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Sports Medicine
ISSN 0112-1642
Sports Med
DOI 10.1007/s40279-015-0408-6
Effects of Intermittent Fasting, Caloric
Restriction, and Ramadan Intermittent
Fasting on Cognitive Performance at Rest
and During Exercise in Adults
Anissa Cherif, Bart Roelands, Romain
Meeusen & Karim Chamari
1 23
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REVIEW ARTICLE
Effects of Intermittent Fasting, Caloric Restriction, and Ramadan
Intermittent Fasting on Cognitive Performance at Rest
and During Exercise in Adults
Anissa Cherif
1
•
Bart Roelands
2,3
•
Romain Meeusen
2,4
•
Karim Chamari
1
Ó Springer International Publishing Switzerland 2015
Abstract The aim of this review was to highlight the potent
effects of intermittent fasting on the cognitive performance
of athletes at rest and during exercise. Exercise interacts with
dietary factors and has a positive effect on brain functioning.
Furthermore, physical activity and exercise can favorably
influence brain plasticity. Mounting evidence indicates that
exercise, in combination with diet, affects the management
of energy metabolism and synapt ic plasticity by affecting
molecular mechanisms through brain-derived neurotrophic
factor, an essential neurotrophin that acts at the interface of
metabolism and plasticity. The literature has also show n that
certain aspects of physical performance and mental health,
such as coping and decision-making strategies, can be neg-
atively affected by daylight fasting. However, there are
several types of intermittent fasting. These include caloric
restriction, which is distinct from fasting and allows subjects
to drink water ad libitum while consuming a very low-calorie
food intake. Another type is Ramadan intermittent fasting,
which is a religious practice of Islam, where healthy adult
Muslims do not eat or drink during daylight hours for 1
month. Other religious practices in Islam (Sunna) also
encourage Muslims to practice intermittent fasting outside
the month of Ramadan. Several cross-sectional and longi-
tudinal studies have shown that intermittent fasting has
crucial effects on physical and intellectual performance by
affecting various aspects of bodily physiology and bio-
chemistry that could be important for athletic success.
Moreover, recent findings revealed that immunological
variables are also involved in cognitive functioning and that
intermittent fasting might impact the relationship between
cytokine expression in the brain and cognitive deficits,
including memory deficits.
Key Points
Both exercise and nutrition influence brain structure
and function. Exercise while fasting can be a genuine
challenge for athletes’ cognitive function.
Physical activity exerts neuroplasticity-enhancing
effects that are potentially mediated by
neuroimmune mechanisms and brain-derived
neurotrophic factor.
Systemic inflammation can also occur in intermittent
fasting through the maintenance of neurotrophic
support for hippocampal neurons, which are part of a
major brain structure involved in spatial learning.
1 Introduction
Physical activity and exercise promote health, assist with
weight management, and avoid and reduce health prob-
lems, vascular disease and inflammatory disease [1].
& Anissa Cherif
anissa.cherif@aspetar.com
1
Athlete Health and Performance Research Center, Aspetar-
Qatar Orthopaedic and Sports Medicine Hospital,
PO Box 29222, Doha, Qatar
2
Department Human Physiology, Faculty of Physical
Education and Physiotherapy, Vrije Universiteit Brussel
(VUB), Brussels, Belgium
3
Fund for Scientific Research Flanders (FWO), Brussels,
Belgium
4
School of Public Health, Tropical Medicine and
Rehabilitation Sciences, James Cook University, Townsville,
QLD, Australia
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Sports Med
DOI 10.1007/s40279-015-0408-6
Author's personal copy
Moreover, they have both been associated with the reduced
prevalence of a number of physical and mental disorders
[2]. In their review, Dishman et al. [3] stated that physical
activity and exercise can favorably influence brain plas-
ticity by facilitating neurogenerative, neuroadaptive, and
neuroprotective processes [3]. Moreover, Chytrova et al.
[4] showed that exercise acts on specific molecular systems
that control axonal growth and synaptic plasticity, which
are also modulated by diet [4]. Exercise, coupled with a
balanced diet, works as a means to prevent or even reverse
negative health effects. For instance, obesity, which is
induced by nutritional imbalance, may cause a variety of
diseases such as cardiovascular diseases, type 2 diabetes,
and depression [3]. Obesity is also an important factor that
can be responsible for a decline in cognitive function [3].
Therefore, exercise and nutrition are both powerful means
that influence brain structure and function [5]. Diet and
regular exercise are two non-invasive approaches that can
be used to enhance neural signaling by influencing synaptic
transmission, brain plasticity, and cogni tive function [4, 6].
Regular exercise enhances certain types of learning,
including the executive functions of cognition, learning and
memory span, and it also stimulates neurogenesis [3, 7].
Diet can also provoke significant change s in energy
expenditure, oxidative damage, insulin sensitivity, and
inflammation, including functional changes in both the
neuroendocrine and sympathetic nervous systems [8].
Gomez-Pinilla [1] showed that exercise, in combination
with dietary factors, affects the management of energy
metabolism and synaptic plasticity by affecting molecular
mechanisms through brain-derived neurotrophic factor
(BDNF), which acts at the interface of metabolism and
plasticity [1]. Interestingly, the results of recent research
indicate that insufficient levels of exercise and poor dietary
practices are considered risk factors for various neurode-
generative diseases such as Alzheimer’s [9, 10].
Elite sporting efforts require optimal physical and
cognitive capabilities for maximal performance. The lit-
erature indicates that certain physical performance aspects
can be negatively affected by daylight fasting [11, 12].
Furthermore, there are many types of intermittent fasting
(IF) that are practiced differently from one religion to
another. Caloric restriction (CR) is distinct from fasting
and allows subjects to drink water ad libitum while
consuming a very low-calorie food intake. Ramadan
intermittent fasting (RIF) is a religious practice of Islam
during which healthy adult Muslims neither eat nor drink
during daylight hours. Moreover, some religious practices
in Islam (Sunna) advise all adul t Muslims to also practice
IF outside of the month of Ramadan. The current litera-
ture regarding the effects of different types of dietary
restrictions on cognitive performance is summa rized in
Sect. 2.
Interestingly, the majority of the experiments investi-
gating the effects of fasting on cognitive performance in
athletes have assessed athletes while in resting conditions,
i.e., not during exercise sessions. This represents a signif-
icant limit to the conclusions drawn by these studies.
Indeed, it is not possible to conclude that fasting does not
impact the cognitive performance of athletes during exer-
cise when the cognitive tests are performed outside of an
exercise session. Furthermore, regarding the assessment of
cognitive performance during exercise, the available
information is scarce [13–15], and currently, it indicates
that depending on exercise intensity, cognitive function
could be improved or negatively impacted [16]. Moreover ,
these studies focused on continuous endurance exercise.
This aspect of studying cognitive function while exercising
has to be combined with the effects of fasting to verify if
the responses of fasted subjects differ from those of fed
subjects. Moreover, depending on the sport or activity,
exercise patterns during competition are not always con-
tinuous and of constant intensity. Indeed, during team
sports (e.g., soccer, handball, rugby, etc.), performance is
composed of repeated bouts of intense exercise and athletes
must make important decisions while exercising and
between or even within intensive actions (e.g., decision of
movement and reaction to a corner kick in soccer).
Therefore, the repeated-sprint ability (RSA) tests were
designed to replicate the demands of an intense period of
play during multiple-sprint sports and involve the repeti-
tion of explosive actions with relatively short periods of
rest in between [17].
Food and fluid intake before, during, and after both
training and competition has important implications for
performance [17]. The absence of fluid intake in the day
may have an even greater impact on performanc e than the
absence of food [18]. Even mild dehydration may have
adverse effects on a number of physiological and cognitive
functions that are important components of performance.
Collectively, these changes may cause perturb ations that
alter the physiological responses to exercise, which may
have detrimental effects on sports performance [19].
Therefore, the present review article will elucidate the
fascinating and potent effects of IF on the cognitive per-
formance of athletes at rest and during exercise (Table 1).
The relevant literature was reviewed, including studies
on healthy subjects with control groups/conditions. Studies
testing subjects with pathologies were excluded. Addi-
tionally, experiments on the effects of any type of fasting in
extreme conditions such as altitude or hyperthermia were
also excluded from the current review. A literature search
was conducted from 1992 to 2015 through the PubMed and
Web of Knowledge databases, using specific key words:
‘exercise,’ ‘brain,’ ‘cognitive performance,’ ‘physical
performance,’ ‘nutrition,’ ‘collaborative effects of diet and
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Table 1 Effects of different dietary interventions on cognitive performance of athletes at rest and during exercise
Caloric restriction Intermittent fasting Ramadan intermittent fasting
Authors Effect Authors Effect Authors Effect
Mattson [30] : Lifespan
; Many age-associated diseases
: The general health of overweight humans
Izumida et al. [50] ; Weight
Delayed aging
Optimized health
Chaouachi et al. [11],
Thomson and
Sutherland [72]
; Afternoon performance in
many sports
: Fatigue at the end of
Ramadan intermittent fasting
Mattson and Wan
[31]
; Several risk factors for coronary artery
disease
; Blood pressure
: Insulin sensitivity
Greenberg et al. [51] : Brain function and peripheral
energy metabolism
Mansur et al. [86],
Dantzer et al. [87]
Protected neurons against
dysfunction and
degeneration
: Levels of antioxidant
defenses and anti-
inflammatory IL-10
: Protein chaperones (heat
shock proteins)
Green et al. [28] : Lethargy, depression, irritability
; Heart rate
; Intellectual functioning
; Concentration and memory
; Ability to remember
; Simple reaction times
Mattson [48], Cahill [49],
Izumida et al. [50]
: Parasympathetic activity
: Gut motility
; Heart rate
; Blood pressure
: Lipolysis
Egan et al. [133] :
Dehydration
; Cognitive function
; Performance on a sustained attention task
Mansur et al. [86], Dantzer
et al. [87]
Protected neurons against
dysfunction and degeneration
: Levels of antioxidant
defenses and anti-
inflammatory IL-10
: Expression of BDNF and
protein chaperones such as
HSP-70
; Levels of circulating pro-
inflammatory IL-1b, IL-6, and
TNF-a
Bruss et al. [111] ; Inflammation
Improved glucose
Green et al. [32] ; Cognitive function Kim and Diamond [74] ; Lipopolysaccharide (LPS) Boden et al. [116] Improved fat metabolism
Singh et al. [25],
Singh Kalra and
Fults [26]
: Performance on behavioral tests of
sensory and motor function and learning
and memory
Benton, [117], Boden et al.
[116]
; LDL, TC, TG, and HDL
levels
Improved fat metabolism
Kim and Diamond [74] : Expression of BDNF
Lee et al. [27] : Brain function in adult rats
: Synaptic plasticity
: Production of new neurons from neural
stem cells
Benefer et al. [118], Boden
et al. [116], Bruss et al.
[111]
; Insulin levels
Improved glucose
: Glucose tolerance
Mansur et al. [86],
Dantzer et al. [87]
; Levels of circulating pro-
inflammatory IL-1b
, IL-6,
and TNF-a
Fasting, Cognitive Performance and Exercise
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exercise on cognitive performance,’ ‘impact of intermittent
fasting dietary restriction on physical performance,’ and
‘BDNF.’
2 Effects of Caloric Restriction, Intermittent
Fasting, and Ramadan Intermittent Fasting
There has been a recent increasing awareness of the par-
ticular effects of different dietary interventions, and their
specific mechanisms are beginning to be understood. In the
present review, we will highlight the three most published
protocols in the literature: CR, IF, and RIF.
2.1 Caloric Restriction
Recently, CR has gained considerable popularity, as some
physicians find these diets easy to follow. CR is distinct
from fasting and typically refers to a 20–40 % daily
reduction in calorie intake. CR is used in clinics by
physicians and allows patients to drink water ad libitum
while consuming a very low-calorie food intake for a week
or more. This diet is used for weight management and/or
disease treatment [20–22]. More recently, the effects of CR
have been studied in different model organisms to dete r-
mine the molecular mechanisms by which dietary inter-
ventions may modulate lifespan in both human and non-
humans [23, 24]. These studies indicated that reduced
nutrient intake without falling into malnutrition could
increase the mean and the maximum lifespan of rats [24].
According to Singh et al. [25], moderate CR in rats
enhances performance on behavioral tests for sensory and
motor functions, as well as lea rning and memory [26]. CR
can also increase brain function in adult rats, where it has
been associated with increased synaptic plasticity and
increased production of new neurons from neural stem
cells [27]. In contrast, other studies revealed that severe
food deprivation might contribute to dieting-related deficits
in cognitive function [28, 29].
Ongoing studies of CR in humans now allow the anal-
ysis of changes in the brain and explain some of the
mechanisms related to associated alterations in cognitive
performance. CR has been demonstrated to prolong lifes-
pan, preventing many age-associated diseases, and it
improves the general health of overweight humans [30].
Mattson and Wan [31] also revealed that CR has an
important role in regulating both cardiovascular and brain
functions. More over, CR can effectively prolong lifespan,
preventing most age-associated diseases by ameliorating
several risk factors for coronary artery disease, such as
increased blood pressure and decreased insulin sensitivity
[31]. However, long-term food restriction was associated
with lethargy, depression, irritability, and reduced heart
Table 1 continued
Caloric restriction Intermittent fasting Ramadan intermittent fasting
Authors Effect Authors Effect Authors Effect
Mattson [23] : Brain function
Might forestall age-related cognitive
decline in humans
Cahill [49] : Maintenance of muscle mass
Witte et al. [34] : Performance on memory tests after 30 %
caloric reduction for 3 months
: Performance on memory tests
Warren and Frier [101] : Brain function by enhancing
Neurogenesis and synaptic
plasticity
: BDNF
Lee et al. [27],
Suzuki et al. [98]
: Hippocampal neurogenesis
: BDNF, IGF-1, and VEGF
: increases, ; decreases, BDNF brain-derived neurotrophic factor, HDL high-density lipoprotein, HSP-70 heat shock protein, IGF-1 insulin-like growth factor 1, IL interleukin, LDL low-density
lipoprotein, TC total cholesterol, RIF ramadan intermittent fasting, TG triglycerides, TNF-a tumor necrosis factor, VEGF vascular endothelial cell growth factor
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rate, as well as a range of self-reported impairments in
intellectual functioning, including the inability to concen-
trate and poor memory [32]. Dieting to lose weight has also
been associated with impairments in cognitive function,
including poorer performance on a sustained attention task
[33]. This result was simulated in another study that
demonstrated that in addition to a deficit in sustained
attention, self-reported dieting was associated with a
reduced ability to remember and slower simple reaction
times (RTs) [32 ].
Therefore, a combination of moderate CR and exercise
could potentially enhance brain function and may forestall
age-related cognitive decline in humans. Witte et al. [34]
demonstrated that when the caloric intake of 50 normally
fed elderly subjects was reduced by 30 % for 3 months,
their performance on memory tests significantly improved
compared with two different control diet groups [34].
Nutrition can also substantially influence the development
of brain structure and function. Indeed, nutrition provides
the proper building blocks for the brain to create and
maintain neural connections, which are critical for
improved cognition [5]. Dietary factors have broad and
positive actions on neuronal function and plastici ty [5].
Brain function is undoubtedly dependent on adequate
nutrition, and short-term variations in the amount and
composition of nutrient intake in healthy individuals may
influence measures of cognitive function [5].
In summary, diet manipulation can generate positive or
negative cognitive outcomes, depending on the dieting
pattern, which is predominantly influenced by the extent of
CR. Recent studies on animal models and human subjects
revealed strong beneficial effects of regular exercise or CR
on cognitive function [23].
2.2 Intermittent Fasting
IF generally involves a ‘feast day’ on which food is con-
sumed ad libitum, which alternates with a ‘fast day,’ during
which food is withheld or strongly reduced. Another form
of IF involves eating only one meal per day. For instance,
during the month of Ramadan, healthy adult Muslims are
required to abstain from ingesting both food and fluids
during daylight hours (from dawn to sunset). Other types of
fasting are commonly found in other religious practices
such as Christianity [22, 35], Judaism [36, 37], and Bud-
dhism [38]. For instance, Greek Orthodox Christians fast
for a total of 180–200 days each year, and their principal
fasting periods are the Nativity Fast (40 days prior to
Christmas), Lent (48 days prior to Easter), and the
Assumption (15 days in August). These fasting periods can
be described as a variant of vegetarianism [22]. During the
Nativity fast, fasters abstain from dairy products, eggs, and
meat during the 40 consecutive days. They also abstain
from fish and olive oil consumption on Wednesdays and
Fridays during this period. During Lent, fasters also abstain
from dairy products, eggs, and meat every day; they abstain
from consuming olive oil on weekdays and from fish every
day except March 25th and Palm Sunday. During the
Assumption, fasters abstain from dairy products, eggs, and
meat; they abstain from olive oil on weekdays and from
fish every day except August 6th. In addition to these
principal fasts, every Wednesday and Friday that fall out-
side of a principal fasting period call for the proscription of
cheese, eggs, fis h, meat, milk, and olive oil. Exceptions to
these proscriptions occur on the week following Christmas,
Easter, and the Pentecost [22, 39]. IF can also include
alternate-day fasting or 3-days-a-week fasting, every 2 or
more weeks. Some religious practices in Islam (Sunna) also
advise adult Muslims to fast the Islamic way every Monday
and Thursday and for 3 consecut ive days in the middle
(days 13, 14, and 15) of lunar months in the Islamic Cal-
endar [40]. IF has shown potential to impact the physical
and cognitive performance of fasters, even if this is chal-
lenged by several studies [41–43]. However, this impact
appears to be dependent on the task performed, the dura-
tion of the fast, and the time of day of the assessments [44].
In rats, the combination of IF (alternate-day fasting) and
treadmill exercise resulted in greater maintenance of
muscle mass than IF or exercise alone [45]. Findings from
animal experiments, as well as emerging human stud ies,
indicate that fasting may be an effective strategy to reduce
weight, delay aging, and optimize health [46 ]. According to
Longo and Mattson [47], IF modifies brain neurochemistry
and neuronal network activity in ways that optimize brain
function and peripheral energy metabolism [47]. Four brain
regions that are particularly important in adaptive respon-
ses to IF include the hippocampus (cognitive processing),
striatum (control of body movements), hypothalamus
(control of food intake and body temperature), and brain-
stem (control of cardiovascular and digestive systems) [3].
The brain communicates with all peripheral organs
involved in energy metabolism [48]. IF enhances
parasympathetic activity (mediated by the neurotransmitter
acetylcholine) in the autonomic neurons that innervate the
gut, heart, and arteries, resulting in improved gut motility
and reduced heart rate and blood pressure. By depleting
glycogen from liver cells, fasting also results in lipolysis
[49, 50]. In addition, when food is scarce, the liver
becomes the storage site for triacylglycerols (TAGs), thus
acting as a reservoir of energetic substrates that can be
liberated [51]. When the stored TAGs are depleted, the free
fatty aci ds (FFAs) and glycerol released are directly oxi-
dized as an energy source by certain tissues (liver and
muscle) [50 ]. Moreover, adenosine triphosphate can be
produced through the oxidation of FFAs, and glycerol can
be used as a substrate in gluconeogenesis or lipogenesis
Fasting, Cognitive Performance and Exercise
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[50]. Therefore, adipose tissue can directly and indirectly
modulate the availability of other metabolic substrates
[52].
Certain beneficial effects of IF on both the cardiovas-
cular system and the brain are mediated by BDNF sign al-
ing in the brain [53]. Interestingly, cellular and molecular
effects of IF and CR on the cardiovascular system and the
brain are similar to those of regular exercise, suggesting
shared mechanisms [31]. Indeed, the Dishman et al. [3]
review suggested that chronic physical activity increases
the expression of genes that encode several brain neu-
rotrophins such as BDNF and nerve growth factor [3].
Widenfalk et al. [ 54] studied the potential effects of
physical training on the expression of neurotrophic factors
and their receptors in the rodent brain. They found that
chronic exercise increased the expression of genes that
encode several brain neurotrophins such as BDNF [54]. In
addition, chronic physical activity may als o have neuro-
generative and neuroprotective influences on the brain by
stimulating the growth and development of new cells and
protecting against ischemic neuronal damage in the hip-
pocampal formation [55]. Both the action and function of
BDNF are presented later in this review.
2.3 Ramadan Intermittent Fasting
RIF is one of the five pillars of Islam. It occurs during the
ninth month of the Islamic lunar calendar, during which
healthy adult Muslims abstain from food and fluid intake
from dawn (el fajr) to sunset for approximately 30 days
[56]. The duration of the daytime fast varies and is sig-
nificantly impacted by the location and season. The typical
fasting duration is generally 10 h, but can exceed 18 h [57–
62]. A longer daylight period is found at extreme latitudes,
and for these extreme fasting durations, some religious
exceptions may apply [63]. Several studies examined the
effects of RIF, and their findings indicated that it may
induce either positive or negative effects on mental health
[64], coping strategies, and decision-making strategies
[65]. RIF causes major changes in sleep patterns, eating
habits, and physical activity, which may cause changes in
metabolism. Many aspects of these changes have been
studied. For example, Alabed et al. [66] developed a
questionnaire to assess subjective estimates of physical,
mental, and social activities, as well as fatigue. They dis-
covered that there were several changes that occurred
during daytime fasting, as the daytime mental, physical,
and social activities all decreased below control values
[66]. There is now ample evidence that RIF negatively
affects afternoon performance in many sports and elicits
higher feelings of fatigue at the end of RIF [19, 67].
However, morning and evening (after breaking the fast)
performances are generally not affected by RIF [19, 68].
Several cross-sectional and longitudinal studies have
demonstrated that RIF has a crucial effect on the physical
and intellectual performance of Muslims by affecting var-
ious aspects of bodily physiology and biochemistry that are
important to athleti c success. Thus, both the physical and
cognitive aspects of exercise can be a true challenge for
fasting Muslim athletes during the daytime throughout RIF.
3 Fasting/Caloric Restriction and Cognitive
Function
3.1 Effects on the Immune System, Syste mic
Inflammation, and Cytokines
According to the results of recent studies, system ic
inflammation/sepsis can be considered a risk factor for
cognitive impairment [69, 70]. There is now ample evi-
dence that pro-inflammatory mediators may disturb hip-
pocampal neuronal functions through the relationship
between neuronal plasticity and working memory, a fun-
damental process for specific brain functions [71–73].
Cytokines such as interleukin-1b (IL-1b), IL-6, and tumor
necrosis factor-a (TNF-a) are important in hippocampal
neural signal transmission (long-term potentiation) and
dendritic convergence, which are processes involved in
memory formation and memory preservation [69, 74].
Several studies showed that there is considerable evidence
for a relationship between cytokine expression in the brain
and cognitive deficits, including memory deficits [75, 76].
Indeed, neuroinflammation can negatively affect neuroge-
nesis and lead to impaired survival and proliferation of new
neurons. This negative effect is a result of immunoresponse
to different exogenous and endogenous stimuli through
cells within the brain such as microglia and the action of
signaling molecules such as pro- or anti-inflammatory
cytokines [73]. Moreover, TNF-a and IL-6 are critical for
neuroinflammation-induced memory impairment and are
known to disrupt cognition through pathways related to
neural plasticity, neurogenesis, and long-term potentiation
[69, 77–79]. Certain neurons in the preoptic nucleus have
receptors for IL-1b, IL-6, and TNF-a, to which the
cytokines bind and thus pass from circulation into the brain
[80]. Consequently, hippocampal IL-1 b overexpression
impairs contextual and spatial long-term memory [69].
Therefore, previous animal studies have shown that CR and
IF protect neurons against dysfunction and degeneration by
increasing the levels of antioxidant defenses and anti-in-
flammatory IL-10, increasing the expression of BDNF and
protein chaperones such as heat shock protein (HSP-70),
and reducing the levels of circulating pro-inflammatory IL-
1b, IL-6, and TNF-a [81, 82]. In addition, IF can also
inhibit lipopolysaccharide (LPS)-induced increases in
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serum interferon-c (IFN-c), sugges ting that the anti-in-
flammatory effect of IF is not restricted to the central
nervous system [69]. Vasconcelos et al. [69] showed that
systemic inflammation can also be established by IF
through the maintenance of the neurotrophic support for
hippocampal neurons [69], which are part of a major brain
structure involved in spatial learning [83].
Recently, peripheral infection has also been shown to
activate the immune system thr ough a message to the brain
that leads to the production of cytokines [84]. Conse-
quently, excessive expression of pro-inflammatory cytoki-
nes in the brain has been indicated to be a central factor in
the development of cognitive impairment [85–88]. There-
fore, regulating the inflammatory response in the brain
following a peripheral infection may be important in pro-
tection against behavioral disorders [89].
Furthermore, one possible mechanism by which the
peripheral inflammatory response may affect cognitive
function could be through interference with the expression
of BDNF [73, 90, 91]. Lapchak et al. [92] showed a sig-
nificant reduction of BDNF gene expression within the
brain by injecting pro-inflammatory IL-1b into the rat
hippocampus [92]. Moreover, physical activity may also
exert neuroplasticity-enhancing effects potentially medi-
ated by neuroimmune mechanisms. In fact, Lee et al. [27]
demonstrated that exercise and CR might enhance hip-
pocampal neurogenesis by similar mechanism s involving
the upregulation of the expression of trophic factors
including BDNF, insulin-like growth factor 1 (IGF-1), and
vascular endothelial cell growth factor (VEGF) [27, 93]. A
study by Nascimento et al. [94] on the effects of physical
exercise on peripheral BDNF levels and on TNF-a and IL-
6 as pro-inflammatory markers in cognitive, healthy indi-
viduals showed that exercise is effective in reducing pro-
inflammatory cytokines and increasing peripheral BDNF
levels with positive effects on cognition [94]. Moreover,
Whiteman et al. [95] showed an increase in plasticity
mechanisms in the hippocampus [95], and Van Praag et al.
[96] demonstrated that exercise and IF could optimize
brain function by enhancing neurogenesis and synaptic
plasticity [96]. The latter is indeed a critical aspect of the
brain responsible for learning and memory through BDNF,
IGF-1, and other growth factors and hormones [95]. These
data confirm that immunological variables are involved in
cognitive functioning and that fasting or CR might impact
this relationship.
3.2 Effects on Biochemical Parameters: Insulin,
Glucose, Free Fatty Acids, Cholesterol,
and Triglycerides
Nutrition provides the building materials for the brain to
produce and preserve connections between brain structures
and function, which is important for enhanced cognition
[5]. Because of the important role of glucose for the brain
as the source of energy [97
, 98], acute hypoglycem ia
results in a rapid deterioration of some aspects of cerebral
function [97]. Glucose passes through the blood–brain
barrier for entry into both neurons and astrocytes. Glyco-
gen is stored in astrocytes [99] and is rapidly converted into
pyruvate/lactate and metabolized in the tricarboxylic acid
cycle or used for the biosynthesis of glutamate [100]. Both
glucose and lactate can then be exported to neurons as fuel
[99]. Draelos et al. [97] examined neuropsychological
function during experimentally induced periods of hyper-
glycemia and hypoglycemia to determine the impact of
glycemic control on cognitive function. The outcomes of
their study showed that severe hypoglycemia (\2.2 mmol/
L) causes impairments in all measured aspects of cognitive
function including RT (simple and choice) [97]. Further-
more, even modest hypoglycemia (a blood glucose level of
2.6–3.0 mmol/L) can cause a measurable performance
decrease, with complex tasks being more sensitive to
hypoglycemia than simple tasks [101]. Dalsgaard et al.
[102] indicated that glucose and lactate uptake by the brain
increased out of proportion with O
2
when the brain was
activated by exhaustive exercise [102]. Therefore, these
metabolic changes seem to be influenced by the will to
exercise and the exercise load [102]. Moreover, mental
stimulation was considered by Madsen et al. [103]tobea
physiological activation during which the ratio O
2
/glucose
becomes reduced [103]. Findings by Williamson et al.
[104] indicated that intense exercise increases physiologi-
cal activation of the brain [104], and in that case, energy
demand surpasses energy production [105]. This imbalance
in the energy produced and the energy demanded may
cause glycogen depletion in the brain regions activated
during intense exercise and has been proposed as a possible
cause of the end of exercise [102]. In contrast, a review by
Amigo and Kowaltowski [106] reported that reduced food
intake over short periods of IF consistently improves glu-
cose tolerance. They also note, however, that in vertebrate
organisms, the brain is responsible for *25 % of total
body glucose consumption [106]. This energy consumption
is required to maintain ionic balance in neurons, produce
action potentials, generate post-synaptic currents, and
recycle neurotransmitters [107, 108]. All of these charac-
teristics show the reliance of the brain on glucose and that
it is an organ highly sensitive to energy deficits [106 ]. In
addition, during fasting, Brow n [109] demonstrated that
astrocytes, but not neurons, can accumulate glucose in the
form of glycogen, which acts as a short-term energetic
reservoir in the brain [109]. Indeed, this argument has been
tested in vivo by Suzuki et al. [98] by injecting inhibitory
avoidance compounds into rat hippocampus. Their out-
comes revealed that astrocyte–neuron metabolic coupling
Fasting, Cognitive Performance and Exercise
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mechanisms play a critical role in memory formation. They
also demonstrated that learning leads to a significant
increase in extracellular lactate levels, which are derived
from glycogen, an energy reserve selectively localized in
astrocytes [98]. Therefore, Suzuki et al. [98] revealed that
astrocytic glycogen could be directly related to learning
and that the glycolytic end product lactate appears to play a
role in long-term memory formation; however, the exact
mechanism has not yet been established [98]. Amnesia can
be caused by disturbing the expression of astrocytic and
neuronal lactate transporters, suggesting that lactate import
into neurons is necessary for long-term memory. To
demonstrate that astrocytic glycogen metabolism is
required in the hippocampus for long-term memory for-
mation, Suzuki et al. [98] injected an inhibitor of glycogen
phosphorylation, 1,4-dideoxy-1,4-imino-
D-arabinitol
(DAB), into the rat hippocampus before or immediately
after training. The obtained results indicated that DAB
injection did not affect short- and long-term memories.
However, to prove that astrocyte–neuron lactate transport
is required for long-term memory formation, Suzuki et al.
[98] injected a combination of DAB and
L-lactate into the
hippocampus of rats before and after training using in vivo
microdialysis [110]. Their results confirmed that DAB-in-
duced amnesia could be rescued by the administration of
exogenous lactate and that astrocyte–neuron lactate trans-
port is required for long-term memory formation [98].
Accumulating evidence suggests that in healthy adults,
most syst emic changes induced by IF, CR, or RIF, such as
decreased inflammation and improved glucose- [106] and
fat-metabolism [111], protect against brain damage [106].
Many studies have confirmed that IF decreases serum low-
density lipoprotein (LDL), a major protein component of
LDL cholesterol, and also decreases total cholesterol,
triglycerides, and high-density lipoprotein cholesterol levels
[112]. Moreover, certain evidence suggests that after 3
weeks of alternate-day fasting, body fat and insulin levels
decrease [113]. Elevated concentrations of FFAs in plasma
cause insulin resistance (IR) in humans throu gh the inhibi-
tion of glucose transport activity [114]. Furthermore, both
local and circulating FFAs could be considered important
factors in the induction of IR, hyperlipidemia, and inflam-
matory processes [114, 115]. Indee d, Boden et al. [116]
found, through studying mechanisms by which FFAs cause
hepatic IR in male rats, that FFA-caused hepatic IR is
associated with the increased expression of inflammatory
cytokines such as TNF-a and IL-1b and also with hyper-
glycemia and the overproduc tion of glucose [116].
3.3 Effects of Dehydration
Water is a major constituent of cells, and approximately
60 % of the body is composed of water, which is necessary
in numerous basic functions [117]. To study the effect of
hydration on cognition, Benefer et al. [118] examined the
relationship between fluid intake and cognitive function
following endurance exercise in a group of recreational
runners and walkers. Based on the water intake factor
scores, their outcomes showed a significant improvement
in short-term memory [118]. Other studies have used
extreme conditions to show the impact of hydration on the
brain, such as a study by Lieberman et al. [119] in which
subjects who had exercised for 53 h in hot conditions
experienced alterations in mood and performance for a
range of cognitive functions, including vigilance, RTs,
attention, memory, and reasoning [119]. In contrast, the
effect of hydration in cold conditions was tested and
exhibited no effect on cognitive, psychomotor, or self-re-
ported parameters [120]. Food and fluid intake before,
during, and after both training and competition have an
important impact on sport performance [121], and early
symptoms of dehydration are headaches and feeling tired
and lightheaded. Additionally, dehydration deteriorates
mental performance by *10 %, and drinking more water
improves the ability to learn [117].
It has been shown that certain components of football
performance (physiological and cognitive functions) can be
indirectly affected by dehydration [122]. These change s
can indirectly disturb the physiological responses to exer-
cise, which may negatively affect sports performance [19].
There is now ample evidence that attention is reduced in
conditions of thirst [
123, 124]. In fact, dehydration
exceeding a 1 % loss of body weight resulted in poorer
performance on a visual vigilance task and slower RTs on a
working memory task [125]. Several cross-sectional and
longitudinal studies have established the assoc iation
between the aforementioned negative effects of dehydra-
tion and cognitive performance [123, 125]. Prolonged
states of reduced water intake can also result in an
increased perceived effort during exercise. Kempton et al.
[126] used magnetic resonance imaging and showed that
when dehydrated, subjects used a higher level of neuronal
activity to complete the same performance level [126].
However, few studies have reported on the effect of
dehydration due to IF without fluid consumption. One such
study by NasrAllah and Osman [127] explored the effect of
fasting among 52 patients with chronic kidney disease
during RIF. Their results suggested that dehydration occurs
during daytime fasting and is reversed at sunset but that its
effects are difficult to assess because of these daily fluc-
tuations. Despite variations in kidney function, they did not
notice any changes in blood pressure, which, however,
does not necessarily exclude the possi bility of dehydration
[127]. Further studies should explore the possible impact of
fasting and dehydration on cognitive functioning in greater
depth and detail.
A. Cherif et al.
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4 Effect of Exercise and Nutrients on the Brain:
Brain-Derived Neurotrophic Factor
Exercise and nutrition are both powerful factors that influ-
ence the brain [128]. Studies on both animals and humans
describing the important effects of exercise and diet on the
health and plasticity of the nervous system are increasingly
emerging [5]. This combination undeniably affects funda-
mental and molecular processes related to the management
of energy metabolism and broad aspects of synaptic plas-
ticity; the latter is believed to be essential for learning and
memory. Therefore, learning capacity is affected by the
action of BDNF, an essential neurotrophin [5, 129] that is a
central contributor to the effects of exercise on synaptic and
cognitive plasticity [ 130]. BDNF regulates not only synaptic
plasticity but also neurogenesis and neuronal survival in the
adult brain [131]. The induced mechanisms include neuro nal
protection and survival, neurite expression, axonal and
dendritic growth and remodeling, neuronal differentiation,
synaptic plasticity (such as synaptogenesis in arborizing
axon terminals), and synaptic transmission efficacy [132].
The principal BDNF function is essential to learning and to
maintaining memory capacity in humans [133, 134]. There is
a direct link between the pathways associated with metabo-
lism and synaptic plasticity, and this association can deter-
mine important aspects of behavioral plasticity such as
learning and memory [130, 135]. Specifically, exercise
modulates molecular systems in the brain associated with
energy balance and energy transduction. Thus, exercise has
the capacity to affect learning and memory by (1) activating
the secretion of IGF-I, which plays a role in synapt ic plas-
ticity [93, 136]; (2) stimulating neurotransmitter synthesis
and release [137]; and (3) supporting cognitive function
[138, 139]. Therefore, the general conclusion is that exercise
has a positive influence on cognition, and it simultaneously
increases BDNF levels [5]. Recently, an exer cise regimen
known for its capacity to enhance learning and memory was
reported to mediate its effects through a BDNF-related
mechanism [140]. Of all the neurotrophins, BDNF is con-
sidered most susceptible to regulation by exercise and
physical activity, and it acts at the interface of metabolism
and brain plasticity [1, 132]. Consequently, exercise and
BDNF have been associated with reduced symptoms of
depression and the promotion of cognitive enhancement
[141]. Therefore, exercise can influence the epigenome to
reduce depression and enhance cognitive abilities [1, 7, 142].
The BDNF levels in blood samples from subjects who
underwent endurance training for 3 months versus more
sedentary control subjects showed evidence that endurance
training increases BDNF release from the human brain [143].
Moreover, a review by Dishman et al. [3] suggested that
chronic physical activity increases the expression of genes
that encode several brain neurotrophins including BDNF and
nerve growth factor [3]. Widenfalk et al. [54] studied the
effects of physical training on the expression of neurotrophic
factors and their receptors in the brain using animal models
and also discovered that chronic exercise can increase the
expression of genes that encode several brain neurotrophins,
such as BDNF [54]. Recently, IF has also been prove n to
stimulate BDNF production in the hippocampus, cerebral
cortex, and striatum. Vasconcelos et al. [69] showed that the
reduction of hippocampal BDNF levels in an LPS-treated rat
model of systemic inflamm ation was prevented by IF [69].
Additionally, IF reduces cognitive deficits in rats by sup-
pressing the expression of pro-inflammat ory cytokines, such
as IL-1 b, and enhancing neurotrophic support. Because
BDNF plays critical roles in hippocampal synaptic plasticity
and cogni tive function, the maintenance of BDNF signaling
most likely contributes to the beneficial effects of IF on
cognitive function in LPS-treated rats [92]. There is now
ample evidence that both acute aerobic and anaerobic exer-
cise elevate serum BDNF in athletes and sedentary partici-
pants when compared with participants at rest. A wealth of
literature confirms that an acute bout of intensive aerobic or
anaerobic physical activity is capable of elevating serum
BDNF levels in both sedentary subjects and athletes [132,
144, 145]. Vaughan et al. [146] showed that a multimodal
exercise program resulted in neurocognitive and physical
performance improvements and increased levels of plasma
BDNF in older women when compared with controls.
Therefore, this study shows that both acute and chronic
exercise could increase BDNF concentrations in humans,
most likely explaining the positive effects of physical
activity on cognitive performance [146]. BDNF can also
reduce food intake, increasing glucose oxidation, which
consequently results in a decrease in blood glucose levels
and an increase in insulin sensitivity [147]. In animals, a
high-fat diet reduces the hippocampal concentration of
BDNF [148], but exercise is able to reverse this dietary-
related decrease [149].
In summary, studies on animals have shown that exer-
cise and IF increase BDN F expression in several regions of
the brain and that BDNF partially mediates the exercise-
and IF-induced enhancement of synaptic plasticity. BDNF
signaling in the brain may also affect behavioral and
metabolic responses to fasting and exercise, including the
regulation of appetite, activity levels, and peripheral glu-
cose metabolism.
5 Conclusion
Exercise impacts brain functioning, but information on the
effects of the combination of exercise and IF (CR, RIF and
IF) on cognitive function is scarce. Research has revealed
Fasting, Cognitive Performance and Exercise
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that regular exercise enhances certain types of learning,
including the executive functions of cognition, learning,
and memory span, and it also stimulates neurogenesis.
Moreover, depending on the type of IF, cognitive function
and physical performance could be either improved or
negatively impacted. Several studies have demonstrated
that long-term food restriction was associated with
impairments in cognitive function, including poor perfor-
mance on a sustained attention task. However, other studies
have shown that memory performance significantly
improved during fasting. In the investigation of the
mechanisms by which dietary restriction acts on cognitive
function and to determine how these diets work, further
detailed and unified research studies are necessary.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the prepa-
ration of this article.
Conflicts of interest Anissa Cherif, Bart Roelands, Romain
Meeusen, and Karim Chamari declare that they have no conflicts of
interest relevant to the content of this review.
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