Scientists have collected plenty of evidence linking exercise to brain health, with some research suggesting fitness may even improve memory.
But what happens during exercise to trigger these benefits?
New UT Southwestern research that mapped brain changes after one year of aerobic workouts has uncovered a potentially critical process:
Exercise boosts blood flow into two key regions of the brain associated with memory. Notably, the study showed this blood flow can help even older people with memory issues improve cognition, a finding that scientists say could guide future Alzheimer’s disease research.
“Perhaps we can one day develop a drug or procedure that safely targets blood flow into these brain regions,” says Binu Thomas, Ph.D., a UT Southwestern senior research scientist in neuroimaging.
“But we’re just getting started with exploring the right combination of strategies to help prevent or delay symptoms of Alzheimer’s disease. There’s much more to understand about the brain and aging.”
Blood flow and memory
The study, published in the Journal of Alzheimer’s Disease, documented changes in long-term memory and cerebral blood flow in 30 participants, each of them 60 or older with memory problems. Half of them underwent 12 months of aerobic exercise training; the rest did only stretching.
The exercise group showed 47 percent improvement in memory scores after one year compared with minimal change in the stretch participants. Brain imaging of the exercise group, taken while they were at rest at the beginning and end of the study, showed increased blood flow into the anterior cingulate cortex and the hippocampus—neural regions that play important roles in memory function.
Other studies have documented benefits for cognitively normal adults on an exercise program, including previous research from Thomas that showed aging athletes have better blood flow into the cortex than sedentary older adults. But the new research is significant because it plots improvement over a longer period in adults at high risk to develop Alzheimer’s disease.
“We’ve shown that even when your memory starts to fade, you can still do something about it by adding aerobic exercise to your lifestyle,” Thomas says.
Mounting evidence
The search for dementia interventions is becoming increasingly pressing: More than 5 million Americans have Alzheimer’s disease, and the number is expected to triple by 2050.
Recent research has helped scientists gain a greater understanding of the molecular genesis of the disease, including a 2018 discovery from UT Southwestern’s Peter O’Donnell Jr. Brain Institute that is guiding efforts to detect the condition before symptoms arise.
Yet the billions of dollars spent on researching how to prevent or slow dementia have yielded no proven treatments that would make an early diagnosis actionable for patients.
UT Southwestern scientists are among many teams across the world trying to determine if exercise may be the first such intervention.
Evidence is mounting that it could at least play a small role in delaying or reducing the risk of Alzheimer’s disease.
For example, a 2018 study showed that people with lower fitness levels experienced faster deterioration of vital nerve fibers in the brain called white matter. A study published last year showed exercise correlated with slower deterioration of the hippocampus.
Regarding the importance of blood flow, Thomas says it may someday be used in combination with other strategies to preserve brain function in people with mild cognitive impairment.
“Cerebral blood flow is a part of the puzzle, and we need to continue piecing it together,” Thomas says. “But we’ve seen enough data to know that starting a fitness program can have lifelong benefits for our brains as well as our hearts.”
Walk, learn, be active, do! A large number of messages about healthy behaviors to reduce age-related functional decline has flooded into our daily lives. Aging is related to major risk of cardiovascular diseases, metabolic syndrome, mitochondrial dysfunction, obesity, sarcopenia, and consequent higher inflammation, oxidative stress, and brain and cognitive impairment (Sallam and Laher, 2016).
Healthy aging has become a matter of interest for the scientific community and for most people and governments that stand for social health policies. Since the aged population is expected to triple by 2100 and will represent 29% of people in the world (United Nations Department of Economic Social Affairs Population Division, 2017), we need policies and strategies that enhance independence and quality of life while considering economic, social, environmental, and personal determinants as well as health and social services (World Health Organization [WHO], 2002, 2015).
Cognitive training and aerobic exercise are two lifestyle interventions that have proved to produce positive effects on health (Cotman et al., 2007; Sallam and Laher, 2016), reduce cognitive impairment (Harada et al., 2013), and delay the onset of dementia (Hall et al., 2009). However, questions about which, when and why remain unclear.
Gates and Valenzuela (2010) define cognitive training as an intervention consisting of repeated practice of standardized exercises targeting a specific cognitive domain or domains. Computerized cognitive training (CCT) has emerged as a new tool to systematically apply these exercises. CCT facilitates the administration by allowing investigators to adapt the content and challenge of the task to individual performance and including visual engaging interfaces (Lampit et al., 2014; Shao et al., 2015).
There is evidence that CCT may maintain or improve global cognitive function and specific trained functions such as verbal memory (Shao et al., 2015; Barban et al., 2016; Bahar-Fuchs et al., 2017), processing speed (Kueider et al., 2012; Lampit et al., 2014; Shao et al., 2015), and executive function (Kueider et al., 2012; Barban et al., 2016).
Brain related benefits such as increases in gray matter volume of default-mode network (DMN) areas (De Marco et al., 2016), functional activity of frontal-parietal networks (Klingberg, 2010; Jolles et al., 2013; Kim et al., 2017) and connectivity of the hippocampus (Lisanne et al., 2017) and posterior DMN (De Marco et al., 2016) have also been described. These structural and functional changes appear to be directly related to the types of trained tasks (Taya et al., 2015).
Despite this, the biological pathways by which CCT produces these effects remain poorly understood in humans. Shao et al. (2015) hypothesized that these mechanisms might be related to brain neuroplasticity. According to Hebb (1949), a group of neurons that are repeatedly and simultaneously activated will tend to form stronger associations.
This framework suggests that CCT may influence cognition by promoting the strength of synaptic connections (Patterson et al., 1996; Taya et al., 2015).
Based on animal models, Valenzuela and Sachdev (2009) suggested that brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) might be the molecules promoting cell survival and proliferation after cognitive stimulation in humans.
Physical activity (PA), defined as any body movement produced by skeletal muscles that results in energy expenditure (Caspersen et al., 1985), promotes health, cognitive and psychological benefits (DiLorenzo et al., 1999; Penedo and Dahn, 2005).
Exercise, which is considered a planned, structured and repetitive subtype of PA that aims to improve physical fitness (Caspersen et al., 1985), produces an acute body reaction that includes increased energy expenditure, repetitive muscle contractions and an inflammatory and oxidative response (van Praag et al., 2014; Sallam and Laher, 2016).
Different types of exercise, applied in a regular manner, may produce different physiological, brain and cognitive benefits (Barha et al., 2017; Cabral et al., 2019). Several systematic reviews conclude that aerobic exercise (AE), the type of exercise that involves oxygen consumption and movement of large groups of skeletal muscles during a sustained period of time (Chodzko-Zajko et al., 2009; Thomas et al., 2012), may improve executive function, processing speed, attention and memory in healthy older adults (Etnier et al., 1997; Colcombe and Kramer, 2003; Paterson and Warburton, 2010; Smith et al., 2010; Guiney and Machado, 2012; Karr et al., 2014; Scherder et al., 2014; Lü et al., 2016; Barha et al., 2017; Northey et al., 2017).
However, other reviews reported that the evidence was too limited to draw firm conclusions (Snowden et al., 2011; Cox et al., 2016; Brasure et al., 2017; Sáez de Asteasu et al., 2017) or reported no significant effects of exercise on cognition (Angevaren et al., 2007; Kelly et al., 2014; Young et al., 2015).
Regular AE has direct effects on our body: higher oxygen and glucose consumption related to increased energy expenditure, and reduction of body fat and increased muscle strength, which have been hypothesized as specific pathways for the physiological relationship between exercise and cognitive function (Cotman et al., 2007; van Praag et al., 2014; Sallam and Laher, 2016; Stimpson et al., 2018).
The increase of energy expenditure reduces visceral fat that may lead to less production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and an increase of M2:M1 macrophage ratio and the release of adiponectin.
Energy expenditure is also related to higher glucose consumption which may be related to better energy metabolism and insulin sensitivity and reducing resistance to leptin and insulin (van Praag et al., 2014).
The activity in the muscles induces IL-ra, IL-10, and heat shock proteins (HSP), reducing the inflammatory environment while suppressing IL-1 and TNF-alpha and upregulating IL-15 and promoting the reparation of the vessels to facilitate blood flow and, as a consequence, oxygen and nutrient circulation (Sallam and Laher, 2016).
Skeletal muscles may also improve the use of lipids instead of glycogen in energy expenditure processes. Exercise increases circulating HDL and reverses cholesterol transport, reducing cholesterol levels in blood (Mann et al., 2013).
The activity in the cardiovascular system produces laminar shear stress on vascular endothelial cells which may be related to the downregulation of oxidative processes, and activates the hypothalamic-pituitary-adrenal axis which triggers the release of glucocorticoids that may help to inhibit the inflammatory system.
The anti-oxidative response is mediated by redox-sensitive transcription factors: NF-KB and AP-1, which reduce RONS, and PGC-1, which promotes mitochondrial biogenesis (Sallam and Laher, 2016).
Laminar shear stress is also related to greater release of insulin growth factor (IGF) and vascular endothelial factor (VEGF) which benefits the cardiovascular system, helping to repair the body vasculature and promoting greater blood flow, brain angiogenesis and neurogenesis (Cotman et al., 2007; Sallam and Laher, 2016; Stimpson et al., 2018; Cabral et al., 2019).
IGF promotes the release of BDNF in the brain, which has been identified as one of the principal factors mediating the effect of exercise on cognition. BDNF may support newborn cells, regulate synaptic changes and facilitate long-term potentiation which may be related to the identified brain changes and cognitive benefits (Stimpson et al., 2018; Cabral et al., 2019).
Cardiorespiratory fitness (CRF), the health-related component of physical fitness reflecting these parameters, has shown to be related to better cognitive function in healthy adults (Colcombe and Kramer, 2003). However, Etnier et al. (2006) and Young et al. (2015) could not find the relationship between changes in CRF and changes in cognition in their systematic reviews.
Erickson et al. (2014) found a positive relationship between PA or CRF and gray matter volume in older adults in prefrontal, temporal and parietal areas (Erickson et al., 2007; Gordon et al., 2008; Weinstein et al., 2012). Higher levels of CRF have been also related to greater hippocampus volume and memory performance (Erickson et al., 2009; Szabo et al., 2011) and bigger caudate nucleus and nucleus accumbens (Verstynen et al., 2012). However, Rosano et al. (2010) and Smith et al. (2011) did not find a significant association between PA and gray matter volume.
Sexton et al. (2016) systematically reviewed the effects of exercise on white matter volume – global, local, lesions, and microstructure – and found cautious support for this association given the fact that evidence was inconsistent.
Recent research aims to identify the effect of exercise on functional connectivity. CRF has been associated with higher general efficiency and lower local efficiency and executive function performance (Kawagoe et al., 2017). Brain network modularity at baseline may predict the effects of exercise intervention (Baniqued et al., 2018).
Other variables have been identified as potential modifiers of the association between exercise and cognition. Groups with a higher percentage of women (Barha and Liu-Ambrose, 2018) or APOE E4 genotype carriers (Etnier et al., 2007) may benefit more from exercise.
The combination (COMB) of PA and cognitive stimulation may induce greater cognitive benefits compared to each intervention separately (Kraft, 2012; Curlik and Shors, 2013; Fissler et al., 2013; Bamidis et al., 2014; Law et al., 2014; Lauenroth et al., 2016).
However, Shatil (2013) found improvements only on those participants engaged in cognitive training, single or combined. Zhu et al. (2016) replicated these results in a systematic review of twenty studies, concluding that COMB may have a small positive effect only when compared to a control and physical activity group but not to a cognitive intervention.
To our knowledge, the specific cognitive benefits of COMB, in sequence or dual task, remain unknown; undefined “greater effects” or “more enduring” are usually hypothesized. General cognitive function (Oswald et al., 2006; Shatil, 2013), executive function (Anderson-Hanley et al., 2012; Theill et al., 2013; Barcelos et al., 2015; Eggenberger et al., 2015), processing speed (León et al., 2015), memory (Fabre et al., 2002) and vocabulary (Schmidt-Kassow et al., 2013) performance may tend to benefit more from a COMB.
However, evidence is not consistent across trials and negative results have also been found in these same domains (Fabre et al., 2002; Oswald et al., 2006; Legault et al., 2011; Anderson-Hanley et al., 2012; Linde and Alfermann, 2014; Rahe et al., 2015). Li et al. (2014) and Pieramico et al. (2012) reported that a multimodal intervention produced a reorganization of functional connectivity between the DMN areas. Shah et al. (2014) identified higher verbal memory related to increased glucose metabolism in the brain in the COMB group only.
In order to explain these potential greater benefits, Olson et al. (2006) and Fabel et al. (2009), based on animal models, hypothesized that neuroplasticity may be facilitated by exercise and guided by cognitive training.
The anti-inflammatory, anti-oxidative stress and cardiovascular and neural repairing responses related to regular PA may enhance cell proliferation through BDNF.
Cognitive stimulation may promote the survival of newborn cells and regulate synaptic changes (Hebb, 1949).
Systematic reviews and papers cited before, independently of the intervention, reported inconsistencies across results which likely relate to genetic and environmental variables of participants; type, duration and schedule of assessments; type, duration, frequency, intensity and adherence of interventions; as well as methodological issues of the design, such as type of control group and statistical approaches (Kraft, 2012; Young et al., 2015; Gates et al., 2019).
These discrepancies challenge a clear theoretical model and lead to different conclusions and the identification of potential moderators even at the systematic and meta-analytic analysis level. These issues highlight the need to better identify not only the cognitive effects of these interventions but also the individual variables that may predict them and the brain changes and physiological molecular correlates that may be mediating any benefits.
Projecte Moviment is a multi-domain randomized trial that addresses the effect of CCT, AE, and COMB on cognition and psychological status in healthy physically inactive older adults compared to a passive control group.
We also aim to identify variables that may predict the effects of the intervention and the underlying brain changes and physiological molecular correlates that may mediate the effects. The purpose of this paper is to describe the protocol in accordance with SPIRIT Guidelines.
Aims of the Study
The primary objective of Projecte Moviment is to examine the effect of CCT, AE, or COMB on cognitive outcomes in healthy physically inactive older adults. The primary hypotheses sustaining this goal are:
- 1.Computerized cognitive training – 5 times per week for 3 months – will improve general cognitive function as well as trained cognitive functions (executive function, processing speed and memory) measured by composite scores using a battery of validated neuropsychological tests at 3 months compared to a control group.
- 2.Aerobic exercise – 5 times per week for 3 months – will improve executive function, attention-processing speed and memory measured by composite scores using a battery of validated neuropsychological tests at 3 months compared to a control group.
- 3.Combined training – 5 times per week for 3 months – will show greater improvements in general cognitive function, executive function, attention-processing speed and memory measured by composite scores using a battery of validated neuropsychological tests at 3 months compared to a control group.
The secondary objectives of Projecte Moviment are: (a) to determine the effects of these interventions on psychological status and subjective performance on daily activities, CRF, brain structure and function and physiological molecular correlates; (b) to identify genetic, demographic, physiological and brain variables that might predict the effect of the intervention; (c) to identify the association between cognitive effects and other psychological, physiological correlates. Specific hypotheses for each objective will be specified in each article when reporting results. General secondary hypotheses include:
- 1.All intervention conditions will positively impact psychological and subjective daily functional performance assessed by questionnaires compared to controls.
- 2.Aerobic exercise and COMB will similarly increase CRF and energy expenditure in daily activity compared to cognitive and control conditions.
- 3.All intervention conditions will positively impact the structure and function of the brain assessed by whole brain analyses, structures of interest and white matter lesions volume and microstructure, cortical thickness and functional connectivity compared to a control group.
- 4.Aerobic exercise and COMB will improve immunity, reduce inflammation and improve vascular risk factors compared to cognitive and control conditions.
- 5.Individual variables (i.e., sex, age, cognitive baseline, CRF baseline) will predict the effect of the interventions on cognition.
- 6.Changes in cognition will be related to specific changes in secondary outcomes depending on the intervention.
Journal information:Journal of Alzheimer’s Disease
