cognitive engagement, it may not necessarily facilitate other types of engagement such as behavioral engagement . SpecifiAlthough client engagement is generally desirable for mental health interventions ••, the pTaken together, this paradoxical issue highlights the importance of achieving an optimal level of engagement that is critical for gamified interventions in mental health contexts. This optimal level may be attained if the level of engagement is sufficient to motivate clients to continue participating in the intervention and achieve the desired mental health goals, while avoiding harmful consequences such as over-engagement and behavioral addiction to gamification elements ••, 76. MBy leveraging gaming elements and mechanics in mental health interventions, gamification has the potential to facilitate engagement and motivate clients to attain their therapeutic goals, which include promoting mental wellness and relieving psychological symptoms. While some studies have reported promising results with gamification as a standalone or additional component of existing mental health interventions, others have shown more modest benefits. Recent reviews of the literature suggest that these heterogeneities may be related to differences in the gaming elements used and the suitability of specific gamification components for clients with varying demographic characteristics. Therefore, the implementation of gamified interventions may require careful planning and execution to ensure their effectiveness and suitability for clients’ individual needs and preferences. Practitioners and game designers may consider weighing the potential benefits and costs of personalization versus standardization of gamification, particularly with regard to treatment adherence and the evaluation of effectiveness. By striving to strike a balance between a sufficient level of engagement and over-engagement, the design of gamified interventions could be optimized to help clients attain their mental health goals and improve their overall well-being. Table As research and practice regarding gamified mental health interventions are still in the nascent stages, further investigations and evaluations are needed to optimize their design and implementation. By exploring the potential of gamification to address specific mental health disorders and symptoms, as well as the factors that may influence its effectiveness, scholars and practitioners need to identify the optimal components and mechanics of gamified interventions for diverse populations and therapeutic contexts. Such research data would inform the development of evidence-based interventions that can improve the well-being of clients with mental health challenges. In addition, future research could explore the potential risks associated with gamification and identify approaches to circumvent them. In short, continued investigation in this emerging field is needed to guide the development of tailored gamified interventions that improve client engagement, treatment adherence, and mental wellness.


Space exploration objectives will soon move from low Earth orbit to distant destinations like Moon and Mars. The present work provides an up-to-date roadmap that identifies critical research gaps related to human behavior and performance in altered gravity and space. The roadmap summarizes (1) key neurobehavioral challenges associated with spaceflight, (2) the need to consider sex as a biological variable, (3) the use of integrative omics technologies to elucidate mechanisms underlying changes in the brain and behavior, and (4) the importance of understanding the neural representation of gravity throughout the brain and its multisensory processing. We then highlight the need for a variety of target-specific countermeasures, and a personalized administration schedule as two critical strategies for mitigating potentially adverse effects of spaceflight on the central nervous system and performance. We conclude with a summary of key priorities for the roadmaps of current and future space programs and stress the importance of new collaborative strategies across agencies and researchers for fostering an integrative cross- and transdisciplinary approach from cells, molecules to neural circuits and cognitive performance. Finally, we highlight that space research in neurocognitive science goes beyond monitoring and mitigating risks in astronauts but could also have significant benefits for the population on Earth. Leveraging the outcomes of previous similar exercises  as well as opening up the knowledge-building process to the scientific community across disciplines, it has been possible to clearly define gaps and risks that are currently considered highly critical but unmitigated in space science and technology. The process of creating the roadmaps has involved hundreds of individuals from the wider life science and engineering communities, ESA and international partners. This strategy allowed to maximize cross-disciplinary synergies (interactions between working groups were strongly encouraged as of the start of the project). The outcome of this work has been summarized in a series of papers presented by each working group. The current manuscript highlights the ESA SciSpaceE research gaps identified in the field of Neuroscience as part of the Behavioral Health & Performance Roadmap; the Psychology expert group provided additional feedback on some aspects at the boundary between neuroscience and psychology. In the following sections, we identify and discuss some key knowledge gaps related to neurobehavioral performance during human future exploration space missions. Next, we address potential countermeasures to mitigate these risks. We conclude with a summary of key priorities for the roadmaps of current and future space programs, and how addressing these knowledge gaps can benefit people and industrial applications on Earth.5. The same research group also observed white structural disruption in areas critical for visuo-motor control and higher-order visuo-spatial processing after spaceflight6. Notably, other groups reported increases in white matter immediately after spaceflight that persisted seven months after return to Earth7. Robust effects have also been observed for ventricular volume expansions13, which did not return to preflight levels six months13 and even up to one year after landing10.There is now considerable evidence that spaceflight conditions can negatively affect the brain. Koppelmans and colleagues (2016) reported extensive volumetric gray matter decreases, including large areas covering the temporal and frontal poles and around the orbits in response to spaceflight14. Likewise, it was also shown that spaceflight-induced changes in cortical thickness of vestibular and sensorimotor regions, including the posterior insula and the superior temporal gyrus, predicted postural balance performance15. The effects on cognitive performance (as compared to sensorimotor control) are less clear16. While various neurobehavioral effects have been observed in response to specific spaceflight stressors , most data collected during spaceflight show stability, or performance increases throughout the mission18. The inconclusive findings can at least somewhat be attributed to study designs and methodological limitations such as mission duration, the type of tasks to assess cognitive performance, and the number and spacing of data sampling time points. For instance, Moore and colleagues (2019) observed significant impairments in manual dexterity, degradation in manual tracking, during dual tasking, and a car driving simulator task immediately upon return from space19. Notably, the effects recovered quickly (3–5 days post-landing), and the authors attributed their findings to post-flight blunting in low-frequency (‘tilt’) otolith function in addition to fatigue and environmental factors unique to prolonged stays in a spacecraft 19. Such effects could have a profound impact on operator proficiency such as controling a vehicle during the exploration of novel terrains, or performing rendezvous and docking maneuvers. It may also be possible that certain effects are delayed, and are only detected after weeks to months. For example, the NASA Twin Study showed that year-long human spaceflight does not immediately affect cognitive performance but reveals some adverse effects 6 months after return to Earth20. The temporal dynamics of cognitive performance trajectories during and after spaceflight are still to be explored. Along the same lines it is unclear whether there is a dose-response relationship between neurobehavioral adaptations and mission duration. It is therefore critical that future studies will go beyond 6-month duration missions, and consider following up space crews throughout the recovery of plus one year. Previous cognitive assessments also seem to have been driven by classical neuropsychological test paradigms. It is possible that spaceflight would benefit from more complex tasks that are specifically targeted to the astronaut population, and capture cognitive domains associated with visuo-spatial processing that are expected to be tightly coupled with operational tasks6. Moreover, it is expected that such tasks could be relevantly affected by gravitational changes because its close link to the vestibular system, which goes beyond maintaining gaze and balance. Interactions between the otoliths and semicircular canals critically contribute to spatial perception including self-motion, orientation, and navigation. It is possible that weightlessness affects various visuo-spatial abilities because of reduced gravitational stimulation. For example, it is known that spaceflight causes changes various vestibular responses leading to orientation illusions, sensory localization errors, and changes in vestibulo-ocular reflexes21. Cognitive tasks involving the neurovestibular system such as mental rotation22, perceived orientation23, and distance judgments24 are also affected during spaceflight. Some astronauts have reported a "time compression syndrome" in orbit25. They also require more time than normal to perform standard mental activity27. Previous microgravity research has also demonstrated the effects of weightlessness on posture, gaze, functional mobility, and spatial orientation, reporting misperceptions of visual orientation, depth and distance, and difficulties in shape recognition28. It is expected that any impairments in visuo-spatial abilities will also have adverse effects on spatial navigation performance. Given that the perception of self-motion depends on integrating visual information with gravitational cues processed by the vestibular system, spatial updating deficits are expected when gravity levels change. Data from parabolic flights though show that both micro- and hypergravity can lead to less precise spatial updating, a fundamental ability underlying spatial navigation29. This prediction is also in line with emerging evidence highlighting the cortical projections of the vestibular system.The implications of these changes on human performance and behavior are unclear. Some of the most robust effects have been found for postural control. Using task functional magnetic resonance imaging (MRI) Hupfeld and colleagues (2022) demonstrated widespread reductions in cortical deactivation in somatosensory and visual areas after spaceflight that were associated with postural changes in balance decline30. Animal data suggest that the hippocampus and related brain structures  could be particularly vulnerable to the stressors associated with long-duration spaceflight such as radiation31, increased CO2 levels32, vestibular dysfunction33, stress34, sleep deprivation35, and isolation and confinement37. The effects of prolonged isolation and confinement on hippocampal plasticity have been demonstrated in humans, revealing significant reductions in dentate gyrus volume which were associated with reductions in key neurotrophins and adverse cognitive effects38. It is possible that the physiological effects of microgravity, environmental toxicants, and operational stressors interact and aggravate the consequences on brain plasticity during long-duration space missions.Given the pivotal role of visuo-spatial abilities and time evaluation for mapping spatial relationships and operations such as docking, landing, and exploring and navigating in new environments and on planets with low gravity, it is imperative to understand the impact of spaceflight on spatial cognition and its neural basis. One of the key brain areas for mapping spatial relationships and performing navigational tasks is the hippocampus41]. It is unclear whether such differences also exist in astronauts, and if and to what extent spatial navigation and related brain changes are differently affected after spaceflight in men and women. In fact, our current understanding of neurobiological sex differences associated with spaceflight is critically limited because of the significant disproportion of sexes enrolled in previous astronaut corps. According to our best knowledge there are currently no data comparing brain changes between male and female astronauts. Elucidating the effect of sex is mandatory to fully understand brain plasticity and behavior and their molecular mechanisms43. This notion is in line with the world’s leading research centers to consider sex as a biological variable44, and the space agencies’ goal to increasingly strengthen the role of women in future space expeditions. For instance, the newest class of NASA astronaut candidates included almost 50% women45. In 2020 astronaut Christina Koch broke the record for the single longest spaceflight by a woman. With 328 days in space, she is among the top five all-time records for the longest single spaceflight. NASA also announced that the next person on Moon and the first person on Mars will likely be a woman46. Due to the increasing and essential role of women in future space missions, studies of both men and women are critically needed to better understand sex-dependent vulnerabilities to adverse neurobehavioral effects during future exploratory space expeditions such as a mission to Mars.It is also unclear whether neurobehavioral differences in response to spaceflight are characterized by sex- and genetic-specific adaptations. For instance, on Earth there is little doubt that spatial navigation and its neural circuitry are characterized by sex-specific differences [e.g.,47, a more synoptic understanding of the effects of altered gravity, space radiation, and prolonged spaceflight on the morphology and physiology of the various cell types of the nervous system and their synapses will be important to the success of future long-duration missions to the Moon or Mars. Morphological and functional alterations at the synapse could result in physiological impairments which fundamentally alter information processing in the nervous system. A more comprehensive understanding of spaceflight-induced physiological and structural alterations at the synapse and synaptic active zones, as well as the resulting changes in short and long-term plasticity and neurotransmitter homeostasis, are just a few of the relevant topics that need to be addressed in the years to come. These questions are not just relevant to glutamatergic, GABAergic, and cholinergic transmission but should be investigated in all relevant neurotransmitter systems  as well as the neuropeptides and gaseous signaling molecules.A central tenet of neuroscience is the cellular understanding of nervous system functions. Although great strides in quantifying the effects of spaceflight on neuronal physiology have been made, and despite the numerous constraints of space researchDetails regarding the effects of spaceflight on the nervous system have been poorly described so far. Animal experiments offer great potential to better understand the mechanisms underlying the neuronal responses to spaceflight. Spaceflight can significantly affect neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system. Micro- and hypergravity responsive gene signatures identified several candidate targets with terrestrial roles in neuronal function and/or cellular metabolism, which are linked to regulation by daf-16/FOXO signaling. This could help to understand the basis of spaceflight-induced maladaptation.20.Given the sparse availability of samples, the use of integrative omics technologies in multidimensional longitudinal studies to quantify metabolites, gene expression, and DNA methylation as well as DNA, RNA, protein, and chromatin dynamics after exposure to long-duration spaceflight will be paramount for furthering the understanding of space induced changes in cellular neurobiology50. In microgravity, the gravitational force vector, which is predominantly sensed via the otolith organs (saccule > utricle), no longer acts as a sensory reference. The resulting mismatch between the vestibular, and the visual, proprioceptive and other sensorimotor signals can affect spatial orientation, hand-eye coordination, vertical but not horizontal oculomotor behavior, postural control and self-motion perception 51. The earliest symptom for this sensory mismatch phenomenon and modulation of otolith function is the elevated susceptibility for motion sickness during parabolic flight as well as during the first days of exposure to microgravity and upon return to Earth after a long-duration space mission52. This is most likely an adaptation process associated with the altered integration and interaction of information from the semicircular canals and the otolith organs. It is known that spaceflight causes various changes in several vestibular downstream responses including transient core level modulations in vestibulo-ocular reflexes21 leading to room tilt illusions and sensory localization errors. When tasks are performed during or shortly after any gravitational transitions sudden head movements especially in the yaw plane are not advised, further highlighting the role of canal-otolith integration.Future crewed missions to the Moon and Mars will expose astronauts to varying levels of gravity. The neurophysiological responses to changing hypogravity  and hypergravity levels  are poorly understood. Gravity plays a fundamental role in human behavior and performance by providing critical cues to the vestibular system  and supporting the concept of verticality (which way is “up” or “down”). The otolith organs detect linear, i.e., inertial and gravitational, accelerations acting on our bodies53, only a few have addressed the re-adaptation processes following re-entry: astronauts also experience a condition called “entry motion sickness”, which slows the speed of decision making and alters their ability to control the vehicle and their movements54. Neurovestibular challenges that occur when the crew member returns to normal gravity include alterations in manual control20, inability to exit the vehicle55, postural imbalance56, and locomotion disorders57. The first three weeks in space and the first two weeks back on Earth present critical adaptation periods that are characterized by impairments in perceptual-motor skills and higher attentional processes. However, the dynamics of re-adaptation when transitioning back to the original environment  or to a new gravity level  is not well understood. This lack of knowledge may be partially explained by current methodological limitations and operational constraints; it is extremely challenging to collect data during or upon entry in a new environment or immediately after landing. The quantification of the dynamics of sensory processes with a short time constant adaptation) requires accurate measurements immediately before and after entry, landing, or any other event that induces significant changes in the environment. Consequently, current methods of preflight training and post-flight rehabilitation have not been optimized to minimize the functional impacts of these natural adaptive responses during gravitational transitions or to restore environment-appropriate sensorimotor functions after these transitions.Gravitational transitions can also induce aftereffects that will persist for some time after as the neurovestibular systems adapt to the new gravito-inertial loading. These neurological phenomena have been shown to impair behavior and performance across dimensions. While many studies have demonstrated that humans and animals eventually adapt to new gravitational environments (mostly microgravity)58, in which proprioceptive, somatosensory, visual and vestibular signals are integrated for processing gravity-related cues. For instance, Mittelstaedt (1996) proposed a somatic component for graviception that is located in the trunk, and particularly in the kidneys59. Humans use an internal model to dissociate gravity and inertial acceleration from a composite acceleration signal60. As a result of the complex integration of graviception and its interaction with motor control, understanding how the nervous system adapts to changes in gravity is challenging.Current research suggests a multimodal representation of gravity63. Early access to astronauts (immediately upon entry or after landing) is critical to characterize the dynamics of this highly dynamic adaptation process . This point has been emphasized in a previous white paper by White et al. (2016)3, and remains a critical issue. The next steps to deepen our understanding of the neural bases of adaptation to changes in gravity will require to address current methodological constraints such as technologies to measure brain function of cortical and sub-cortical structures in real-time. Furthermore, the modularity of dedicated discrete sensory organs and brain regions for processing gravity cues suggest a distributed role of structures and functions for perception and control50. In addition to visual, vestibular and internal (prior) information, somatosensory (proprioceptive) feedback and its influence on planning and control may serve as a calibration signal that is conditioning our perception and the scaling of motor commands. The importance of this sensory information has not been fully acknowledged so far. Finally, the experimental context itself faces several methodological challenges. Structural and functional magnetic resonance imaging (MRI) of the brain cannot be used to acquire data during gravity transitions. Data collected before and after an interventions  can probe neural adaptations in response to acute exposures to altered gravitational levels. Yet, they must be cautiously interpreted because they do not allow to draw any conclusions about the effects of gravity levels and transitions. Although there is solid evidence of the existence of a vestibular network that processes gravity signals64, current approaches are insufficient to draw clear-cut conclusions, firstly for methodological reasons, and secondly because gravity in essence influences all systems at the same time. Technologies to observe brain function such as electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) are mobile and could potentially be used to capture cortical neurophysiological changes in response to altered gravity in real-time. EEG records electrocortical activity at the scalp surface with temporal resolution and moderate spatial resolution . In contrast, (f)NIRS reflects brain activation by measuring brain hemodynamic responses at lower temporal but higher spatial resolutions. Combining EEG and fNIRS may therefore overcome some of the previous methodological challenges and open new avenues to pinpoint how the brain creates an internal representation of gravity66. However, such approaches require cautious validation studies because of the potential confounding associated with cephalic fluid shifts on functional brain recordings67.The precise nature and properties of this internal multimodal representation going beyond the vestibular system during acute gravitational transitions are also still to be determined. Experiments performed under altered gravitational levels have identified a rapid adaptation process. At the same time the data have also revealed biases indicative of partial habituation that could be observed throughout the entire (often short-term) exposure to weightlessnessGiven the variety of environmental and psychological stressors associated with prolonged exploratory class missions, a combination of different treatments and interventions will be needed to mitigate neurobehavioral risks, maximize performance, and ensure astronaut health and safety, and mission success. Considering that responses to different spaceflight stressors are expected to vary between astronauts and their phenotypic differences, the strategies for neurobehavioral risk mitigation need to be personalized in terms of type, frequency, and intensity throughout a space mission. We here summarize some of the current and future approaches to maintaining neurobehavioral health and performance.68 and fluid loading to reduce orthostatic intolerance; resistive exercise and nutritional interventions to minimize muscle and bone loss; or aerobic exercise to maintain cardiorespiratory fitness69.Long-duration stay in microgravity on the various space stations demonstrated how gravity, or the lack thereof, has a significant impact on all organ systems such as bone decalcification, muscle loss, cardiovascular deconditioning, orthostatic intolerance, visual impairment, suppression of the immune system and other changes indicative of premature aging. Previous countermeasures to mitigate the effects of weightlessness have addressed different organ systems using target-specific approaches, i.e., lower body negative pressure70. The idea of using AG to compensate for the negative effects of weightlessness is as old as spaceflight itself and has been considered a standard against which other countermeasures should be measured71. A large, ground-based, rotating platform that could house human subjects for long periods (weeks to months) while exposing them 24/7 to higher-than-normal gravity levels would offer a unique means to validate the long-term beneficial effects of small hypergravity on the human body across all organ systems72. Whereas the idea of generating AG by means of rotating parts of a spacecraft is compelling, rotation can have a number of undesirable side effects on performance73. For example, consider the Orion spacecraft which is about 5 m in diameter. To generate a force of about 1 g in a circular space with a 2.5-m radius, a rotation rate of 20 rpm would be required to generate a force of about 1 g. Depending on the location relative to the center of rotation body weight  changes. Likewise, walking in the direction of rotation will increase the centripetal force, and hence AG, and therefore also increase body weight73. In addition, such rotation speeds create significant Coriolis forces generated by body movements. To systematically study such effects DiZio and Lackner established a unique rotating chamber at the Ashton Graybiel Spatial Orientation Laboratory. This research resulted in a series of seminal studies on how lateral Coriolis forces can disrupt body movements and object transport and manipulation, how reaching errors carry-over in the opposite direction when the rotation stops, and that the human body can adapt to the Coriolis force and compensate the perturbations very rapidly73.Delivering Earth-like gravity levels using artificial gravity (AG) could provide a holistic approach by mitigating physiological risks associated with prolonged exposure to weightlessness across all organ systems74. Exposing crewmembers to AG of 1 to 2 g at the heart for 0.5 to 2 h has been shown to be a promising countermeasure for reducing the effects on body unloading and fluid shifts75. AG has been shown to mitigate cardiovascular deconditioning79; muscle and bone loss82; improve neuromotor reflex function83; decrease headache severity associated with head-down tilt bedrest84; and alleviate some of the conditions of the spaceflight associated Neuro-Ocular Syndrome (SANS)75. AG also provides critical cues to the vestibular system. This is important because the vestibular system goes beyond maintaining gaze and postural stabilization. There is increasing evidence indicating that the vestibular system plays a critical role in brain plasticity and cognitive performance such as learning and memory formation33. For instance, patients with bilateral vestibular loss exhibited bilateral atrophy of the hippocampus of nearly 20%, which was correlated with spatial memory deficits in a virtual Morris water maze task85. The manipulation of the vestibular system has been shown to impair firing patterns of head direction cells , hippocampal function, and medial entorhinal cortex89. Together these data highlight that vestibular stimulation provides critical cues for brain health and cognitive performance, supporting the notion that AG as a countermeasure could go beyond the musculoskeletal and cardiovascular system and also benefit brain and behavioral health. In addition, recent cell experiments suggest that hypergravity can have profound beneficial effects on neuronal health that are independent of vestibular stimulation. For instance, Lichterfeld et al. (2022) recently showed that hypergravity attenuates astrocytic reactivity, which is critical to limiting severe astrogliosis and the formation of the glial scar90. Likewise, exposure of murine primary hippocampal neurons to 2 g hypergravity increased neurite number by 30% and neurite projection length by 20%. In addition, mature synaptic contacts were formed under hypergravity conditions in neurons of later developmental stages91. These data provide evidence that hypergravity ameliorates neuronal cell growth and synaptic plasticity in vivo. Whether the effects of hypergravity on the cellular level also translate to humans is unclear.However, data on the long-term benefits of prolonged use of rotating chambers on the human body are lacking. In addition, the design and technical implementation of AG using rotating chambers in spacecrafts remains a considerable challenge. In contrast to the continuous rotation of a spacecraft to mimic Earth’s gravity, an efficient comprise could be the use of a short-arm radius centrifuge92. Animal studies demonstrate that voluntary running increases synaptic plasticity and neurogenesis in the hippocampus93. The causal link between physical activity and hippocampal plasticity and cognitive benefits such as spatial memory performance has also been reported in a number of human studies96. The selective effects of AG and exercise on the brain suggest that the integrative approach of AG combined with exercise could go beyond affecting the cardiovascular and musculoskeletal system and also mitigate neurobehavioral risks associated with long-duration spaceflight in a highly efficient manner. While the hybrid approach of combining AG with physical exercise is promising it remains to be determined whether the benefits will go beyond exercise (or AG) per se and whether future crew vehicles will allow supporting the space and infrastructure of SAHC.Recent advances by space agencies are attempting to unravel the effects of AG on all organ systems including brain and behavior and to identify the most efficient protocols for using AG as a countermeasure. For instance, the NASA/ESA AGBRESA bed rest study carried out at DLR in 2019/2020 aimed to compare intermittent vs continuous AG exposures. Currently, ESA is carrying out two long-term bed rest studies investigating the effects of AG with different types of physical exercise. Specifically, the concept involves a hybrid approach of AG and physical exercise, i.e., exposing subjects to physical exercise while they are being centrifuged. Given the benefits of exercise across all organ systems, it is hypothesized that AG combined with physical exercise will interact in synergistically. With respect to the mitigation of neurobehavioral risks, it is noteworthy that physical exercise is also a potent stimulus for structural and functional brain plasticityFuture long-duration space expeditions will be among the most difficult, dangerous and complex operations in history. Astronauts will be required to stay physically and socially isolated in confined spaces for 30 months, and longer. It is expected that not all skills and knowledge required for these missions can be retained and retrieved based on pre-mission training alone. Limited and delayed communication will significantly constrain support from Mission Control and crews will increasingly rely on autonomous onboard technologies to successfully perform rendezvous maneuvers, and telerobotic operations post-landing. Augmented feedback and autonomous self-adaptative, just-in-time training of spaceflight-relevant tasks may help to maintain operational performance.Adaptive, just-in-time training relevant to these specific requirements could address this need by delivering tasks that adjust the difficulty level to the individual astronaut’s knowledge and skill learning curve. To mitigate this risk, research needs to identify the neural bases of key operational tasks, and design neuroscience-based adaptive visuomotor training programs that can be flexibly adapted to specific mission requirements and crew demands. These approaches should be characterized by (1) consolidating and improving sensorimotor skills relevant for inflight and post-landing operational tasks; (2) featuring an autonomous and adaptive training approach that does not rely on feedback from flight operations on ground; (3) maximizing the transfer of mission-relevant motor skills; (4) allowing the assessment of the neural circuitry underlying the task; and (5) delivering the training in a motivating and meaningful way to astronauts.98. The data of this work are promising, showing pointing performance improvements and supporting the idea to design human-machine interfaces leveraging haptic feedback98. The effects of a simulation of weightlessness (0 g) and hypergravity (1.8 g) on the same task parameters have also been investigated on ground . Remarkably, the simulation of gravitational fields different from 1 g applied locally to the effector produced effects that were comparable to immersion in an altered gravitational field99. These data demonstrate that the application of simple focal forces is sufficient to reproduce the effects of gravitational changes on relevant task parameters. In other words, more complex systems that simulate distributed force fields on the body, e.g., the upper arm, are not necessary. Together, the results underline the importance of the proprioceptive signals for the encoding of gravity, and also call for future research to better understand these effects with potential applications in robotic rehabilitation.How can human motor skills for operating human-machine interfaces such as controlers be maintained when gravitational levels change? Can fine skills be supported by manipulating vestibular and visual cues and controlling somatosensory and haptic information? Does the use of 1g-dynamics at the human/machine interface during altered gravity promote skill acquistion? Or would such feedback even impair learning and adaptation processes due to conflicting sensory information? Addressing these questions is complex because graviception and the internal representation of gravity is an integrative multimodal process. The basic rationale for using augmented feedback to maintain operational performance is that the central nervous system masters the motor control of complex tasks in 1 g. Delivering controler dynamics mimicking 1 g levels and/or providing haptic feedback could be expected to speed up learning and maintaining operational tasks. A few studies tested whether the simulation of a local terrestrial gravity (1 g) applied at the level of the hand improves pointing performance during altered gravity (0 g and 1.8 g)100. These promising results demonstrate that stochastic resonance represents a flexible and non-invasive technique that can be applied to a variety of scenarios beyond astronauts, including in ambulant elderly, skilled movements, sports, and to patients with sensorimotor or autonomic dysfunctions101.Finally, noise, like gravity, is also omnipresent in any environment and cannot be completed removed in the chain of physiological signal processing. Counter-intuitively, noise—or uncertainty in sensory signals—can be beneficial in some conditions. Stochastic resonance is a mechanism whereby a particular level of noise enhances the response of nonlinear systems to weak sensory signals. The effects of stochastic resonance on sensory modalities and, more particularly on somatosensory information have been demonstrated, paving the way toward its potential for improving sensorimotor performance as well as cognitive and autonomic functionsFuture research on the use of self-adaptive, automous operational training and augmented feedback will help to better understand the fundamentals of fine motor skill acquisition and adaptation, and provide insightful information on the optimal design and control of human-machine interfaces and wearable robots in space environments and other immersive dynamics.102. The variety of approaches, the consideration of phenotypic differences, and the dynamic nature of individual preferences for specific needs during long-duration expeditions will be critical to maximize the benefits and synergies of neurobehavioral countermeasures.The variety and specificity of neurobehavioral hazards and risks associated with spaceflight highlight the need for a combination of different approaches and methodologies to mitigate environmental and psychological stressors associated with prolonged space missions. These interventions comprise a range of methodologies, technologies, and approaches such as: self-adaptive training systems and augmented feedback to maintain operational performance; exercise and relaxation programs; schedules supporting sleep hygiene and maintaining regular work/rest cycles; engaging in meaningful work and learning; food, plant growth, VR sensory stimulation and entertainment; team building; family support; psychological counseling; balancing social and personal space; and habitat characteristics promoting health and well-being. Like personalized medicine, the administration of these measures should be based on the crewmembers’ individual needs instead of facilitating a single “one fits all” strategy applied to every crew member. Furthermore, the combination and prioritization of countermeasures should also be considered a dynamic process that varies within individuals and across time. In other words, the relative importance of specific strategies will vary during the course of a mission, requiring a constant reevaluation of the crewmembers’ individual needs. Stahn & Kühn (2021) referred to this concept as “Individualized Countermeasures” (ICount), which defines countermeasures as a dynamic construct that is optimized relative to the individual requirements as a function of mission duration. It requires the development of a systematic “toolbox” that combines a multiplicity of methodologies and approaches that can be flexibly utilized to meet crews’ individual needsFuture long-duration space missions will be considerably longer than current 6-month missions on ISS. Mitigating cognitive and behavioral risks during such missions is a high priority for successful mission completion requiring several strategies that are summarized in Box Together, the combination of various levels of knowledge, methodologies, and outcomes highlighted here could provide the basis to better understand and characterize the type, extent, cause, and mechanisms of neurobehavioral changes in response to spaceflight and their phenotypic signatures. The complexity, expertise, effort, and costs cannot be leveraged by a single experiment. However, the way spaceflight and spaceflight analog studies are typically conceptualized has already the potential to address such a framework. Space agencies solicit announcements of opportunities to propose specific experiments. Following peer-review, feasibility assessment, and a definition phase, a final protocol integrates several experiments that typically address a range of physiological and behavioral research questions, including but not limited to cardiovascular, musculoskeletal, vestibular, immunological, and neurobehavioral outcomes. It is intriguing that researchers and agencies could leverage the integrative nature of such platforms and projects. Such an approach goes beyond data use agreements between experiments but starts with the identification of deliverables using a hypothesis-driven rationale that promotes a holistic understanding of intellectual frameworks that together exceed the individual disciplinary perspectives.Box 1 Summary of key recommendations for mitigating operational performance deficits during exploration class missionsPromote an integrative research framework that allows to collect data across neural and behavioral dimensions that maximize the understanding of cognitive and operational performanceUnderstand sex as a biological variable: include the number of female astronauts being studiedBetter understand the internal representation of gravity, and its role in maintaining visuo-spatial abilities during changing gravity conditionsInvestigate the effects of spaceflight on spatial cognition and its neural basisEstablish brain imaging that goes beyond the identification of clinical manifestations, e.g., task functional MRI sequences that have high operational relevance and allow to quantify the neural basis of cognitive impairments, and predict future performance in navigation tasks, docking maneuvers, and other spaceflight-relevant behavioral measures.Develop cognitive tasks using a hypothesis-driven approach that are specifically targeted at the astronaut population and expected to be particularly vulnerable to spaceflightEnhance unobtrusive monitoring technologies to foster integrative data collection across neural and behavioral dimensionsConsider artificial gravity and individualized countermeasures as cornerstones for mitigating human spaceflight risksPromote data sharing and collaboration at all levels between researchers and agencies to leverage and maximize integrative research approach across disciplines103. Overarching aspects linking to all scientific disciplines are clear. The inaccessibility of operational performance data to the scientific community complicates the study of the relationships between physiological changes and potential performance deficits  during critical mission phases. Protocols should be established for the disclosure of operational performance data to qualified researchers. Promoting closer partnerships among the scientific, operations, and training communities could be an efficient step to pave this way. Furthermore, the development of a data repository archiving past experimental data sets and information on their contexts could be very valuable to enhance the usability of previous data .To efficiently leverage such integrative approaches national and international collaborations between researchers and space agencies will be increasingly critical104. Bed rest or dry immersion can be considered models of aging. Likewise, isolation studies can serve as models of social distancing associated with pandemics. Changes that typically evolve over years can be mimicked in time-lapse, providing unique opportunities to explore aging-related diseases and their prevention. In addition, the high standardization and control of these studies  could promote the understanding of causal relationships between inactivity, brain function, and cognitive alterations. Collectively, these characteristics can translate the knowledge gained from these studies to the prevention and treatment of various clinical conditions associated with cognitive impairments, for which reduced physical activity levels are a critical risk factor such as chronic heart failure, Type II diabetes, obesity, myotonic dystrophy, fibromyalgia, various types of cancer, depression, anxiety, and dementia.Understanding how the brain adapts to spaceflight and processes gravitational information to shape actions is a fundamental yet challenging question. Every step toward this ambitious objective will open new doors to unexplored arenas, all of which with the potential to bring innovation transferrable to terrestrial applications. Mobile miniaturized monitoring technologies developed for spaceflight could foster the unobtrusive collection of neurophysiological data to detect adverse neurobehavioral outcomes at an early stage, and potentially avoid clinical manifestations in response to environmental conditions, psychological stressors, and unhealthy life-styles. Spaceflight analogs provide unique settings that promote novel insights into brain and behavioral plasticity on Earth105. Technologies such as augmented feedback and virtual reality—also in combination with physical exercise—can help patients to accelerate recovery or serve as a training tool for promoting brain health106. Given the fundamental role of gravity on the human body the use of artificial gravity may open new avenues for promoting health and disease. In addition to short bouts of artificial gravity induces by short-arm human centrifuges, large rotating habitats that can house subjects for days could serve to better understand the effects of artificial gravity on the human organism, and potentially probe new interventions for modern epidemic health issues such as obesity, osteoporosis, sarcopenia, and cardiovascular deconditioning.In addition to better understanding such phenomena and their mechanisms spaceflight research can also boost innovative and efficient technologies for monitoring and predicting adverse neurobehavioral conditions, and promote the development of innovative treatment strategiesAs space-faring nations across the globe are fueling a new race of human space exploration that goes well beyond the Moon, national agencies and private entities across the globe have accelerated the research and development that will promote the safety and success of such missions. These missions will be some of the most difficult, dangerous, and dynamic operations in history, and considerably longer than current standard missions on ISS. Under current and notional NASA plans, crewed orbital missions to Mars could exceed 1,000 days, and exploration campaigns could even span decades. Such prolonged mission durations could introduce potential unprecedented astronauts’ health and performance risks. Adverse behavioral conditions and psychiatric disorders are considered one of the most serious but also least understood risks during such long-duration space missions. The effects of extreme environmental conditions and psychological stressors on brain and behavior are currently not fully understood. Future work in this field should be characterized by an interdisciplinary approach that promotes collaborations across space agencies, considers sex as a biological variable, and integrates multimodal brain imaging, psychological and behavioral, neurovestibular, cardiovascular, omics, sleep, and circadian data. Such an approach could promote a holistic understanding of intellectual frameworks that together exceed individual disciplinary perspectives. The knowledge from such approaches could go beyond their application to spaceflight and translate to the prevention and treatment of various clinical conditions on Earth including but not limited to neurogenerative diseases.