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Resistance Training and Muscle-Brain Crosstalk: Implications for Cognitive Decline in Aging and Spinal Cord Injury
Get PDFBackground and objectives: Exerkines are signalling factors that are released from organs throughout the body during physical exercise (El-Sayes et al., 2019). Some of these exerkines are thought to contribute to the well-documented benefits of exercise on brain health and cognitive function, potentially delaying age-related cognitive decline (Erickson et al., 2011). However, research is still far from establishing a mechanism-based, evidence-driven exercise programme to prevent such decline. To date, most studies have focused on endurance training, leaving other training modalities underexplored. Moreover, few studies have simultaneously examined exercise-induced effects on blood, brain, and cognitive domains, limiting more holistic understanding of the underlying mechanisms. Research has also primarily involved healthy adults, whereas older adults at risk of Mild Cognitive Impairment (MCI) are less frequently studied. Importantly, the effects of exercise on cognition have never been investigated in persons with Spinal Cord Injury (SCI), a population with an elevated risk of age-related cognitive decline and dementia.
The primary objective of the dissertation was therefore to gain a more comprehensive understanding of the mechanisms underlying the beneficial effects of exercise training, specifically resistance exercise in older adults and Neuromuscular Electrical Stimulation (NMES) in individuals with SCI, on brain health and cognitive function, with a particular focus on the role of exerkines in (exercise-induced) neuroplasticity.
Methods: Eleven studies were conducted. Study 1 was a literature review describing exerkine release following acute and chronic endurance or resistance exercise and their effects on neuroplasticity via long-term synaptic potentiation. Study 2 summarised the findings from transcriptome and secretome studies identifying muscle-derived exerkines (myokines). Studies 3 and 4 were cross-sectional studies in older adults (n = 74) investigating the relationships between participant characteristics, blood (inflammatory and neurotrophic) and brain biomarkers (neurometabolites, regional grey matter volumes), and cognitive function. Studies 5–8 evaluated the effect of a single bout (n = 37) and a 12-week resistance exercise programme (n = 74) on blood and brain biomarkers and cognitive function in older adults. Studies 6 and 7 further compared outcomes between cognitively healthy older adults and those at elevated risk of MCI (based on the Montreal Cognitive Assessment). Study 9 systematically reviewed evidence on the effects of exercise interventions on cognitive performance in individuals with SCI and highlighted factors underlying their elevated risk of cognitive decline. Study 10 tested the effect of a single bout of NMES on exerkines and cognitive performance in persons with SCI. Study 11 described the protocol of a 12-week NMES intervention in individuals with SCI to examine the effect on exerkines and cognitive outcomes.
Results: Study 1 identified 16 exerkines with known (in)direct effects on long-term synaptic potentiation. Study 2 reported 1,126 putative myokines, most with still unknown effects on the brain and body. Study 3 found associations between the circulating inflammatory marker kynurenine and signs of neuroinflammation and neurodegeneration in older adults. Study 4 showed that older adults with normal-to-slightly-elevated body weight and greater handgrip strength maintained larger brain volumes. Study 5 demonstrated improved working memory performance in older adults immediately after a single session of resistance exercise training compared to control group. Study 6 suggested hippocampal volume preservation over time in the resistance exercise group, and Study 7 revealed executive function improvements in older adults at elevated risk of MCI after 12 weeks of resistance training compared with control group. Study 8 demonstrated neurometabolic changes in older adults who contracted COVID-19 during participation. Study 9 confirmed that no prior studies have investigated exercise effects on cognitive function in individuals with SCI. Study 10 found increases in lactate levels, but no changes in cognitive performance after a single NMES session in persons with SCI. Study 11 described the design for a future 12-week NMES intervention study for individuals with SCI.
Conclusions: The dissertation advances the understanding of exercise effects on brain health and cognition in older adults and individuals with SCI, providing a neurobiological basis for future research. Kynurenine levels, handgrip strength, and a healthy body weight emerged as potential biomarkers of brain health for older adults. The findings underscore the importance of monitoring cognitive functioning in persons with SCI.
Although further research is needed to clarify the effect of different exercise modalities across populations with varying cognitive risk profiles, the present evidence reinforces the notion that physical exercise benefits brain function. A multimodal, enjoyable, and sustainable exercise programme maintained throughout life is likely to be the most effective strategy to mitigate or delay age-related cognitive decline.
Keywords: aging, cognition, myokines, exercise, spinal cord injur
Jėgos treniravimas ir raumenų-smegenų sąveika: smegenų silpimo pasekmės senėjimo ir nugaros smegenų sužalojimo atvejais.
No full textCognitive decline is inherent to aging [1]. It can manifest in various ways, including concentration difficulties, disorientation, slower information processing, frequently being unable to recall things, absent-mindedness, or forgetfulness, while the ability to use previously acquired knowledge, skills, and experiences generally remains intact [2]. Depending on individual and environmental factors, cognitive aging will sooner or later lead to a need for assistance [3]. Some major risk factors include educational level, physical inactivity, obesity, type 2 diabetes mellitus, smoking, high blood pressure, alcohol use, brain trauma, depression, air pollution, hearing loss, and social isolation. It is estimated that the prevalence of dementia could be reduced by 40% at the population level by eliminating these risk factors [4]. However, worldwide, the opposite trend is occurring. For example, the prevalence of physical inactivity increased by 5% between 2005 and 2017 [5], type 2 diabetes mellitus increased by 50% between 1990 and 2015 [6], and the prevalence of obesity rose by 300% between 1975 and 2014 [7]. A 2013 research article estimated that by 2025, the current healthcare system would no longer be able to provide necessary care due to the aging population and an increase in individuals living with chronic diseases if no additional efforts are made in prevention [8]. Exercise plays an important role in maintaining good physical and mental health. It has positive effects on nearly every body system, including the brain [9]. An improvement in cognitive functions has been confirmed in an impressive number of studies involving participants of all ages [10][11][12]. Despite this knowledge, which has been around for decades, there remains uncertainty and a lack of consensus on the underlying mechanisms [13]. An interesting finding was made in 2003 by Bente Pedersen’s research group in Denmark. They discovered that the cytokine interleukin-6 (IL-6) was released by muscle cells during contractions, triggering signaling cascades in other organs, and they called it a ‘myokine’ [14]. It later became clear that during exercise, thousands of factors enter the bloodstream from almost all body systems, each with its own local and/or systemic effects. These exercise-related factors were called ‘exerkines’ [15]. Only a limited number of these exerkines are known to have effects on the brain or to be associated with cognitive changes after exercise [16]. The function of most exerkines remains unknown. The primary goal of this dissertation was to gain more knowledge and understanding of the role of exerkines in promoting brain health and cognitive function after exercise in older adults. Research into the role of exerkines, and the mechanism underlying the effect of exercise on cognitive functioning in general, is essential for developing evidence-based exercise programs aimed at preventing age-related cognitive decline. For our intervention studies, we chose resistance training, as more research has been conducted on endurance training up till now, while some researchers argued that myokines might be released to a greater extent after resistance training compared to endurance training [17]. In addition, research was conducted on individuals with spinal cord injuries. In this population, neuromuscular electrical stimulation was chosen as an intervention, as it may release even higher amounts of myokines than resistance training [18][19]. In Part I of this dissertation, a literature review was conducted on the effects of exerkines on neuroplasticity. In the first study (Chapter 1), we detailed the signaling cascades activated by 16 exerkines with known (in)direct effects on long-term synaptic potentiation (LTP) [20]. LTP is a form of neuroplasticity at the level of the synaptic connection between two nerve cells. In these synaptic connections, a chemical reaction occurs that leads to the transmission of a nerve impulse from one nerve cell to the next. To reach the threshold at which a new nerve signal is generated in the following nerve cell, the chemical signal must be sufficiently strong. LTP increases the chemical signal released by the pre-synaptic nerve cell and lowers the threshold for transmitting the signal in the post-synaptic nerve cell [21]. Although the described signaling cascades are based on animal research, they can be seen as an indication of the neurobiological effects of exerkines at the molecular level. Therefore, this knowledge forms an important theoretical background for research into the effects of exerkines. Additionally, we described changes in exerkine levels in circulation after exercise from human studies and in the brain, primarily from animal studies. Overall, we can state that exerkines with neurotrophic or anti-inflammatory effects increased after a single session of exercise (acute exercise) and after exercise over several weeks (chronic exercise). Exerkines with pro-inflammatory effects also increased after acute exercise but decreased after chronic exercise. Thus, sustained exercise appears to have a neurotrophic and antiinflammatory effect, mediated by changes in exerkines. It is important to note that the effect of exercise depended on various influencing factors, such as the type of exercise (resistance training, endurance training, multimodal training, mind-body training, balance exercises, etc.), the intensity and duration of the training, or the volume of the exercise program, as well as weight loss associated with the intervention, age, gender, or comorbidities of the study participants. In a second article (Chapter 2), we described the protocol for a future literature review with meta-analysis [16]. In this review, we aim to systematically map the current state of knowledge regarding the role of myokines in cognitive functioning in older adults and, if possible, conduct an analysis of the mediating role of these myokines on cognitive functioning. We plan to update this article every six months over a minimum of five years post-publication. To be as comprehensive as possible, we developed a list of 1,126 potential myokines derived from various secretome and transcriptome studies on human skeletal muscle. After an initial literature analysis, we included 33 studies in the meta-analysis. The results are currently being analyzed. Part II of this dissertation contains the results of a cross-sectional analysis we conducted to investigate the relationship between baseline exerkine levels and signs of brain aging [22][23]. More specifically, we assessed the levels of inflammatory (interleukin-6, IL-6; kynurenine) and neurotrophic (insulin-like growth factor-1, IGF-1) factors in the blood of older adults and looked for associations with neurometabolic signs of neuroinflammation and neurodegeneration, as well as gray matter atrophy in the brain (Chapter 3). We then analyzed the influence of participants’ personal characteristics on blood factors and markers of brain aging (Chapter 4). Based on previous research, we specifically tested whether age, global cognition, body fat percentage, or characteristics of sarcopenia (muscle strength, muscle volume, and physical performance) in older adults were related to the levels of neurotrophic or inflammatory factors in the blood, total gray matter volume in the brain, and neurometabolic status and gray matter volumes of five selected brain regions [23]. We found the following: Older adults with underweight or obesity had lower total brain volumes. Additionally, lower handgrip strength was associated with lower total brain volumes. Furthermore, older adults with lower handgrip strength had lower levels of N-acetylaspartate in two of the five measured brain regions, the dorsal posterior cingulate cortex and the dorsolateral prefrontal cortex. Lower levels of this neurometabolite may indicate that fewer nerve cells are present per volume, a sign of neurodegeneration. Finally, lower handgrip strength was associated with higher levels of kynurenine in blood serum [23]. Higher kynurenine levels in blood serum were also associated with neurometabolic changes consistent with neuroinflammation and neurodegeneration [22]. This suggests that handgrip strength and kynurenine may potentially serve as proxy measures for assessing brain health [22][23]. Part III of this dissertation presents the results of our intervention studies in older adults. We investigated whether a lower-body resistance training intervention could influence circulating blood factors (IL-6, kynurenine, and IGF-1), neurometabolites related to neurodegeneration and neuroinflammation, subregional gray matter volume in the hippocampus, or cognitive performance in older adults, and whether there were relationships between changes in these outcomes in the intervention group. In the first intervention study (Chapter 5), we compared cognitive changes immediately after a single high-load resistance training session with a control group [24]. Cognition was tested using three computerized cognitive tasks and a balance-cognition dual-task [24]. In the dual-task, participants were asked to maintain balance while standing in tandem Romberg position on a force plate, while simultaneously solving a math problem. In this study, we confirmed that even a single session of resistance training led to immediate improvements in working memory. This acute effect of exercise has been found in other studies and generally lasts for 15-60 minutes. In a second intervention study (results are presented in Chapters 6 and 7), we evaluated the effect of a twelve-week moderate-tohigh-intensity resistance training intervention in seventy older adults with either intact cognitive function or an elevated risk of mild cognitive impairment (MCI) [25][26]. We discovered that older adults at higher risk of MCI had higher kynurenine levels and lower subiculum volumes (a part of the hippocampus) compared to cognitively healthy adults. We observed a non-significant increase in IL-6 levels and in total N-acetylaspartate levels in the hippocampus and a reduction in age-related decline of the gray matter volume of the dentate gyrus of the hippocampus, with a moderate effect size. The findings for hippocampus volume suggested that the intervention group experienced prevention of further volumetric loss rather than improvement. We can speculate that the effects might have been significant if the intervention had lasted longer. It is estimated that an intervention period of at least 6 months is necessary. This will need to be confirmed in future research. Finally, our results showed improvements in the Go/No-go test in the intervention group compared to the control group, but this effect depended on the cognitive status of the older adults and was only significant in those at high risk for MCI. The Go/No-go test is a cognitive inhibition test in which participants must respond as quickly as possible to a ‘Go’ signal, but withhold a response to a ‘No-go’ signal. It is a component of executive functioning. The twelve-week intervention study with older adults took place during the COVID-19 pandemic, which caused additional challenges in recruiting participants and continuing the experiments. Some older participants decided to withdraw from the experiment or had to stop due to illness. It is important to note that an infection with the COVID-19 virus (SARS-CoV-2) may have neurological consequences, which could have potentially affected our results. We had the opportunity to make a unique comparison of pre- and post-COVID-19 structural and neurometabolic brain measurements in three participants (Chapter 8) [27]. In this case series, we discovered neurometabolic changes in the hippocampus that could indicate neuroinflammation immediately after recovery from COVID-19. Finally, our research findings showed increased hippocampus volume in the experimental participants with COVID-19. In contrast with our statement above that hippocampal volume did not change in experimental group, at group level, but rather decreased in controls, this may indicate that on an individual basis some participants did show increases in volume following resistance exercise and this was not influenced by COVID-19. Part IV of this dissertation contains all studies related to individuals with spinal cord injuries. Chapter 9 consists of a literature review, in which we suggested that there is accelerated age-related cognitive decline in this population, likely caused at least in part by a chronic neuroinflammatory response originating from the location of the spinal cord injury [28]. Based on our previous findings and knowledge from older adults, we hypothesized that the anti-inflammatory and neurotrophic effects of exercise could prevent or delay cognitive decline in individuals with spinal cord injuries. However, a systematic review of this topic did not yield any intervention studies evaluating the relationship between exercise and cognition in this population [28]. Therefore, we conducted our first intervention study (Chapter 10) aimed at evaluating the acute effects of muscle training with low- or high-intensity neuromuscular electrical stimulation on lactate levels, IGF-1 levels, and information processing speed [29]. The study had a crossover design. We found that lactate increased significantly after both interventions. Lactate has previously been shown to have positive direct and indirect effects on neuroplastic processes in the brain [30][31]. However, we did not find a significant increase in IGF-1 or significant improvement in information processing speed. Additional findings showed that a longer time since the spinal cord injury was associated with smaller changes in IGF-1 in the low-intensity group, and a higher injury level was associated with smaller improvements in information processing speed. Using this information, we ultimately designed a new intervention study with a chronic (12-week) intervention using neuromuscular electrical stimulation (Chapter 11). This research is currently ongoing at Maastricht University, Netherlands, but the protocol for this study is included in this dissertation [32]. In conclusion, there is neuroscientific evidence for an effect of exerkines on synaptic plasticity in animal studies [1]. This suggests that exerkines may, at least in part, mediate the positive effects of exercise on cognitive functions. Elevated serum kynurenine levels and decreased handgrip strength are potential markers of brain aging in older adults. Older adults should aim for a healthy body fat percentage, as both underweight and obesity were associated with brain volume loss. Both a single session and a twelve-week resistance training intervention have positive effects on executive functioning in older adults, as demonstrated by a working memory task in healthy older adults and a cognitive inhibition task in older adults with high MCI risk, respectively. Increases in IGF-1 in the exercise group and IL-6 in the total group were associated with improvements in working memory. However, these findings need to be confirmed in larger and longer-duration studies. From the final part of this dissertation, we can conclude that individuals with spinal cord injuries experience accelerated cognitive aging, which may be partly caused by chronic neuroinflammation. To date, there are no studies that have examined the effects of exercise on cognitive functions or brain health in this population. We conducted a pilot study where the intervention consisted of a single session of neuromuscular electrical stimulation. We found an increase in lactate but no changes in IGF-1 or cognitive performance on an information processing speed test. Based on all that I have learned during the preparation of this dissertation, I would advise everyone to choose multimodal physical exercise in a motivating and enjoyable setting, so that exercise can be sustained throughout life and help prevent or mitigate cognitive aging
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Resistance training and muscle-brain crosstalk:implications for cognitive decline in aging and spinal cord injury
Get PDFThe aim of this thesis was to gain a deeper understanding of the relationship between a healthy brain and a healthy body, and the influence of physical exercise. This was specifically investigated in older adults and individuals with a spinal cord injury. Evidence was found that certain factors, measurable in the blood, form a connection between body and brain. On the one hand, there appears to be a link between inflammatory factors and brain aging, as measured by brain scans and cognitive tests. These inflammatory factors likely contribute to accelerated cognitive aging in individuals with a spinal cord injury compared to those without such an injury. On the other hand, factors with neurotrophic and anti-inflammatory effects on the brain are released from our muscles after physical exercise, which are associated with improvements in executive functioning. These factors are called myokines. Myokines may slow down the process of brain aging
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