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Abstract Background Vagally-mediated heart rate variability (vm-HRV) shows promise as a biomarker of internal training load (ITL) during exergame-based training or motor-cognitive training in general. This study evaluated the test-retest reliability of vm-HRV during exergaming in healthy older adults (HOA) and its validity to monitor ITL. Methods A within-subjects (repeated-measures) randomized study was conducted that included baseline assessments and 4 measurement sessions. Participants played 5 exergames at 3 standardized levels of external task demands (i.e., “easy”, “challenging”, and “excessive”) in random order for 90 s. Test-retest reliability was assessed on the basis of repeated-measures analyses of variance (ANOVA), intraclass correlation coefficients (ICC3,1), standard errors of measurement (SEM), and smallest detectable differences (SDD). Validity was determined by examining the effect of game level on vm-HRV in the ANOVA. Results Fourty-three HOA (67.0 ± 7.0 years; 58.1% females (25 females, 18 males); body mass index = 23.7 ± 3.0 kg·m−2) were included. Mean R-R time intervals (mRR) and parasympathetic nervous system tone index (PNS-Index) exhibited mostly good to excellent relative test-retest reliability with no systematic error. Mean SEM% and SDD% were 36.4% and 100.7% for mRR, and 44.6% and 123.7% for PNS-Index, respectively. Significant differences in mRR and PNS-Index were observed between standardized levels of external task demands, with mostly large effect sizes (mean r = 0.847). These results persisted irrespective of the type of neurocognitive domain trained and when only motoric and cognitive demands were manipulated while physical intensity was kept constant. The remaining vm-HRV parameters showed inconsistent or poor reliability and validity. Conclusion Only mRR and PNS-Index demonstrated reliable measurement and served as valid biomarkers for ITL during exergaming at a group level. Nonetheless, the presence of large SEMs hampers the detection of individual changes over time and suggests insufficient precision of these measurements at the individual level. Future research should further investigate the reliability and validity of vm-HRV with a specific focus on comparing different measurement methodologies and exercise conditions, particularly focusing on ultra-short-term HRV measurements, and investigate the potential implications (i.e., superiority to other markers of ITL or monitoring strategies?) of using vm-HRV as a biomarker of ITL.

Introduction A collaborative international guideline recommends physical exercise (PE) for the secondary prevention of mild neurocognitive disorder (mNCD; Veronese et al., 2023). PE is proposed to promote brain plasticity, maintain or increase cognitive reserve, and alleviate the pathological state in individuals with mNCD, which is characterized by an abnormal accumulation of proteins, excessive oxidative stress, metabolic disorder, and neuroinflammation within the brain (Lu et al., 2023). Individuals with mNCD often also have disrupted self-regulatory capacity to flexibly adapt to daily life challenges. This capacity is supported by the central autonomic network (CAN), which can be viewed as an integrated component of an internal regulatory system in which the brain controls visceromotor, neuroendocrine, and behavioral responses that are critical for goal-directed behavior, adaptability, and health (Thayer, 2009). To maximize the effectiveness of secondary prevention of mNCD, interventions should be designed to also target this network specifically. This could be achieved by combining motor-cognitive training with resonance breathing guided by heart rate variability biofeedback (HRV-BF). HRV-BF training aims to increase cardiac autonomic control, enhance homeostatic regulation, and regulate emotional state. It is effective in improving cardiac autonomic control, cognitive functioning (in particular executive functions), and emotional regulation (i.e., by decreasing symptoms of depression, anxiety, and stress) across different age groups and clinical populations (Laborde et al., 2022; Lehrer et al., 2020). Evidence also supports a causal role of cardiac autonomic control in modulating plasma Alzheimer’s disease-related biomarkers (Min et al., 2023). Although HRV-BF has been suggested as a complementary treatment (Lehrer et al., 2020), its combination with motor-cognitive training remains to be investigated. Methods We systematically designed, developed, and evaluated a novel training concept (called ‘Brain-IT’) specifically for older adults with mNCD. It addresses the mechanism of action described above. The projects’ methodology (Manser & de Bruin, 2021) followed the guidelines of the Medical Research Council for the development and evaluation of complex interventions as well as the Multidisciplinary Iterative Design of Exergames (MIDE) - Framework. The Brain-IT project was structured in three phases. In phase 1, we systematically combined a comprehensive literature synthesis (Manser & de Bruin, 2021) with qualitative research including primary end users (older adults with mNCD), secondary end users (physiotherapists, occupational therapists, healthcare professionals), exergaming researchers, as well as experts from the exergaming industry (Manser et al., 2023) to specify a set of design requirements for the Brain-IT training concept. In phase 2, possible concepts were co-designed and elaborated based on the set of design requirements defined in phase 1. The first prototype of the resulting Brain-IT training concept (Manser & de Bruin, 2021) then entered the iterative cycle of feasibility, usability, safety, and acceptance testing and integrating study results for further development based on co-design until an "acceptable" solution was achieved. In this regard, we conducted a pilot randomized controlled study (RCT) including 18 individuals with mNCD. (Manser et al., 2023) Finally, in phase 3, the effectiveness of the addition of the Brain-IT training to usual care to improve global cognitive functioning is investigated in a RCT including 41 individuals with mNCD (study protocol: Manser et al., 2023). As secondary objectives, the effects of the Brain-IT training on: (1) domain-specific cognitive functioning, (2) spatiotemporal parameters of gait, (3) instrumental activities of daily living and (4) psychosocial factors (i.e. quality of life, and levels of depression, anxiety, and stress), and (5) cardiac vagal modulation are explored. Additionally, brain structure and function is evaluated by magnetic resonance imaging to explore underlying neural changes of the training in relation to adaptations in cognitive performance. Results Ten secondary end users, exergaming researchers, and experts from the exergaming industry (80% females) and eight older adults with mNCD (38% females) contributed to the qualitative research (Manser et al., 2023) which allowed us to successfully integrate all the acquired knowledge of phase 1 to determine a set of design requirements (Manser & de Bruin, 2021). This set of design requirements built the basis for phase 2, where we developed a first prototype of the Brain-IT training concept. Our reflections on the design considerations and our proposed solutions are summarized in (Manser & de Bruin, 2021; Manser et al., 2023). The Brain-IT training concept represents a guideline for applying a combination of exergame-based motor-cognitive training and HRV-BF training by standardizing the training characteristics as well as the structure and content of training and can be implemented with different hardware and software solutions. For an overview, the Brain-IT training consists of a personalized and individually adapted multi-domain exergame-based simultaneous motor–cognitive training with incorporated cognitive tasks combined with HRV-BF training. It is adopted with a deficit-oriented focus on the neurocognitive domains of (1) learning and memory, (2) executive function, (3) complex attention, and (4) visuospatial skills. Each participant is instructed to train ≥ 5x/week for ≥ 24 min per session resulting in a weekly training volume of ≥120 min. All training sessions are planned to take place at participants’ homes. In this project, we used technology of Dividat AG, Polar, and Kubios Oy to implement our training concept. In the pilot RCT we showed that Brain-IT training is feasible (mean adherence and compliance rates of 85.0 and 84.1%, respectively) and usable (mean system usability scale = 71.7 ± 15.4). In addition, high levels of exergame enjoyment, an increase in exergame enjoyment, and internalization of training motivation with large effect sizes (p = 0.03, r = 0.75 and p = 0.03, r = 0.74, respectively), as well as acceptable perceived usefulness were observed. Phase 3 is ongoing. To date, 41 participants were included into the study, of which two withdrew consent before pre-measurements, two dropped-out during intervention (one in each group), and 29 (72.6 ± 9.3 years; 24.1% females) successfully completed the study. Preliminary data suggest significant effects with large effects sizes in favor of the intervention group for global cognitive functioning (F(1, 29) = 4.692, p = 0.039, partial η2 = 0.153) as well as immediate (F(1, 29) = 6.501, p = 0.018, partial η2 = 0.213) and delayed (F(1, 29) = 5.227, p = 0.031, partial η2 = 0.179) verbal recall. The remaining (underpowered) statistical analyses revealed no significant effects, but favorable changes in descriptive statistics with small to moderate effects in favor of the intervention group, especially with regards to quality of life. Discussion/Conclusion The development of novel (exergame-based) training concepts is greatly facilitated when it is based on a theoretical framework. Applying the MIDE-framework resulted in a structured, iterative, and evidence-based approach that led to the identification of multiple key requirements for the exergame design as well as the training components that otherwise may have been overlooked or neglected. This resulted in a user-centered, personalized, and highly innovative training concept that is feasible, usable, and highly accepted by individuals with mNCD. Preliminary data regarding the effectiveness of the intervention is promising, suggesting that the training significantly improved global cognitive functioning, verbal immediate, and delayed recall with large effect sizes, and tends to be beneficial in improving quality of life. To be able to conclude about the effectiveness of the Brain-IT training concept, a full-scale confirmatory randomized controlled superiority trial is warranted. References Laborde, S., Aelle, M. S., Borges, U., Dosseville, F., Hosang, T. J., Iskra, M., Mosley, E., Salvotti, C., Spolverator, L., Zammit, N., & Javelle, F. (2022). Effects of voluntary slow breathing on heart rate and heart rate variability: A systematic review and a meta-analysis. Neuroscience & Biobehavioral Reviews, 138, Article 104711. https://doi.org/10.1016/j.neubiorev.2022.104711 Lehrer, P., Kaur, K., Sharma, A., Shah, K., Huseby, R., Bhavsar, J., Sgobba, P., & Zhang, Y. (2020). Heart rate variability biofeedback improves emotional and physical health and performance: A systematic review and meta analysis. Applied psychophysiology and biofeedback, 45(3), 109-129. https://doi.org/10.1007/s10484-020-09466-z Lu, Y., Bu, F.-Q., Wang, F., Liu, L., Zhang, S., Wang, G., & Hu, X.-Y. (2023). Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction. Translational Neurodegeneration, 12(1), 9. https://doi.org/10.1186/s40035-023-00341-5 Manser, P., Adcock-Omlin, M., & de Bruin, E. D. (2023). Design considerations for an exergame-based training intervention for older adults with mild neurocognitive disorder: Qualitative study including focus groups with experts and health care professionals and individual semistructured in-depth patient interviews. JMIR Serious Games, 11, Article e37616. https://doi.org/10.2196/37616 Manser, P., & de Bruin, E. D. (2021). Making the best out of it: Design and development of exergames for older adults with mild neurocognitive disorder - A methodological paper . Front in Aging Neuroscience, 13, Article 734012. https://doi.org/10.3389/fnagi.2021.734012 Manser, P., Michels, L., Schmidt, A., Barinka, F., & de Bruin, E. D. (2023). Effectiveness of an individualized exergame-based motor-cognitive Training concept targeted to improve cognitive functioning in older adults with mild neurocognitive disorder: Study protocol for a randomized controlled trial. JMIR Resarch Protocols, 12, Article e41173. https://doi.org/10.2196/41173 Manser, P., Poikonen, A., & de Bruin, E. D. (2023). Feasibility, usability, and acceptance of “Brain-IT”—A newly developed exergame-based training concept for the secondary prevention of mild neurocognitive disorder: A pilot randomized controlled trial [Original Research]. Frontiers in Aging Neuroscience, 15, Article 1163388. https://doi.org/10.3389/fnagi.2023.1163388 Min, J., Rouanet, J., Martini, A. C., Nashiro, K., Yoo, H. J., Porat, S., Cho, C., Wan, J., Cole, S. W., Head, E., Nation, D. A., Thayer, J. F. & Mather, M. (2023). Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults. Scientific Reports, 13(1), Article 3967. https://doi.org/10.1038/s41598-023-30167-0 Thayer, J. F. (2009). Heart rate variability: A neurovisceral integration model. In L. R. Squire (Ed.), Encyclopedia of Neuroscience (pp. 1041-1047). https://doi.org/10.1016/B978-008045046-9.01991-4 Veronese, N., Soysal, P., Demurtas, J., Solmi, M., Bruyère, O., Christodoulou, N., Ramalho, R., Fusar-Poli, P., Lappas, A. S., Pinto, D., Steen Frederiksen, K., Corbi, G. M., Karpenko, O., Georges, J., Durães, J., Schlögl, M., Yilmaz, O., Sieber, C., Shenkin, S. D., Smith, L., Reginster, J.-Y., … & World Psychiatry Association-Preventive Psychiatry Section. (2023). Physical activity and exercise for the prevention and management of mild cognitive impairment and dementia: a collaborative international guideline. European Geriatric Medicine, 14(5), 925-952. https://doi.org/10.1007/s41999-023-00858-y

BackgroundExergames provide a promising new approach to implement simultaneous motor–cognitive training, which may support preventing the decline in cognitive functioning in older adults who have a mild neurocognitive disorder (mNCD).ObjectivesTo evaluate feasibility, system usability, and acceptance of “Brain-IT”, a newly developed training concept combining exergame-based motor-cognitive training and heart rate variability (HRV) guided resonance breathing for the secondary prevention of mNCD.MethodsA pilot randomized controlled trial (RCT) with an allocation ratio of 2:1 (i.e., intervention:control) was conducted. The control group proceeded with usual care. The intervention group performed a 12-week training according to the “Brain-IT” training concept implemented with the “Senso Flex” (Dividat AG) exergaming system in addition to usual care. Feasibility and usability outcomes were analyzed using descriptive statistics. User acceptance was analyzed qualitatively and using Friedman analysis of variance (ANOVA), as well as Wilcoxon signed-rank tests.ResultsEighteen participants (77.3 ± 9.8 years; 44.4% females) were included. On average, we recruited 2.2 participants per month, and 35.3% of the individuals contacted were included. The intervention group had an attrition rate of 20% and mean adherence and compliance rates of 85.0 and 84.1%, respectively. The mean system usability score, measured with the system usability scale, was 71.7. High levels of exergame enjoyment, an increase in exergame enjoyment, and internalization of training motivation with large effect sizes (p = 0.03, r = 0.75 and p = 0.03, r = 0.74, respectively), as well as acceptable perceived usefulness, were observed. Preliminary data on the effects of the “Brain-IT” training are promising.ConclusionThe feasibility and usability of the “Brain-IT” training are acceptable. However, frequent occurrences of technical problems and difficulties in using the exergame training system were identified as barriers to performing the “Brain-IT” training. To optimize feasibility, either improvements or alternative solutions are required in the hardware and software of the exergame used to implement the “Brain-IT” training. The “Brain-IT” training itself was well-accepted by older adults who have mNCD. Therefore, the effectiveness of the “Brain-IT” training concept should be investigated in future studies.Trial registrationclinicaltrials.gov/ct2/show/NCT04996654.

Background: Utilizing information technology (IT) systems, for example in form of computerized cognitive screening or exergame-based (also called active videogames) training, has gained growing interest for supporting healthy aging and to detect, prevent and treat neurocognitive disorders (NCD). To ameliorate the effectiveness of exergaming, the neurobiological mechanisms as well as the most effective components for exergame-based training remain to be established. At the same time, it is important to account for the end-users’ capabilities, preferences, and therapeutic needs during the design and development process to foster the usability and acceptance of the resulting program in clinical practice. This will positively influence adherence to the resulting exergame-based training program, which, in turn, favors more distinct training-related neurobiological effects.Objectives and Methods: This methodological paper describes the design and development process of novel exergame-based training concepts guided by a recently proposed methodological framework: The ‘Multidisciplinary Iterative Design of Exergames (MIDE): A Framework for Supporting the Design, Development, and Evaluation of Exergames for Health’ (Li et al., 2020).Case Study: A step-by-step application of the MIDE-framework as a specific guidance in an ongoing project aiming to design, develop, and evaluate an exergame-based training concept with the aim to halt and/or reduce cognitive decline and improve quality of life in older adults with mild neurocognitive disorder (mNCD) is illustrated.Discussion and Conclusion: The development of novel exergame-based training concepts is greatly facilitated when it is based on a theoretical framework (e.g., the MIDE-framework). Applying this framework resulted in a structured, iterative, and evidence-based approach that led to the identification of multiple key requirements for the exergame design as well as the training components that otherwise may have been overlooked or neglected. This is expected to foster the usability and acceptance of the resulting exergame intervention in “real life” settings. Therefore, it is strongly recommended to implement a theoretical framework (e.g., the MIDE-framework) for future research projects in line with well-known checklists to improve completeness of reporting and replicability when serious games for motor-cognitive rehabilitation purposes are to be developed.

Background: Monitoring phasic responses of heart rate variability (HRV) in terms of HRV reactivity [i. e., the absolute change from resting state to on-task (i.e., absolute values of HRV measured during exercise)] might provide useful insights into the individual psychophysiological responses of healthy middle-aged to older adults (HOA) to cognitive and physical exercises.Objectives: To summarize the evidence of phasic HRV responses to cognitive and physical exercises, and to evaluate key moderating factors influencing these responses.Methods: A systematic review with meta-analyses was performed. Publications up to May 2020 of the databases Medline (EBSCO), Embase, Cochrane Library, CINAHL, Psycinfo, Web of Science, Scopus, and Pedro were considered. Controlled clinical trials and observational studies measuring phasic HRV responses to cognitive and/or physical exercises in HOA (≥50 years) were included.Results: The initial search identified 6,828 articles, of which 43 were included into the systematic review. Compared to resting state, vagally-mediated HRV indices were significantly reduced during all types of exercises [Hedge's g = −0.608, 95 % CI (−0.999 to −0.218), p = 0.002] indicating a significant parasympathetic withdrawal compared to rest. The key moderating variables of these responses identified included exercise intensity for physical exercises, and participant characteristics (i.e., level of cognitive functioning, physical fitness), task demands (i.e., task complexity and modality) and the individual responses to these cognitive challenges for cognitive exercises. In particular, higher task demands (task complexity and physical exercise intensity) were related to larger HRV reactivities. Better physical fitness and cognition were associated with lower HRV reactivities. Additionally, HRV reactivity appeared to be sensitive to training-induced cognitive and neural changes.Conclusion: HRV reactivity seems to be a promising biomarker for monitoring internal training load and evaluating neurobiological effects of training interventions. Further research is warranted to evaluate the potential of HRV reactivity as a monitoring parameter to guide cognitive-motor training interventions and/or as a biomarker for cognitive impairment. This may facilitate the early detection of cognitive impairment as well as allow individualized training adaptations that, in turn, support the healthy aging process by optimizing individual exercise dose and progression of cognitive-motor training.