Brain Resilience Imagens

REVIEW
published: 20 January 2021

doi: 10.3389/fnbeh.2020.626769
The Contribution of Physical Exercise

to Brain Resilience
Ricardo Mario Arida 1* and Lavinia Teixeira-Machado 2
1
Department of Physiology, Federal University of São Paulo, São Paulo, Brazil, 2 Department of Education in Health, Federal
University of Sergipe, Sergipe, Brazil
Increasing attention has been given to understanding resilience to brain diseases, often
described as brain or cognitive reserve. Among the protective factors for the development
of resilience, physical activity/exercise has been considered to play an important role.
Exercise is known to induce many positive effects on the brain. As such, exercise
represents an important tool to influence neurodevelopment and shape the adult brain
to react to life’s challenges. Among many beneficial effects, exercise intervention has
been associated with cognitive improvement and stress resilience in humans and animal
models. Thus, a growing number of studies have demonstrated that exercise not only
recovers or minimizes cognitive deficits by inducing better neuroplasticity and cognitive
reserve but also counteracts brain pathology. This is evidenced before disease onset
Edited by:
or after it has been established. In this review, we aimed to present encouraging data
Juliana Nery Souza-Talarico, from current clinical and pre-clinical neuroscience research and discuss the possible
University of São Paulo, Brazil
biological mechanisms underlying the beneficial effects of physical exercise on resilience.
Reviewed by:
We consider the implication of physical exercise for resilience from brain development
Joerg Bock,
Otto von Guericke University to aging and for some neurological diseases. Overall, the literature indicates that
Magdeburg, Germany brain/cognitive reserve built up by regular exercise in several stages of life, prepares the
Olga Mikhailovna Bazanova,
State Research Intstitute of
brain to be more resilient to cognitive impairment and consequently to brain pathology.
Neuroscience and Medicine, Russia
Keywords: brain reserve, cognitive reserve, physical activity, exercise, neurological disorders, neuroprotection,
*Correspondence: stress, brain resilience
Ricardo Mario Arida
[email protected];
[email protected] INTRODUCTION
Specialty section: Stressful life events can have a considerable impact on brain function and structure, resulting
This article was submitted to in the development of several psychiatric disorders (Ludwig et al., 2018; Chow and Choi, 2019).
Individual and Social Behaviors,
Interestingly, most individuals do not develop such illnesses after experiencing stressful life events
a section of the journal
and are thus thought to be resilient. Resilience is defined as the capacity to adapt successfully to
Frontiers in Behavioral Neuroscience
acute stress, trauma, or chronic adversity (Russo et al., 2012). In this context, researchers have
Received: 06 November 2020
introduced the concept of brain resilience, often described as brain reserve or cognitive reserve
Accepted: 23 December 2020
(Medaglia et al., 2017). Brain reserve is related to the structural properties of the brain (brain
Published: 20 January 2021
volume, the number and size of neurons, cortical thickness) and cognitive reserve refers to a
Citation:
process where the brain copes with brain pathology. Reserve of either type expresses alteration in
Arida RM and Teixeira-Machado L
(2021) The Contribution of Physical
the function or structure of the brain that modifies cognitive and behavioral capacities following
Exercise to Brain Resilience. brain damage (for review, see Medaglia et al., 2017). Some key brain structures involved in
Front. Behav. Neurosci. 14:626769. specific generation and regulation of emotional, cognitive, and behavioral responses to stressors
doi: 10.3389/fnbeh.2020.626769 include insula, nucleus accumbens, amygdala, hypothalamus, hippocampus, medial prefrontal, and
Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 January 2021 | Volume 14 | Article 626769

Arida and Teixeira-Machado Brain Resilience and Exercise
anterior cingulate cortex (Gupta et al., 2017) and dysregulation in (Deuster and Silverman, 2013; Clark et al., 2019). Thus, healthy
these circuits has been related to emotional distress, anxiety, and behaviors obtained early in life and maintained throughout
mood disorders (Gupta et al., 2017; Iadipaolo et al., 2018). a long period of life can build brain resilience against age-
Changes in these neural circuits affect numerous related diseases (Gale et al., 2012; McEwen, 2016; Lesuis et al.,
neurotransmitter systems and molecular pathways. Among 2018).
them, hormones, neuropeptides, neurotransmitters systems, Several key positive factors that occur from childhood
and neurotrophic factors are involved in the responses to or adolescence through to adulthood contribute to brain
stress. Alterations in their functions determine the individual resilience (Burt and Paysnick, 2012). Among them, physical
variability in stress resilience (Feder et al., 2009; Russo et al., activity/exercise has an important role. Indeed, in many
2012). For instance, early life stress has been linked to long- publications on resilience, one frequently mentioned factor for
lasting changes in the hypothalamus-pituitary-adrenal axis, promoting resilience is physical exercise/fitness (Wu et al.,
resulting in chronically high levels of corticotrophin releasing 2013; McEwen, 2016). The beneficial influence of physical
hormone and cortisol. These events usually lead to structural activity/exercise on resilience can in part be attributed to
changes in brain regions such hippocampus and amygdala the understanding that it can induce positive physiological
(McEwen and Milner, 2007). Stress also induces the release of and psychological improvements, protect against the effects of
noradrenaline and serotonin in several brain areas associated stressful events, and prevent or minimize several neurological
to anxiety disorders and mood regulation, and dopamine in diseases. In this sense, this review will consider the following
response to aversive or rewarding stimuli. Thus, considering question with the target population being all life stages,
the involvement of neurotrophins in the regulation of different including some neurological disorders, using physical exercise as
forms of normal and pathological behavior, they play a intervention and brain resilience as outcome: How can physical
critical role in resilience to chronic stress (Taliaz et al., 2011; exercise contribute to brain resilience in all life stages and in some
Rothman and Mattson, 2013). Positive adaptive changes in neurological disorders? Here, we outline data generated from
these systems are suggested to promote resilience (Feder et al., clinical and pre-clinical studies and discuss the possible biological
2009). In this regard, adaptive coping strategies in stressful mechanisms underlying the positive impact of physical exercise
situations, such as neurofeedback training have been used to on brain resilience in the following conditions: (1) exercise
reduce depressive symptoms and improve emotion regulation during the pre-natal period and its effect on offspring’s brain
(Keynan et al., 2019) and a relationship between functional (infancy and adolescence), (2) exercise during post-natal brain
network at rest and resilience has been evidenced (Paban et al., development (infancy and adolescence), and (3) exercise in brain
2019). adulthood, aging, and in some neurological diseases (Figure 1).
Studies have used resilience measurement scales to be applied We focused on the impact of exercise on psychosocial stressors
in general and clinical populations and the Connor–Davidson with regard to educational (cognitive performance), professional,
Resilience Scale (CD-RISC) presents suitable psychometric and physiological performance.
properties and allows for valuable measurement of resilience
(Campbell-Sills and Stein, 2007; Smith et al., 2008; Windle et al., Search Strategy
2011). Adapted version of brief resilience scale has been large The literature search was conducted between February and
used to this purpose. August 2020. A comprehensive PubMed search was conducted
Brain resilience or vulnerability following a stressor is to identify studies investigating the role of exercise in brain
influenced by innate difference (genetically determined) and resilience. The following terminology was applied: (“exercise” OR
the experiences or exposures of an individual across the “physical activity” OR “sport”) AND (“stress” OR “resilience” OR
life span (education, occupation, engagement in physical/sport “brain resilience” OR “cognitive reserve” OR “brain reserve” OR
activities, or social activities) (Stern et al., 2018). Therefore, “neural reserve”) AND (“neurobiological factors” OR “endocrine
the interplay between genetic predisposition and lifestyle factors system” OR “genes” OR “genetic” OR “epigenetic”) AND
has a critical role in determining resilience to brain disorders (“psychiatric disorders” OR “depression” OR “anxiety” OR “brain
(Walhovd et al., 2019). Genetic variation, resulting alterations diseases”). Written in English, original studies, letters as well
in neurotransmitter systems have been of particular interest as reviews were included. Studies identified were selected and
for brain resilience. Differences between individuals possible excluded by examining the titles, abstract, or full text articles.
reflect the interaction between genetic predisposition, early-life Studies that did not address physical activity/exercise for brain
experiences and experiences across the lifespan. Accordingly, resilience in either clinical or pre-clinical studies were excluded.
environmental stimuli during the early life period can exert The terms physical activity, exercise, and physical fitness are
prominent effects on the risk of neurological disorders (Lesuis often used in the literature, and for clarification it is important to
et al., 2018). In this regard, a considerable number of scientific differentiate these denominations. For instance, physical activity
publications have reported that the combination of both physical has been used interchangeably with the term exercise.” The
and cognitive stimulation can affect brain resilience (Deuster frequently cited article by Caspersen et al. (1985) defines physical
and Silverman, 2013; Bozzali et al., 2015; Pedrinolla et al., 2017; activity as any bodily movement produced by skeletal muscles
Casaletto et al., 2020). The literature has clearly demonstrated which results in energy expenditure, while exercise is a physical
that an active lifestyle is inversely associated with stress-related activity that is planned, structured, repetitive, and purposeful. In
health problems resulting in the development of chronic diseases contrast with physical activity, physical fitness is characterized

FIGURE 1 | Design of intervention studies on brain resilience in this review. Dotted lines represent follow up outcomes. (1). Exercise during pre-natal period and its
effect on brain offspring (infancy and adolescence). (2) Exercise during post-natal brain development (infancy and adolescence) and its effect in later life. (3) Exercise in
adulthood, aging and in some-neurologic disease.
by a number of components that an individual achieves In humans, a limited number of studies has examined whether
related to health, particularly cardiorespiratory endurance, body exercise during the maternal period can influence offspring. A
composition, muscular strength, and flexibility. Being physically classic study conducted over 25 years ago demonstrated a better
active is not necessarily the same as having high aerobic fitness. performance on tests of general intelligence and oral language
skills in children aged 5 years from mothers who exercised
during pregnancy (Clapp, 1996). In another investigation,
RESULTS physical activity before and during gestation positively influenced
Of the 147 potentially relevant articles from the PubMed offspring’s academic performance in youth (from 6 to 18
database, 12 studies addressed physical exercise for brain years) (Esteban-Cornejo et al., 2015). These outcomes suggest
resilience. Most were excluded because they did not address that routine exercise before and during the pre-natal period
physical activity/exercise (n = 92) or the brain resilience outcome may produce benefits for infants’ and adolescents’ academic
(n = 43). To conduct a scoping review looking at all life stages performance. However, whether pre-natal exercise contributes to
and some neurological conditions, both clinical and pre-clinical brain resilience at later stages of life has not been explored in
research, we included 114 more studies through a free search humans. Animal studies have provided promising data and are
on pregnancy (n = 9), childhood and adolescence (n = 18), highlighted elsewhere in this review.
adulthood and aging (n = 16), Alzheimer’s disease (n = 17), In contrast with restricted investigations in humans, a
Parkinson’s disease (n = 14), Epilepsy (n = 20), Stroke (n = 16), substantial number of animal studies has examined the influence
systematic reviews (n = 3), and clinical guidelines (n = 1). of exercise during the maternal period on offspring. Evidence
from laboratory animals has shown that regular physical exercise
during pregnancy can affect several aspects of cognition and
DISCUSSION behavior in offspring. These findings result from experiments
using different models of physical exercise, including forced
For didactic reasons, we will present the translational treadmill running, forced swimming, and voluntary wheel
contribution of physical exercise to brain resilience and in running. For instance, the swimming or treadmill running
neurobiological conditions in the following order: physical exercise during pregnancy improves spatial learning (Parnpiansil
exercise in pregnancy, in childhood and adolescence, in et al., 2003) and short-term memory in offspring (Lee et al.,
adulthood, aging, and neurological disorders. 2006; Kim et al., 2007) and voluntary activity reduces depression-
like behavior and increased learning and memory performance
Physical Exercise in Pregnancy in offspring (Bick-Sander et al., 2006). The influence of
Brain development consists of a complex interaction of exercise during the gestational period is not restricted to the
molecular, cellular, and environmental systems. It begins in offspring’s cognitive functions. For instance, an acceleration
the third gestational week and continues at least through late of visual system plasticity was detected through earlier eye
adolescence. The developing brain is constantly influenced opening and visual acuity in pups from dams who lived in
by internal and external factors and certain events occurring an enriched environment seven days before delivery (Cancedda
during this period may positively or negatively affect the brain’s et al., 2004). These findings indicate that pre-natal sensory-
development (Andersen, 2003). With respect to this scenario, motor stimulation induces accelerated brain maturation in early
evidence has shown that environmental stimuli such as physical post-natal life.
activity/exercise can impact positively on brain development Another question to be clarified is whether the effects of
(Clapp, 1996; Esteban-Cornejo et al., 2015). Investigations on the exercise during pregnancy can be sustained into adulthood. In
influence of exercise at earlier stages of brain development have this regard, Robinson and Bucci (2014) examined the effect
been encouraging, including exercise interventions on pre- and of voluntary wheel running during the gestational period in
post-natal brain development. adult offspring. Improvement in object recognition memory was

observed in progenies from 60 to 88 days of age. In another induced by exercise during gestation may improve brain function
study, treadmill running during pregnancy promoted enhanced in the offspring.
cognitive function (habituation behavior and spatial learning) The results indicate that pre-natal exercise can induce long-
in adult offspring (Gomes da Silva et al., 2016), indicating that term effects on the hippocampal plasticity of progeny (Dayi
exercise during the peri-natal period may increase brain function et al., 2012). These findings are of great importance because
in offspring in adult life. Therefore, positive early life experiences the hippocampal region contributes to long-term potentiation
such as physical exercise during the gestational period may persist (LTP), one of the cellular mechanisms required for learning
in offspring and may consequently play an important role in and memory (Bliss and Collingridge, 1993). It is well-known
increasing brain resilience in later life. that activation of the N-methyl-D-aspartate (NMDA) glutamate
receptor generates LTP, as well as learning and memory. In this
context, better performance in the Morris water maze tests was
Neurobiological Mechanisms observed in pups of trained mothers during pregnancy compared
Considering that few studies in humans have examined the with pups of sedentary mothers and this effect was abolished
effects of physical activity during pregnancy on offspring’s by the NMDA antagonist MK-801 (Akhavan et al., 2008). In
neurodevelopment, the mechanism by which exercise during addition to the cognitive effects, there is supportive evidence
pregnancy impacts on progeny’s cognitive function is just starting that exercise during pregnancy exerts a neuroprotective effect
to be clarified. Two studies conducted by Clapp (1996) and in the progeny. In the study by Herring et al. (2012), voluntary
Clapp et al. (1998) focusing on the first years of life (ages wheel running during pregnancy reduced beta-amyloid plaque
one and five), found no significant difference in the offspring’s burden, APP processing, oxidative stress, inflammation, and
morphometric parameters (head circumference and height). In neurovascular dysfunction in offspring at 5 months of age,
a more recent investigation, a better cerebral maturation in suggesting that pre-natal physical activity may also contribute to
the newborn of exercised pregnant mothers was observed by reducing the future risk of neurological diseases.
means of a neurophysiological index of sound discrimination
and auditory memory (the slow positive mismatch response—
SPMMR) (Labonte-Lemoyne et al., 2017). The long-term effects Physical Exercise in Childhood and
of exercise during pregnancy on the offspring, i.e., in their adult Adolescence
life, still remain to be elucidated. In relation to exercise interference in post-natal brain
Unlike human studies, much more information has been development, i.e., during infancy or adolescence, numerous
collected from laboratory animals and several factors have been human studies have reported positive findings in cognitive
proposed on these effects. Prominent cell proliferation and functioning following acute (Hillman et al., 2009; Ellemberg
survival in offspring following exercise during pregnancy have and St-Louis-Deschênes, 2010) or chronic physical exercise
been observed (Bick-Sander et al., 2006). For instance, swimming (Hillman et al., 2005, 2014). A meta-analysis of 16 studies
(Lee et al., 2006) and treadmill running (Kim et al., 2007) showed a positive association between cognition (learning and
from embryonic day 15–21, the late developmental stage of the intelligence scores) and physical activity in school-age children
rodent fetus, provoked an increase in the number of BrdU- (Sibley and Etnier, 2003). A superior performance in three stroop
labeled cells (marker of proliferating cells) on post-natal day conditions (attention tasks) was observed in children between
29 (P29) in the hippocampus, a region related to learning and seven and 12 years of age with better aerobic fitness (Buck
memory, and this proliferative effect was associated with an et al., 2008) and in arithmetic cognition in fitter pre-adolescent
improvement of cognitive function. Significant changes may children aged nine–ten (Moore et al., 2014). An elegant
also occur in later periods of life. Some studies have shown investigation conducted by a Swedish group who evaluated
an increase in absolute numbers of neuronal and non-neuronal 1,200,000 adolescents showed a positive association between
cells and brain-derived neurotrophic factor (BDNF) levels in physical fitness and better cognitive performance at age 18 years
the hippocampal formation of adult offspring (P60) (Gomes da and occupational status and educational achievement later in
Silva et al., 2016) and increased cell density in the hippocampal life (Aberg et al., 2009). A further important consideration is
CA1 and CA3 areas during the adult period (P120) (Dayi et al., whether regular physical activity during adolescence or adult
2012) of offspring of mothers trained during the gestational life promotes long-lasting cognitive effects. In the study by Dik
period. Of note, increased BDNF levels in the hippocampal et al. (2003), physical activity at 15 and 25 years induced better
formation of pups of exercised mothers were associated with cognitive performance at 62 and 85 years of age. These findings
better spatial learning (Akhavan et al., 2008) and BDNF deletion indicate that regular physical activity in early life is able to
resulted in learning deficits (Gorski et al., 2003). With regard to improve cognitive functioning, supporting the cognitive reserve
this, molecular systems, essentially involving BDNF, have been hypothesis. Although very optimistic, confirmatory studies have
reported to play an important role in exercise-induced cognitive yet to be conducted in further human studies.
improvement. Overall, offspring of exercised mothers during While promising findings on the effects of exercise during
pregnancy show increased neurogenesis, hippocampal BDNF infancy or adolescence have been well-documented, far less is
mRNA and BDNF protein, and improved learning and memory known about its impact on brain resilience. Chronic stress during
throughout life (Lee et al., 2006; Kim et al., 2007; Gomes da the adolescent period may impact negatively, both physically
Silva et al., 2016), indicating that increased BDNF expression and psychologically (Sheth et al., 2017) and regular physical

activity may be of great value in adolescent stress management. exercise model (voluntary wheel running) and a non-spatial
For instance, Norris et al. (1992) conducted a retrospective and form of learning and memory (object recognition memory), it
experimental study to examine the influence of physical activity was observed that rats with free access to wheel running from
and an exercise program on psychological stress and well-being P25 to P55 had a better discrimination ratio between novel
in adolescents. In their retrospective analysis, adolescents who and familiar objects compared to their controls (Hopkins et al.,
engaged in exercise/sports activities more regularly reported less 2011). Notably, 2 and 4 weeks after the exercise had terminated,
perceived stress and depression. In the second part of their exercised rats performed better in the re-test compared to their
study, a group of adolescents submitted to a regular exercise controls. Similar findings were observed in a study conducted
program reported significantly less perceived stress than their by our research group (Gomes da Silva et al., 2012). Treadmill
controls, suggesting that physically fit adolescents seem to be running during the adolescent period (P21–P60) resulted in
less susceptible to life stressors. In a recent cross-sectional improved spatial learning and memory tested at P60–P65, and,
survey (Kim et al., 2019), adolescents from 14 to 19 years old like the study by Hopkins et al. (2011), rats showed better spatial
who engaged in physical activities more than five times per memories in later life (at P96) (Gomes da Silva et al., 2012). These
week were stressed less often than those who were involved in findings also indicate that physical exercise during this critical
fewer physical activities. To indicate whether any psychological period of brain development can result in sustained cognitive
benefits would have been maintained, it would be reasonable to benefits, that is, in a neural reserve that can be useful in old age.
analyze a follow-up period at the end of the physical exercise
program or physical activity. Of note, a cross-sectional study Neurobiological Mechanisms
that examined the relationship between participating in physical Changes in function and brain structure are clearly associated
activity at several time-points in life (teenage, age 30, age 50, with exercise-induced improvement in cognition early in life.
and late-life) and late-life cognitive function showed that teenage Improved fronto-temporal white matter integrity, which is
physical activity was greatly associated with a lower probability related to improved cognitive function, has been observed
of cognitive impairment in elderly people who were physically following 8 months of aerobic exercise in overweight 8–11 year-
active (Middleton et al., 2010). However, the survey did not old children (Schaeffer et al., 2014). Greater hippocampal volume
take account of whether cognitively impaired subjects had been and better performance in relational memory were detected in
through stressful life events. Thus, conditions other than a fitter children compared to less fit children (Chaddock et al.,
stressful early life may influence cognitive reserve in later life, 2010). Also, greater gray matter volumes in frontal, temporal, and
such as nutritional status during childhood (Zhang et al., 2010) subcortical areas were also related to higher cardiorespiratory
and education (Zahodne et al., 2015). Overall, these findings fitness; and some regions such pre-motor cortex, supplementary
suggest that the cognitive reserve built up in physically fit subjects motor cortex, and hippocampus were related to better academic
in the early stages of life prepare the brain to be more resilient to performance (Esteban-Cornejo et al., 2017). On the electro-
cognitive impairment, dementia, and consequently Alzheimer’s physiological level, positive changes in event-related brain
pathology; this probably occurs through brain plasticity. potential that may underlie cognitive performance have been
In addition to cross-sectional studies, we should note how observed in pre-adolescents following an acute bout of treadmill
long-term physical activity can impact in later life. A prospective walking (Hillman et al., 2009) or in fitter children (Moore
6-years follow-up study with 496 adolescent girls designed to et al., 2014). Other factors by which physical exercise can
examine the relationship between physical activity and mental interfere beneficially for cognition include the release of growth
health during adolescence showed a reduced risk for future factors such as BDNF, Insulin-like growth factor 1 (IGF-I), and
depressive symptoms (Jerstad et al., 2010). In another prospective vascular endothelial growth factor (VEGF), possibly providing
and retrospective analysis, physical activity during childhood and reserve against later cognitive decline and dementia. These
adolescence was associated with a reduced risk of depression neurotrophins are produced and secreted in the brain and
20 years later (McKercher et al., 2014). Subsequently, a long- play an essential role in regulating proliferation, development,
term follow-up over a period of 14 years, using a large sample and cellular differentiation. For instance, an aerobic exercise
of subjects from adolescence through adult life (18–29 years program increased serum BDNF levels in adolescents, which was
old), showed that those engaged in higher levels of physical associated with better working memory (Jeon and Ha, 2017).
activity presented lower levels of depressive symptoms over time A single bout of high-intensity, but not low-intensity, exercise
(from adolescence into adulthood) (McPhie and Rawana, 2015). was able to improve memory as shown by remembering more
Collectively, the scientific literature presents strong indicators newly learned vocabulary words compared to the control group
that habitual physical/sport activities at an early age may boost (Hötting et al., 2016). Supporting the above findings, a recent
lifelong brain function and may also reduce the risk of several systematic review and meta-analysis reported significant results
brain disorders. on the levels of BDNF and executive function in adolescents
Similar findings have been found in laboratory animals. In submitted to physical exercise (de Azevedo et al., 2019). Overall,
a classic study conducted by Uysal et al. (2005), young rats the combined effects of neurotropic factors and physical exercise
submitted to treadmill exercise during adolescence and early from childhood to adolescence, a critical window of brain
adulthood (from post-natal day 22 to post-natal day 78; P22 to development, may contribute to improvements in memory and
P78) presented better spatial memory in the water maze test also in various aspects of academic performance, consequently
compared to non-exercised rats during this period. Using another preventing or minimizing age-associated cognitive decline.

With regard to the results of animal studies during post-natal The above studies suggested that although the cognitive
brain development, increased hippocampal cell proliferation was reserve is influenced by intrinsic differences or during childhood,
shown in rats trained over five consecutive days with 4-week-old stimuli at later periods of life can also positively or negatively
(Kim et al., 2004) and neurogenesis in rats trained for one week alter the reserve. Thus, some variables such lifestyle habits, age,
from P29 to P35 (Lou et al., 2008). Our research group observed different follow-ups, physical exercise habits, or types of exercise
that increased hippocampal cell proliferation (stained with Ki67) intervention are confounders that can interfere with the studies’
induced by exercise occurred mainly in the earliest stages of post- outcomes. To deal with any research gaps, a growing number
natal development (de Almeida et al., 2013). In line with this, of meta-analyses have been conducted to verify the impact of
Uysal et al. (2005) reported an association between an increased physical activity in the adult or elderly population. For instance,
number of hippocampal cells in CA1, CA3, and the dentate gyrus individuals aged ≥40 years with better levels of physical activity
and better spatial memory in trained rats during development. presented lower risk of cognitive decline and dementia (Blondell
Improvement in spatial memory was also related to increased et al., 2014). An investigation by Hamer and Chida (2009)
axonal density of granule cells in the dentate gyrus stained by the using a meta-analysis of prospective studies found that habitual
Neo-Timm method in trained adolescent rats (Gomes da Silva physical activity was able to reduce by 28% and 45% the risk
et al., 2012). As highlighted previously, BDNF plays a potential of dementia and the risk of AD, respectively. In a more recent
role in the modulation of cognitive functions. To this end, higher meta-analysis, exercise duration of 45–60 min per session and of
BDNF mRNA (Abel and Rissman, 2013), BDNF expression, and moderate or vigorous intensity was associated with improvement
its receptor tropomyosin-related kinase B (Gomes da Silva et al., in cognition function in subjects older than 50 years (Northey
2012) have been detected in rats trained during adolescence, et al., 2018). Since age is the main risk factor for dementia,
indicating that brain BDNF in early life induced by exercise may particularly Alzheimer’s, sustained physical/sports activities have
be associated with cognitive improvement. been associated with reduced incidence of AD and therefore
increased resilience against developing AD (Rovio et al., 2005;
Lautenschlager et al., 2008).
Studies have demonstrated that psychological stress and other
Physical Exercise in Adulthood, Aging, and psychosocial factors such depression increase vulnerability to
Neurological Disorders AD (Mejía et al., 2003; Aznar and Knudsen, 2011; Yuede et al.,
As outlined, positive early life experiences or lifestyle factors such 2018) and regular physical exercise plays an important role
as physical exercise have been associated with resilience in later in stress management and increased resistance to stress-related
life, suggesting that regular exercise can generate brain protection disorders (Tsatsoulis and Fountoulakis, 2006). Although studies
by means of reserve. For adult, middle-aged or aged people, have examined the effects of stress or physical exercise on
physical exercise is frequently recognized to slow cognitive AD independently, the interaction of stress and exercise needs
decline and protect against the consequences of stressful events. to be better explored. To this end, a review by Yuede et al.
For instance, the practice of physical exercise in mid-life (from (2018) reported attractive findings from pre-clinical studies on
age 25–50) was able to reduce the chance of dementia in older this interface.
adults (Andel et al., 2008) and improve cognition, mainly for AD has also been associated with the occurrence of
executive-control processes (Colcombe and Kramer, 2003). cerebrovascular disease and physical exercise plays a positive role
Despite the growing number of positive findings relating in this condition (Lange-Asschenfeldt and Kojda, 2008). Physical
exercise and cognition in adulthood and aging, some prospective exercise of moderate intensity increases cerebral blood in humans
longitudinal studies have reported null results (Broe et al., (Braz and Fisher, 2016), which could minimize the effects of
1998; Wilson et al., 2002). In the study by Broe et al. (1998), hypoperfusion in AD. Hypotheses by Nation et al. (2011) have
no association was found between exercise and cognitive been formulated concerning the impact of exercise and stress on
performance, and in another survey, cognitive but not physical the cerebrovascular system with increased risk of developing AD,
activities were associated with a reduced risk of cognitive decline highlighting preventive strategies for this disease.
(Wilson et al., 2002). We have to bear in mind that mixed findings In addition to the preventive effect described above,
related to the effect of physical activity in cognition can be partly physical activity/exercise has been demonstrated to promote
attributed to cognitive reserve. Sánchez Rodríguez et al. (2011) neurobiological benefits for brain pathology, consequently
used factor scores to assess cognitive reserve, classifying the attenuating the decline in AD. Authors such Hoffmann et al.
participants into high or low reserve. Patients with Alzheimer’s (2015) demonstrated that a supervised exercise program over 16
disease (AD) with low cognitive reserve scores presented more weeks was able to delay neuropsychiatric symptoms in patients
deficits in neuropsychological tests such as memory, attention, with mild AD. In a subsequent investigation from the same
and language than patients with high cognitive reserve. Higher research group, using the same exercise protocol, a positive
education, higher professional performance, and ludic activities correlation was found between frontal cortical volume and
were factors contributing to cognitive reserve and physical measures of mental speed and attention (Frederiksen et al.,
activity was not considered a factor for cognitive reserve in their 2018). Cardiorespiratory fitness, as measured by maximal oxygen
study. Similarly, Fritsch et al. (2007) found educational level but consumption (VO2max), has been associated with cognition
not physical and social activities to be predictors of cognitive (Wendell et al., 2014) and this evidence has also been reported
function in the elderly. in patients with AD (Vidoni et al., 2012). In line with this, a study

analyzing a direct measure of VO2max in patients with mild impact of dance practice to induce brain plasticity (Teixeira-
AD detected a positive connection between VO2 peak, cognition, Machado et al., 2018).
and neuropsychiatric symptoms (Sobol et al., 2018). In sum, an Concerning white matter integrity, increases were reported
increasing number of studies have reinforced the role of exercise in temporal and parietal regions in older subjects submitted to
in minimizing the reduced cognitive function in AD (Groot et al., 1 year of an aerobic exercise program (Voss et al., 2013). Of
2016). note, better cardiorespiratory fitness in young and older adults
In animals, extensive literature has shown a positive has also been related with increases in hippocampal cerebral
association between exercise and cognition in adulthood and blood volume and memory improvement (Chapman et al., 2013),
aging, supporting the important role of exercise in brain health supporting the idea that regular exercise may build a vascular
as demonstrated here. Classic studies by van Praag et al. reported reserve against AD. With respect to neurotrophic factors, a link
that voluntary wheel running improved hippocampus-dependent between BDNF, exercise, and cognition has been proposed during
learning and memory in young adult (van Praag et al., 1999) and aging, suggesting that this association may have a critical role
aged mice (van Praag et al., 2005). Similar findings have also been for the prevention and minimization of cognitive impairment
demonstrated in other exercise protocols. Results from forced during aging (Wang and Holsinger, 2018). Indeed, some authors
and voluntary exercise showed improved short-term and spatial have elegantly emphasized physical exercise as a means of
memories in young and old rats (Kim et al., 2010; Speisman restoring BDNF in this neurological condition, a finding that is
et al., 2013) and resistance exercise improved performance in also supported by animal studies (Wang and Holsinger, 2018).
the passive avoidance test, a hippocampus-dependent memory Essentially, aerobic fitness and serum BDNF levels in older adults
task, in young adult rats (Cassilhas et al., 2012). With regard to have been correlated with increased hippocampal volume and
whether exercise can impact positively in stressful conditions, a better memory (Chaddock et al., 2010; Erickson et al., 2011).
recent study showed that impaired cognition induced by chronic While the existing literature indicates the positive association
stress in mice was prevented in stressed animals submitted of exercise and BDNF on cognition, further investigations are
to regular moderate and intense exercise (Lee et al., 2018). necessary in elderly and neurological subjects.
This adaptive effect of regular exercise on the homeostatic In pre-clinical studies, positive associations between exercise
system can improve resistance and/or resilience to physical and and cognition in adulthood and several possible neurobiological
psychological stress and may consequently protect against brain mechanisms have been proposed for the improvement of
disease. To this end, exercise can play an important role in cognitive reserve. Extensive literature has reported that exercise
increasing resistance to stress in AD. An elegant review by Yuede can increase adult hippocampal neurogenesis (for a review
et al. (2018) reported findings from studies of different exercise see van Praag, 2008) and hypothalamus-pituitary-adrenal axis
protocols in AD mouse models and discussed the interplay regulation (Wang et al., 2014), suppress apoptosis (Kim et al.,
between stress and exercise in AD. Although research has focused 2010), reduce oxidative stress and mitochondrial dysfunction,
on the effects of aerobic exercise (forced or voluntary exercise) modulate cytokine signaling (Speisman et al., 2013), increase
in AD models (Nichol et al., 2007, 2008; Xiong et al., 2015), vascular density (Ding et al., 2006) and production of BDNF
less is known about the impact of resistance exercise on this and IGF-1 (Vaynman and Gomez-Pinilla, 2005), alter brain
pathology. Our group and others have recently shown that morphology (Stranahan et al., 2007) and electrophysiological
resistance exercise may minimize the alteration in exploratory properties of neurons (van Praag et al., 1999). These findings on
activity (Hashiguchi et al., 2020) and in cognitive function (Liu brain plasticity induced by exercise are believed to support the
et al., 2020) in a transgenic mouse model for AD. improvement in learning and cognitive function.
The above-mentioned mechanisms revealed to be induced
Neurobiological Mechanisms by exercise in the healthy population to improve cognitive
As with pre-adolescents and adolescents, changes in brain performance could also be applied in aging and neurological
structure and function and improvement in several aspects of disorders. In AD, some proposed mechanisms in mice models
cognition have been observed in the adult population as result include increased BDNF expression, reduced inflammation,
of better cardiorespiratory fitness. A meta-analysis conducted reduced amyloid deposition and phosphorylated tau
by Kramer and Colcombe (2018) has elegantly highlighted this accumulation (for a review see McGurran et al., 2019). For
issue. In younger adults, a 6-weeks exercise program was able instance, reduced oxidative stress and Aβ scores were related
to increase hippocampal volume (Thomas et al., 2016). In to better working memory using three types of exercise for 6
older subjects, 6 months of aerobic program (walking) induced weeks (aerobic, resistance, and combined exercises—aerobic +
increases in volume in frontal and temporal gray matter and resistance) (Özbeyli et al., 2017).
white matter regions (Colcombe et al., 2006) and similar effects
were reported by other studies (Erickson et al., 2011; Reiter Exercise in Other Neurological Disorders
et al., 2015). Although cardiorespiratory fitness induced by Besides the neuroprotective effects against aging, and an
conventional physical training such as walking, jogging or cycling extensive number of studies looking at the prevention or
has been extensive reported to promote brain plasticity, a study minimizing of cognitive decline and dementia, regular physical
conducted by Rehfeld et al. (2018) showed that dance training exercise has had a positive influence in other neurological
produced larger brain volumes compared to repetitive exercise diseases. Here, we will focus on some common neurological
in the elderly. Indeed, a recent systematic review highlights the disorders such Parkinson’s, Epilepsy, and Stroke.

Parkinson’s Disease (PD) and long-term exercise minimized the progression of motor
PD is the second most common neurodegenerative disease symptoms (Hsueh et al., 2018; Mul et al., 2018).
worldwide, affecting 1% of the elderly population. A considerable
number of scientific studies have highlighted the role of exercise Neurobiological Mechanisms
in reducing the risk of PD, highlighting its contribution to In PD, limited information on neurobiological mechanisms
resilience in PD. Moderate to vigorous physical sport/activities has been reported in humans. Growing evidence suggests that
including tennis, biking, swimming, heavy housework in mid- physical exercise can minimize dopaminergic neuronal damage
to later life have been associated with a lower risk of PD (Xu within basal ganglia motor circuits. In an in vivo study, the
et al., 2010). Of note, in a prospective study, the intensity of availability of the dopamine transporter by using [11C]CFT
physical activity was an influential factor for better resilience in was reduced in the putamen after 1 h of strenuous walking in
PD. Vigorous, but not moderate, physical activity was related normal subjects but not in PD patients, indicating that this
to a 50% lower risk of PD in men (Chen et al., 2005). Thus, abnormal activation might be linked to the pathophysiology of
an elegant cross-sectional large-scale study with 9,676 elderly the parkinsonian gait (Ouchi et al., 2001). In this regard, BDNF
participants reported physical exercise as the best protective exerts an important influence in the mesolimbic dopaminergic
factor against PD (Zou et al., 2015). More recently, a large meta- pathway and altered BDNF levels have been observed in PD
analysis of more than half a million adults reported an association pathology. In post-mortem analysis, reduced expression of BDNF
between high levels of moderate to vigorous activity and low risk protein was observed in the substantia nigra pars compacta of
of developing PD (Fang et al., 2018). Interestingly, while Yang PD patients compared to control subjects (Parain et al., 1999).
et al. (2015) found that a medium level of daily total physical Thus, blood analysis showed decreased serum BNDF levels in PD
activity lowered the risk of Parkinson’s disease, Logroscino patients when compared with controls (Scalzo et al., 2010). In line
et al. (2006) did not support the finding that physical activity with this, a systematic review and meta-analysis reported reduced
protects against PD. As pointed out by Yang et al. (2015), to serum BDNF levels in PD patients compared to healthy controls
evaluate physical activity/exercise level, epidemiological studies in spite of the presence of co-morbidities such depression
have utilized different activities to measure moderate to vigorous among non-depressed and depressed PD patients (Rahmani
exercise, such as leisure time, household, or energy expended et al., 2019). The physiological mechanisms of BDNF changes
on physical activity in kilocalories per week, which can produce induced by exercise have been proposed in a systematic review
different outcomes. Therefore, one must be cautious when and meta-analysis which reported increased BDNF blood levels
analyzing these outcomes. following a physical exercise program in PD patients (Hirsch
Although there is beneficial evidence of a decrease in the et al., 2018). In sum, the mechanisms and possible directions for
risk of PD, the influence of physical exercise in slowing the neuroprotection in PD have been significantly explored, but more
progression of the disease has not been completely explored. research is needed on the influence of exercise in this scenario
From few clinical trials, positive effects have been observed in humans.
in PD resilience. Robottom et al. (2012) demonstrated that Pre-clinical investigations have revealed important effects
resilience in PD was associated with better health-related quality of exercise on the nigrostriatal pathway, resulting in increasing
of life and reduced disability and non-motor symptoms (less extracellular dopamine release and reduction of striatal
apathy, depression, fatigue). Improvement in motor symptoms dopamine loss terminals (Petzinger et al., 2013). In part, these
and physical functioning in people with PD was reported in benefits are supported to facilitate DA neurotransmission
a review which focused on the long-term effects of exercise and some studies support these affirmations. For instance, 4
(duration lasting at least 12 weeks) (Mak et al., 2017). Besides the weeks of swimming prevented the decrease of dopamine and
classical motor symptoms, behavioral and cognitive symptoms its metabolites DOPAC and HVA levels induced by 6-OHDA
are common in PD and positive results from exercise programs in the striatum of mice and restored long-term memory in
in several cognitive domains have been found in the literature the object recognition test (Goes et al., 2014). Moreover, 2
(da Silva et al., 2018). Authors have reported improvement in weeks of treadmill reduced nigrostriatal dopaminergic cell
the executive functions after aerobic (Altmann et al., 2016) or loss, increased cell proliferation in the hippocampal dentate
resistance training (Silva-Batista et al., 2016). With regard to the gyrus, and minimized short-term memory impairment in
concept that resilience is an active process, the reduced disability 6-OHDA-induced Parkinson’s rats (Cho et al., 2013).
and non-motor symptoms observed in PD could be minimized
through regular physical exercise. Epilepsy
Regarding pre-clinical data, a number of studies have Epilepsy is another common neurological condition affecting
indicated that different types of aerobic exercise can improve over 70 million people worldwide. It is characterized by an
cognitive function in PD. This positive effect has been enduring predisposition to generate spontaneous epileptic
investigated in exercise training applied before, during, and seizures, presenting several neurobiological, cognitive,
after parkinsonism-inducing treatment. Exercise can enhance the psychological, and social consequences (Fisher et al., 2014).
memory of rats by reducing cognitive impairment in a treadmill A number of factors such seizure control and reduced depression
or swimming exercise protocol (Goes et al., 2014; Viana et al., and anxiety can impact positively on the quality of life of people
2017). In a voluntary exercise protocol, short-term exercise was with epilepsy. These protective factors could be characterized as
effective in reducing cognitive deficits and depressive behavior resilience in the context of epilepsy. Thus, regular exercise over

the life course has been associated with resilience to developing in animal models of epilepsy have been very positive and play a
epilepsy. In this scenario, some human investigations have beneficial role in increasing resilience to developing epilepsy.
explored whether previous physical exercise practice is able Findings concerning exercise and cognition have been
to reduce the incidence of epilepsy. For instance, a large and positive in different models of epilepsy. For instance, a 30-days
population-based cohort, consisting of 1,173,079 men, over a swimming exercise reduced learning and memory deficits in
long observation period (up to 40 years) by a Swedish group rats submitted to a kainite acid model (Gorantla et al., 2016).
showed that low cardiovascular fitness evaluated at age 18 was Two types of exercise, voluntary wheel running and swimming,
associated with a risk of presenting epilepsy later in life (Nyberg reduced seizure frequency and improved cognitive performance,
et al., 2013). Reinforcing the above finding, a more recent measured by the object recognition test and the passive avoidance
study conducted by Ahl et al. (2019) compared the incidence test (Lin et al., 2019). Recently, we demonstrated that resistance
of epilepsy over 20 years in a large number of participants of a exercise was able to decrease the number of seizures, which was
long-distance Swedish cross-country ski race (Vasaloppet) with associated with a reduction in memory impairment (de Almeida
the incidence of their match controls in a register of the Swedish et al., 2017). Promising results have been found with regard to
population. They found up to 40–50% lower incidence of investigations about the effects of exercise on cognitive changes
epilepsy in cross-country ski racers before retirement. Notably, in animals submitted to status epilepticus earlier in life. Rats
data sub-analyses demonstrated that faster ski racers had a submitted to penicillin-induced recurrent epilepticus in early life
significant lower incidence of epilepsy compared to those with and then exercised during the final period of adolescence (P49-
a slower finishing time. Both above findings are indicative P54) presented better performance in the water maze test than
that regular physical exercise and better physical fitness can be their controls (Ni et al., 2009). In addition, cognitive impairments
protective against developing epilepsy. induced by lithium-pilocarpine-induced status epilepticus at
Physical exercise also plays a positive role after epilepsy is weaning was decreased in animals housed in environmental
established. Factors such as social functioning, ability to work, enrichment with wheel running (Fares et al., 2013). Thus, an
stigma, prejudice, and adjustment to seizures significantly reduce exercise program in rats conducted during the period of post-
the quality of life of people with epilepsy and are generally natal brain development reduced seizure susceptibility later in
associated with depression and anxiety disorders. From the life, indicating that exercise undertaken in early life may build
limited number of prospective studies in humans, a reduced a neural reserve against brain disorders (Gomes da Silva et al.,
number of seizures, reduced anxiety and depression symptoms, 2011). The authors suggest that physical exercise during early
improvement of quality of life together with better capacity to periods of life may provide an adequate development of neural
cope with stress are observed after exercise programs (Bjorholt circuitry, which can support greater brain damage in later life.
et al., 1990; Roth et al., 1994; McAuley et al., 2001; Vancini Collectively, these studies reinforce the neuroprotective and
et al., 2013). Certainly, physical exercise has been suggested as rehabilitative influence of exercise in epilepsy.
a potential candidate for stress reduction in people with epilepsy
(Arida et al., 2009). The influence of exercise on the reduction in Neurobiological Mechanisms
seizure frequency or seizure susceptibility is an important factor With epilepsy, we can only make suppositions regarding the
in this picture. Seizure frequency has been negatively associated effects of exercise in humans. Some possible mechanisms are
with cognitive function (Tromp et al., 2003; Hoppe et al., 2007). It modulation of the neurotransmitter system and changes in
has been demonstrated that people with temporal lobe epilepsy, metabolic, neuroendocrine, and growth factors. Cellular and
the most common form of epilepsy, with low seizure frequency molecular events underlying epilepsy can impair growth factor
presented better performance on tests of anterograde memory signaling in the brain and current evidence has associated BDNF
compared to those with high seizure frequency (Voltzenlogel with the pathophysiology of epilepsy in humans. Increased
et al., 2014). In line with this, clinical studies have reported levels of BDNF have been found in the surgically resected
that physical exercise programs improve seizure control (Eriksen temporal neocortex (Takahashi et al., 1999) or hippocampus
et al., 1994; Nakken, 1999). However, the influence of physical of patients with TLE, demonstrating that epileptic activity may
exercise on cognition is poorly investigated. To our knowledge, increase BDNF levels and its gene expression (Murray et al.,
only two studies have explored the influence of an exercise 2000). Conversely, in the periphery, decreased levels of plasma
program on cognition in people with epilepsy. Children with (LaFrance et al., 2010) and serum BDNF have been reported in
benign epilepsy submitted to ten supervised exercise sessions adult patients with epilepsy (Hong et al., 2014). Considering that
for 5 weeks showed significant improvements in attention tests regular exercise has been known to reduce neuroinflammation,
(Eom et al., 2014). Although this is an encouraging result, the oxidative stress, and excitotoxicity (Moylan et al., 2013), it can
study presented a small sample, no control group, and only a be suggested that exercise might modulate these effects in this
short period of exercise intervention. Thus, most of them were condition, therefore building brain resilience against epilepsy.
seizure-free and receiving monotherapy. In a recent randomized Although there is no reported effect in epilepsy patients,
study, adults with epilepsy submitted to 12 weeks of a combined positive outcomes have been found in animal models of epilepsy.
exercise program presented an improvement in some domains Modulation of excitatory/inhibitory systems and neurotrophic
of cognitive function such attention and language tasks (Feter factors has been demonstrated in several epilepsy models.
et al., 2020). Although further research in humans is needed, the Reduced levels of synaptic-related proteins and GABAergic
efficacy of exercise programs in improving cognitive functions function in epileptic animals were reversed by exercise, which

was associated with improved cognitive function and reduced (Blanchet et al., 2016; Ihle-Hansen et al., 2019). A meta-
seizure frequency (Lin et al., 2019). Recently, we examined the analysis of randomized controlled trials selecting studies with
influence of exercise on the activation of downstream proteins a duration of training >4 weeks showed a positive impact of
related to BDNF-TrkB receptor. Aerobic exercise increased exercise on some measurements of cognitive performance such
hippocampal BDNF expression, restored the overexpression of as attention/processing speed following a stroke (Oberlin et al.,
full-length TrkB and truncated-TrkB isoforms to control levels, 2017). Taking into account that studies address different or
and altered the hippocampal activation of some proteins linked to combined interventions, i.e., different inclusion criteria across
BDNF-TrkB intracellular signaling (de Almeida et al., 2018) and the studies such as physical activity (leisure time or recreational
resistance exercise restored to control levels the altered BDNF activity), exercise program or cardiorespiratory fitness, a study
levels and ERK and mTOR activation in rats with epilepsy (de conducted by Brouwer et al. (2019) evaluated the influence of
Almeida et al., 2017). Thus, improved learning and memory solely aerobic training on vascular and metabolic risk factors
in rats with epilepsy housed in an enriched environment with for stroke. A beneficial effect on systolic blood pressure and
wheel running was accompanied by increased hippocampal fasting glucose was observed after stroke compared to non-
neurogenesis and BDNF and VEGF transcripts (Fares et al., aerobic exercise. More investigations using physical training
2013). programs will provide a better perception of this intervention
(aerobic exercise) for improving resilience to stroke. With this in
Stroke mind, higher levels of physical activity and exercise are important
Stroke is the second leading cause of mortality and the principal factors in reducing the risk for cardiovascular diseases and
cause of physical disability around the world. Despite extensive consequently increasing resilience for stroke.
efforts, the development of preventive or rehabilitative treatment In addition to physical disability and cognitive impairments,
has not been totally effective (Moskowitz et al., 2010). Among social factors are also common in stroke patients, notably changes
therapies for this condition, physical activity/exercise has been in depressive symptoms, and social desirability. In a survey
proposed in a large number of investigations. The literature with stroke survivors, feelings of depression, fatigue, and low
shows that regular practice of physical exercise is inversely motivation were found to be factors that reduced the desire to
related to stroke risk. Not only in stroke prevention, but also undertake physical activity, while self-determination and goal
in stroke recovery in physical and cognitive tasks (Han et al., achievement were related with greater involvement in physical
2017). activities (Morris et al., 2012). Therefore, healthy habits early or
A large amount of research has reported an inverse association during the life course might influence healthier behaviors and
between cardiorespiratory fitness and stroke. In one investigation cognitive recovery after stroke.
of 16,000 men, those with moderate or high fitness presented In general, animal models of stroke have confirmed that
lower risk of stroke mortality compared to low fitness individuals aerobic exercise of moderate intensity seems to be beneficial to
(Lee and Blair, 2002). In another large cohort study with women cognition. Indeed, increasing reports have indicated that early
during a mean follow-up of 11.9 years, walking was related exercise is protective against stroke (Zhang et al., 2015) and
with lower risks of total, ischemic, and hemorrhagic stroke can minimize memory impairment induced by ischemic brain
(Sattelmair et al., 2010). In accordance with the above findings, injury (Sim et al., 2004, 2005). For instance, 2 weeks of aerobic
a meta-analysis by Lee et al. (2003) found that active individuals exercise introduced 24 h after middle cerebral artery occlusion
presented lower risk of stroke incidence and between the two significantly induced spatial memory recovery (Yang et al., 2017).
categories of active subjects, moderately active and highly active, Although these are positive findings, it is important to note that
individuals had a 20 and 27% lower stroke risk, respectively, the intervention time window and exercise intensity are critical to
than the low active subjects. Although vigorous exercise is the outcome. In this regard, some studies have reported that low-
more effective, it seems that people who usually exercise at intensity exercise induces better effects on a spatial learning task
moderate levels can also see some benefit in preventing stroke. in a water maze test and on both object recognition and location
Considering that participating in moderate activity applies to the tasks than high-intensity exercise (Shih et al., 2013; Shimada et al.,
much of the population, this issue may be better explored in 2013). Overall, animal data suggest that physical exercise plays a
future studies. role in cognitive function, thereby enhancing cognitive reserve.
The benefits of exercise have also been supported by various With regard to pre-stroke, although there is little information on
studies in individuals who have had a stroke. For instance, cognitive effects, animal studies have clearly demonstrated that
there is robust evidence for the beneficial effects of exercise on pre-ischemic exercise may minimize stroke severity in functional
improving cardiorespiratory fitness and mobility after stroke. motor outcomes (Ding et al., 2004).
This evidence is based on a Cochrane Systematic Review which
included 2,797 participants from 58 studies to examine the Neurobiological Mechanisms
influence of physical exercise on stroke recovery (Saunders et al., Several mechanisms by which physical exercise exerts an effect in
2016). The supportive effect of exercise on rehabilitation post- the prevention of and recovery from stroke are similar from those
stroke has also been documented in clinical guidelines (Billinger observed in the neurological diseases mentioned above. Acute
et al., 2014). In addition to the above benefits, improvement ischemic stroke patients reporting a high level of physical activity
in cognitive function has been reported in several controlled prior to stroke were associated with greater VEGF expression and
trials applying structured physical training to stroke patients good outcomes after stroke (López-Cancio et al., 2017).

FIGURE 2 | Model of how exercise can confers brain resilience. Exercise positively influences brain and cognitive reserve by multiple pathways, protecting against the
consequences of stressful events, improving health, and reduce the risk of chronic disease.
Many pre-clinical studies have examined the possible role of activities to reduce physical/psychological stress, improve our
physical exercise in pre-conditioning and tolerance to cerebral health, and reduce the risk of chronic disease. The literature
ischemia. Exercise pre-conditioning-induced neuroprotection is has clearly demonstrated aerobic fitness as one of the best
mediated by multiple processes, such as maintenance of the indicators of resilience. This is supported by evidence from
integrity of the blood-brain barrier, anti-inflammatory effects, a number of studies showing that physical fitness confers
neovascularization, neurogenesis, and reduced excitotoxicity physiological and psychological benefits and protects against
(Islam et al., 2017). For instance, data from animal models the development of stress-related disorders, as well as improves
with cerebral ischemia or stroke submitted to exercise training cognition and motor function that are a consequence of
have demonstrated positive neuroplasticity resulting in better aging and of neurological disorders. Although we have learned
cognitive performance, which can be attributed to increased about neurobiological mechanisms of physical fitness from the
expression of BDNF, synapsin-I, and post-synaptic density neuroplasticity and neuroprotection that confer resilience, these
protein 95 (PSD-95) (Shih et al., 2013). Consistent with findings effects and mechanisms are diverse and complex and need to
reported in health and in different brain diseases, it is supposed be further explored. However, we can summarize that exercise
that BDNF plays an import role in this process because modulates several mechanisms that may increase brain health
the improvement in spatial learning induced by exercise is and counteract brain disorders (Figure 2). Exercise positively
reduced after the TrkB-BDNF receptor is blocked (Griesbach influences neuronal reserve by increasing BDNF expression
et al., 2009). Furthermore, better cognition in exercised which promotes neurogenesis and synaptic plasticity, reduces
animals has been associated with increased neurogenesis after oxidative stress and inflammation, and enhances cerebral and
cerebral ishemia (Luo et al., 2007) and increased antioxidant peripheral blood flow, which stimulates angiogenic factors that
enzyme activity in the hippocampus in rats with bilateral lead to positive changes in the structure and morphology of
common carotid artery occlusion (Cechetti et al., 2012). brain vasculature. All these changes shape brain activity and
In sum, the pre-clinical findings clearly demonstrate that serve as a buffer against stress-related disorders. Positive findings
exercise has an important effect on metabolic and neurotrophic have also been observed concerning the effects of exercise on
influences, which can explain its role in brain health and cognition and therefore cognitive reserve. However, several null
supportive action in terms of both resilience to and prevention findings, not reported here, should be analyzed with caution
of stroke. because different types of exercise intervention are confounders
that can interfere with the studies’ outcomes. The influence of
CONCLUSION exercise variables includes the duration, frequency, intensity,
and length of exercise. To this point, several exercise regimens
Nowadays, we are constantly bombarded by media, physicians, have been used to determine the optimal stimulus on brain
and other health professionals to engage in physical/sports resilience. However, the evidence for dose-response relationship

between exercise and brain/cognitive reserve in different life physical exercise in early life can prevent or delay cognitive
stages is not well comprehensive. Research investigating different decline in later life, (2) the effectiveness of exercise programs for
dose-parameters of exercise both in animal and human has individuals across the life span and for those with neurological
generated inconsistent results. These conflicting results may be diseases, and (3) how much exercise is necessary to gain beneficial
partially attributed to the diversity of classifications used for effects on cognitive health. This is a field of research that
high or low exercise intensity, volume and type (aerobic or deserves more attention. Thus, it is unquestionable that multiple
resistance or anaerobic) of exercise that can be beneficial for interacting factors, not explored in this review, including
brain resilience (Wipfli et al., 2008; Vidoni et al., 2015; Kramer nutritional status and the link between genes and environment,
and Colcombe, 2018; Greene et al., 2019). For older population, mediated by epigenetic changes that occur at critical periods
a systematic review and meta-analysis reported that healthy of development may confer vulnerability or resilience to brain
subjects should perform both aerobic and anaerobic exercises, of disorders. Overall, this review provides an insight into the
moderate intensity, for at least three times per week and those current evidence of physical exercise’s contribution to the
with cognitive impairments, exercise with shorter duration and increase in resilience and brain tolerance to aging, pathology,
higher frequency to obtain better cognitive outcomes (Sanders and insult.
et al., 2019). In general, the American College of Sports Medicine
recommendations should be applied (ACSM American College AUTHOR CONTRIBUTIONS
of Sports Medicine, 2013).
While several models of physical activity or exercise may RMA and LTM participated in the design of the work, the
impact positively on brain resilience such yoga, dance, martial bibliographic review and writing of the manuscript. Both authors
arts, etc., in this review we aimed to focus mainly on the approved the submitted version.
effects of aerobic exercise of low and moderate intensity
or resistance exercise. Thus, physiological markers including FUNDING
heart rate variability, blood pressure and cortisol might be
regularly used as indicator of stress to determine the impact of This work was supported by Coordenação de Aperfeiçoamento
exercise on brain resilience. Some examples of stress systems de Pessoal de Nível Superior—Brasil (CAPES-PRINT #
are the immune-inflammatory system, the HPA—axis and the 88881.310490/2018-01); Conselho Nacional de Desenvolvimento
autonomic nervous system (Meggs et al., 2016). Disturbance Científico e Tecnológico (CNPq # 301732/2018-3;
of these systems could lead to hyperactivity of the HPA-axis, 408676/2018-3); and Fundação de Apoio à Pesquisa e à
sympathetic activation and systemic inflammation. However, Inovação Tecnológica do Estado de Sergipe -Brasil (FAPITEC/SE
there are still unanswered questions concerning (1) whether # 1920300604/2020-8).
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published: 20 January 2021

The Contribution of Physical Exercise

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