Hypothesis

Environmental affordance for physical activity,
neurosustainability and brain health: Quantifying the built
environment's ability to sustain BDNF release through
reaching metabolic equivalents (METs)
Mohamed Hesham Khalil*

Department of Architecture, University of Cambridge, Cambridge CB2 1PX, UK
*E-mail: mhmhk2@cam.ac.uk

Abstract: Unlike enriched environments for rodents, human built environments often hinder
neuroplasticity through sedentary lifestyles, impairing cognition and mental health. This paper
introduces "environmental affordances for physical activity" to quantify the potential of spatial
layout designs to stimulate activity and sustain neuroplasticity, mainly hippocampal
neurogenesis. A novel framework links metabolic equivalents (METs) of urban and architectural
variations to brain-derived neurotrophic factor (BDNF) - a biomarker that promotes and sustains
adult hippocampal neurogenesis and long-term potentiation (LTP). Equations are developed to
assess neurosustainability potential through BDNF changes measurable after brief exposure to the
built environment for 20-35 minutes, as evidenced to be feasible to cause BDNF release through
low to moderate intensity physical activity. The model provides a feasible assessment tool,
bridging design and neuroscience. By sustaining neurogenesis, environmental affordance for
physical activity holds promise for improving mental health and preventing cognitive decline
through the sustainability of hippocampal neurogenesis.

Keywords: Environmental enrichment; Humans; Architectural design; Built environment;
Neuroplasticity; Spatial layout and navigation

1. Introduction
Physical activity is considered the critical element for environmental enrichment in

rodent studies in the form of running wheels or the additive effect of structural
enrichment to the housing cage that promotes physical activity. However, the translation
of physical activity into humans’ lifestyles through the sole reliance on physical exercise
reveals that the built environment cannot promote physical activity through its design,
which can hinder the sustainability of the hippocampal neurogenesis process and
cortical plasticity. In that regard, this article introduces environmental affordance for
physical activity as a sustainable model for neurosustainability through the built
environment. The model was developed after the premise that physical activity
immediately releases brain-derived neurotrophic factors (BDNF) and other growth
factors, which can be measured in blood and are necessary for regulating hippocampal
and cortical plasticity processes. This article explores the relationships between
architectural design and BDNF through the mediating role of metabolic equivalents
(METs) that can quantify the architectural design’s capability for environmental
affordance for physical activity. Figure 1 briefly illustrates the conceptual model before
subsequent sections explore and explain the mechanisms at a quantifiable level.

Brain Sci. 2024, 14, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/brainsci

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Brain Sci. 2024, 14, x FOR PEER REVIEW 2 of 23

Figure 1. Environmental affordance for physical activity as a sustainable model for
neuroplasticity.

2. Physical activity mechanisms for plasticity
Physical exercise has long been considered a critical modulator of an increase in

neuroplasticity changes, neurotrophic factors such as BDNF, and improvements in brain
function. A recent systematic review of human and animal studies confirmed that
physical exercise increases neuroplasticity through the neurotrophic factors (BDNF,
GDNF, and NGF) and receptors that provide improvements in neuroplasticity and
cognitive function in humans and animals alike [1]. While physical exercise is known to
have long-term changes in the human brain, specifically in the hippocampus [2-4], it is
difficult to reduce the volume changes to which plasticity phase and it is more difficult
to tell how can the built environment be a successful promoter for an increase in
hippocampus volume if changes are measured after several months. Therefore, it is
essential to explore the impact of the physical environment’s capability to increase the
immediate release of neurotrophic and growth factors that are known to promote and
regulate the neurogenesis, synaptic plasticity, and neurosustainability of the multistage
plasticity process in the long term in a sustainably consistent manner. Interestingly,
biomarkers are more feasible and testable, and some can be representative by measuring
only after one trial of less than one hour [5,6]. This section explores the most reliable and
evident factors.



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2.1. Neurotrophins and the reliable role of the brain-derived neurotrophic factor (BDNF)
As mentioned, BDNF is an effective mediator of physical activity's role in regulating

neurogenesis and increasing hippocampal volume, but it may not be the only effective
factor.

Till the 1990s, the neurotrophin family was renowned for two factors responsible
for the survival and functional maintenance of neurons: the nerve growth factor (NGF)
and BDNF before the identification of the neurotrophin-3 (NT-3) in the same family
[136], and later the discovery of neurotrophin 4/5 (NT-4/5) [7,8]. Those neurotrophin
growth factors provide essential insights into neuroplasticity as they provide important
insights into how nerve cells communicate during the development of the nervous
system and in neuroplasticity, memory, and learning in the adult nervous system [9].

Regarding the mediating role of the neurotrophins as a result of physical activity, a
recent review highlights a positive relationship between physical activity and BDNF
levels while highlighting less clear evidence published for the other neurotrophins:
NGF, NT-3, NT-4/5 [10]. The review has concluded that 3 months of moderate-intensity
exercise, with 2-3 sessions per week lasting not less than 30 minutes, can be an
inexpensive strategy for boosting BDNF release, which this paper sees as comparable to
the expected effect of environmental affordance for physical activity, therefore, relying
on BDNF among the neurotrophins. Another review came to the same conclusion that
there is no unanimity between BDNF regulation in humans, unlike in rodents, yet still,
BDNF upregulation appears to be in relative agreement, unlike NT-4/5, which displays
inconsistent conclusions [11]. The latter review considered articles focusing on training
protocols ranging from 4 to 48 weeks in humans, which may explain the lack of
unanimity, unlike the other review. More recently, further articles shed light on the
relationship between BDNF and physical activity on humans' cognitive function and
depression [12-13], both are known to be associated with the level of AHN. A study
explores the interactions between BDNF, plasticity, and depression [14]. Therefore, we
can expect BDNF to be an effective mediator between physical activity and AHN, as
even when hippocampal volume is used as a dependent variable instead of actual count
in humans, the dependency of increased cognitive function and reduced depression
proves its mediating role.

To further explain the mediating role of BDNF in changes in depression and
cognition as two proxy measures of AHN, newly formed neurons at different
maturation stages may play distinct roles in learning and memory [15]. Disruptions in
this neurogenic process have been associated with several cognitive and psychological
disorders, including issues with memory encoding, mood disorders, and dementia [16].
Studies found reduced hippocampal volume and decreased neural progenitor cells in
the dentate gyrus of humans with major depressive disorder compared to healthy
controls [17,18], while antidepressant treatments were found to increase hippocampal
volumes and promote AHN in animals and humans [19,20]. Additionally, patients with
a history of depression were found to have reduced hippocampal activation during a
memory task compared to healthy controls [21]. On the other hand, regarding cognitive
function, higher levels of AHN are associated with better performance on a pattern
separation task [22]. Additionally, post-mortem studies identified that individuals with
Alzheimer's disease (AD) exhibit reduced AHN compared to age-matched controls [23].
Therefore, the mediating role of BDNF between physical activity and AHN in humans
can be relied on effectively among all neurotrophins.

The actions of BDNF in the neurogenesis and neuronal function and its
involvement in the abovementioned pathophysiology and brain diseases were discussed
[24], who highlight the important role of BDNF in the differentiation, maturation, and
synaptic function in the central nervous system. They explained that BDNF stimulates
mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK),
phosphoinositide-3 kinase (PI3K), and phospholipase C (PLC)-gamma pathways mainly
through the activation of tropomyosin receptor kinase B (TrkB), which is a high-affinity



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receptor protein for BDNF that plays a key role in neural development [25]. Another
study further elaborates that those signalling pathways have a significant contribution to
neurogenesis and synaptic plasticity [24].

The effect of physical activity and exercise on BDNF in humans has been
extensively reviewed for over a decade. Early in the last decade, a study reported the
effect of a single bout of exercise and training on the BDNF expression in the brain, in
both the working muscles and in the blood, concluding that there are potential benefits
to the release of BDNF in the brain and peripheral tissues after exercise [26]. However,
they highlighted that the effect on humans required more research. Later, a review
revealed through 32 studies that peripheral BDNF concentrations were elevated by acute
and chronic aerobic exercise and not through strength training [27]. Afterward,
researchers explored in their systematic review, meta-analysis, and meta-regression how
different physical exercise parameters modulate BDNF in healthy and unhealthy adult
humans, concluding that a frequency of 2-3 times per week with an intensity of at least
65% of VO2max (the maximum amount of oxygen that an individual can utilise during
intense or maximal exercise) and a moderate-intensity continuous training type for at
least 40 minutes noting that BDNF is further improved in lengthier interventions as well
as in more intense exercise [28]. Later, researchers explored the effect of physical exercise
on neuroplasticity and brain function through a systematic review of both human and
animal studies, finding that physical exercise increases neuroplasticity through growth
factors, including not only BDNF but also NGF and the glial cell line-derived factor
(GDNF), which is shortly discussed subsequently [1]. The authors concluded that
physical exercise was effective in increasing the production of neurotrophic factors, cell
growth, and proliferation, in addition to improving brain function. Similarly, researchers
have explored the physical activity-BDNF-cognition triumvirate, revealing that the
literature is heterogeneous [29]. Nevertheless, the specific physical activity type and
dose for optimal BDNF release is still unclear. In that regard, researchers conducted a
systematic review and Bayesian network meta-analysis on the effects of different
physical activities on BDNF, revealing that resistance training > high-intensity interval
training > combined training > aerobic training and resistance training > aerobic training
alone ​​> control group, suggesting that resistance training at moderate intensity can
promote brain health [30]. The review confirms the additive effects of greater intensities
on elevated BDNF.

To date, and despite the evidence of the positive effect of physical exercise on BDNF
and plasticity in healthy adults, some limitations and gaps still exist. For instance, there
is a lack of evidence clarifying the effects of physical activity on neurotrophic factor
levels in patients with Parkinson's disease [31]. Similarly, in middle and late life,
researchers found in their systematic review and meta-analysis that there is a significant
effect of resistance exercise on insulin-like growth factor 1 (IGF-1), to be discussed
subsequently, but not on BDNF, while the effect on the vascular endothelial growth
factor (VEGF), to be discussed subsequently, could not be determined due to the lack of
sufficient studies [32]. However, another study found an improvement in BDNF among
older women, irrespective of exercise type [33]. We can predict that variances among
elders are due to the association between age, activity intensity, and type of exercise
through the lens of presented reviews. Most recently, researchers have revealed in their
systematic review of 17 articles that aerobic exercise at various intensities, specifically at
high intensity, can influence cortical excitability and result in cognitive improvement
[34]. The authors highlight the role of exercise on neuroplasticity through the reviewed
direct cortical and structural changes. The latter review solidifies the explored role of
BDNF and other brain growth factors in mediating the role of physical exercise and
neuroplasticity. Regarding hippocampal plasticity, researchers found no effect of aerobic
exercise training on hippocampal volume among cognitively unimpaired healthy elders
[35]. This is contrary to earlier studies showing that aerobic exercise training increased
hippocampal volume compared to control groups [36,37], suggesting that intense



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physical activity can contribute to enhancing the hippocampal CA2/CA3 volume in
young adults [38]. This is in line with the earlier study showing that improving
cardiorespiratory fitness after exercise training is associated with an increased volume in
the left dentate gyrus/CA3 subregion in young adults [37], which might be associated
with neurogenesis as there is an increase in the dentate gyrus volume. This paper
concludes that age-related variability needs to be considered when designing and
interpreting experimental studies. This can be supported by a systematic review and
meta-analysis suggested that aerobic exercise interventions can help prevent age-related
hippocampal deterioration and maintain neuronal health [39]. Another systematic
review and meta-analysis revealed that moderate-intensity continuous training and
resistance training can augment hippocampal volume to prevent and treat adults with
neurodegenerative diseases such as Alzheimer's disease [40].

This paper considers BDNF the most reliable and effective growth factor mediating
the relationship between physical activity and AHN. It can be effectively measured after
a single bout of an intervention, yet the long-term effect will always be subject to
consistency, intensity thresholds, and duration. Still, this does not impose the use of
BDNF to test the effectiveness of environmental affordance for physical activity to
increase AHN, hippocampal volume, and BDNF release, reduce depression, and
improve cognition in adult humans.

2.2. Supportive growth factors: VEGF and IGF-1
As evident through the presented state-of-the-art literature, not only the BDNF

from the neurotrophins family is an effective mediator between physical activity and
neuroplasticity but also other brain growth factors. Little is known regarding the effect
of GDNF on neuroplasticity in humans after physical activity. At the same time, the
latest meta-analysis and meta-regression shows through the analysis of 11 studies that
while BDNF, IGF-1, and VEGF are essential for brain plasticity and cognitive function,
physical activity has a significant effect on BDNF and IGF-1 only [41]. Therefore, in
addition to the role of BDNF, the IGF-1 is also explored. IGF-1 manages the effects of
growth hormones (GH) in the body [42-43], and IGF-1 is one of the insulin-like growth
factors family that also includes the IGF-2 and others. Both factors and their receptors
are widely expressed in nervous tissues, playing a role in developing and maintaining
the nervous system, such as in some neurodegenerative diseases and neuroprotective
actions [44]. IGF-1 has been shown to have potent effects on central nervous system
development, plasticity, and post-injury therapy [45]. A study discussed the role of
IGF-1 in hippocampal plasticity after traumatic brain injury [46], while another explored
the role of serum IGF-1 in adult human brain morphology [47], proving through
magnetic resonance imaging (MRI) that IGF-1 and the growth hormone (GH) contribute
to brain growth and that it can be a treatment option for neurodegenerative disorders
and brain injury in humans. Interestingly, a study reported that a reduction in
insulin-like growth factor family member expression predicts neurogenesis marker
expression in schizophrenia and bipolar disorder [48]. A study explains that IGF-1
modulates neuronal excitability and synaptic plasticity at multiple sites, while at the
system level, IGF-1 intervenes in energy allocation, proteostasis, mood, cognition, and
circadian cycles [49]. With the role played by IGF-1 towards neuroplasticity evidenced, it
is essential to investigate its interrelationship with physical activity further to achieve
the aim of this paper. Researchers conducted a systematic review and meta-analysis on
resistance training and IGF-1, revealing that it increases IGF-1 for those who received
training for 16 weeks or less among participants older than 60 years old and among
women [50]. In their systematic review and meta-analysis, researchers show that IGF-1
serum concentrations are altered by exercise type yet in conditions that are not
well-defined and that there is no determinant in the serum IGF-1 changes for the
exercise load characteristics [51]. Regarding the duration, an increase of serum IGF-1,



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ranging from ~10 to 30%, has been measured after 5–10 min of high-intensity bouts of
exercise in healthy individuals [52].

This section concludes that BDNF is the most reliable growth factor among the
neurotrophic family and among all other growth factors when it is related to
neuroplasticity as a matter of investigation. Exploring the effects of physical activity on
BDNF is essential, and exploring it in addition to other growth factors such as IGF-1,
VEGF, and others can provide further insights into integrative processes. Testing
environmental affordance for physical activity quantified through metabolic equivalent
values, which are explored subsequently, is suggested to be achieved through a single
bout exposure, which needs careful consideration for the minimum exposure duration
and intensity of physical activity through the environment before expecting an increase
in BDNF levels or additional growth factors. Various blood test kits can be used to
measure BDNF increase/decrease in humans [53]. This paper suggests that coupling the
blood test with MRI can provide deeper-level insights [54]. However, it may require
longer than a single bout of physical activity if structural changes in the brain need to be
observed.

Furthermore, not only can BDNF be associated with improved plasticity at the
neurological level, but the role played by the increase of BDNF is promising in multiple
mental health and wellbeing issues such as depression [55,56], which is also a proxy
measure for AHN as introduced earlier in this paper or to hippocampal activity. For
instance, a pilot study found that an eight-week exercise intervention improved mood in
individuals with major depressive disorder (MDD) but did not enhance memory
performance, while both MDD and healthy participants exhibited decreased
hippocampal activity, suggesting exercise may increase neural efficiency in low-fit
individuals [57]. The authors conclude that exercise promotes neuroplasticity in both
healthy and depressed brains, which further affirms the complex interrelationship
explored in this paper to urge designing environments with affordance for physical
activity. Additionally, an article explored how environmental factors, particularly
exercise and diet, influence neural plasticity through mechanisms involving BDNF
signalling and proposes leveraging these insights to create a "lifestyle pill" for enhancing
cognitive function [58]. Thus, environmental affordance for physical activity can be a
promising and effective mediator for BDNF, neuroplasticity, and neurosustainability.

3. From physical activity to neurogenesis and plasticity: BDNF Molecular mechanisms
The key role played by BDNF, from responding to METs achieved by

environmental affordance for physical activity to its role in regulating and sustaining
neurogenesis and neuroplasticity, is complex and layered. This section explains the
molecular mechanisms of BDNF and how it achieves its action on adult hippocampal
neurogenesis and neuroplasticity.

It is important to note that BDNF is encoded by the BDNF gene, known for its
intricate structure and regulatory mechanisms [59,60]. BDNF is considered a crucial
protein in the nervous system, integral to neuronal survival, growth, and synaptic
plasticity, but the gene can be read in different ways to produce slightly different
versions of the BDNF protein. In other words, the BDNF gene's ability to produce
multiple protein variants enables it to support a wide range of functions in the brain.
Depending on what the brain needs at any given time—whether during development, in
response to learning new things, or in healing after injury—the gene can produce the
specific BDNF most beneficial for those conditions.

Regarding the mechanisms through which BDNF takes place while acting on
plasticity in response to stimuli, such as physical activity in this case, BDNF is first
synthesised as proBDNF, a precursor that can be cleaved into mature BDNF (mBDNF)
[61,62]. mBDNF is essential for promoting neuronal survival and enhancing synaptic
connections, directly impacting learning and memory. The conversion of proBDNF to



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mature BDNF can occur in a relatively short time frame. Intracellular processing by furin
happens quickly as part of the secretion pathway.

BDNF exerts its effects primarily through binding to the TrkB receptor, leading to
receptor dimerization and autophosphorylation [63]. This binding activates multiple
intracellular signalling pathways that promote neuronal differentiation, survival and
synaptic plasticity [64]:

a. MAPK/ERK Pathway: This pathway is involved in cell proliferation and
differentiation, migration [65].

b. PI3K/Akt Pathway: Critical for promoting cell proliferation, survival, and
metabolism [66].

c. PLCγ Pathway: Involved in synaptic plasticity and neurotransmissions [67].
Those pathways are critical to the perpetual adult hippocampal neurogenesis

process from proliferation to differentiation and survival until the synaptic integration of
new neurons. In addition to its regulation of neurogenesis, BDNF continues to have
effective action on synaptic plasticity after or during synaptic integration, influencing
long-term potentiation (LTP), a long-lasting enhancement in signal transmission
between two neurons, often considered a cellular correlate of learning and memory,
through the activation of MEK-ERK [68]. A summary of how BDNF mediates physical
activity to sustain neurogenesis and regulate LTP through the molecular mechanisms
discussed is illustrated in Figure 2.

Figure 2. Molecular mechanisms BDNF regulates neurogenesis and plasticity by physical activity.

4. Methodological feasibility
The premise on which the concept of environmental affordance for physical activity

is explored subsequently is the feasibility of testing BDNF and other growth factors
immediately or in conjunction with long-term hippocampal changes. Figure 3 explained
the methodological concept of environmental affordance for physical activity, which is
explained in the subsequent section before an assessment tool is developed afterward.

Physical activity is measurable after a single bout of exposure, while other variables
have delayed effects, making it feasible to test environmental affordance for physical
activity. A study showed a possible change of BDNF after 20 minutes of low to moderate
gardening physical activity [6]. Similarly, another study exposed healthy older adults to
35-minute sessions of physical exercise, cognitive training, and mindfulness practice and
then compared the results regarding changes in BDNF levels between the three
activities, showing that a single bout of physical exercise has a significantly larger
impact on serum BDNF levels than cognitive training or mindfulness in the same person



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[5]. BDNF level changes from baseline at 0, 20, and 60 minutes after each intervention
ranged between 2 to 3.5 ng/ml for physical exercise unlike the other two interventions.

Figure 3. Mechanisms and methods of testing environmental affordance for physical activity.

BDNF is an immediate and sustainable factor. The immediate release of BDNF is
argued to be due to its release at the peripheral nervous system (PNS), but it also
releases in the central nervous system (CNS), and BDNF is permeable through the
blood-brain barrier [69,70]. Post-exercise BDNF release is also evident long term [71], yet
it may depend on physical activity type and dose of activity [29], intensity [28], and age
may be another factor.



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Whether to use serum or plasma BDNF is critical to consider in future research. The
amount of BDNF increase in the blood can be tested in plasma or serum. Plasma BDNF
increased after cognitive exercise and physical exercise (up to 222%) and rest (∼67%),
but serum BDNF elevated only after physical exercise (up to 18%) before returning to
baseline after rest. Acute but not prolonged physical exercise increased both plasma and
serum BDNF. Cognitive exercise induced acute changes in plasma BDNF only [72].

5. Environmental affordance for physical activity: BDNF, METs and agents
To increase BDNF release and other growth factors in the human brain, the

environment has to afford inducing metabolic equivalent values (METs), defined as a
simple and practical means of quantifying the energy cost of activities [73], in a given
point in time through its spatial layout. This paper supports the interrelationship
between meeting the MET values and the release of BDNF where a 20-min
low-to-moderate intensity gardening activity intervention activity (Mean 3.5 METs) was
sufficient to significantly increase the levels of BDNF as well as the platelet-derived
growth factor (PDGF) [6], which is one among multiple growth factors that regulate
diverse functions in the central nervous system such as neurogenesis, cell survival,
synaptogenesis and other neuro-related functions. The author later explained in another
study that the gardening intervention revealed an association between increased BDNF
levels, cognitive ability, and serotonin metabolism, showing the additive effects of the
approach [74].

A comprehensive list of METs of household chores and recreational activities was
provided [73], from which this paper derives the means for environmental affordance
for physical activity, which is further explored through existing literature. While the
resource examples for heavy housework such as grocery shopping, washing floors,
washing windows, cooking, ironing, and so forth [73], this paper does not count them as
forms of environmental affordance for physical activity because they are not spatially
dependent but lifestyle-related. However, walking and climbing stairs are forms of
environmental affordance for physical activity, which can be promoted through the
design of the built environment.

5.1. Walking
Walking was quantified depending on the intensity [73], so this paper adopts the

lowest form of walking as 3 km/h, which can be of a light, moderate, or heavy intensity
with MET values of 3, 4, and 5, respectively.

To distinguish between light, moderate, and heavy intensities, the reference
distinguished them as when the activity results in only minimal perspiration and only a
slight increase in breathing above normal (light intensity), results in definite perspiration
and above normal breathing (moderate intensity), and results in heavy perspiration and
heavy breathing (heavy intensity) [73]. This paper supports the argument through a
study showing that low-intensity daily walking activity is associated with hippocampal
volume in older adults [75], and interestingly, this is in line with the effect of treadmill
walking exercise on hippocampal volume preservation [76]. However, it is worth noting
that a study reported that the change in hippocampal volume after 13 months of using
treadmills yet was not mediated by changes in BDNF levels [77]. However, an earlier
study explains that inverse correlations turn into positive correlations with all
circulating BDNF levels immediately after exercise [135]. This suggests that
neuroplasticity-related changes in the hippocampus and BDNF increase are not
synchronous. In other words, it is suggested that measuring BDNF after walking should
take place immediately after the walking activity, while measuring hippocampal
neuroplasticity does not have an immediate result. This distinction further supports the
suggested role of BDNF as one among multiple brain growth factors that promote
neurosustainability by facilitating the neuroplastic changes themselves.



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The MET value through walking can primarily depend on the scale of the
environment, urban or interior. Former environments have abundant networks unlike
the latter, but knowing that people spend the majority of their time inside built
environments poses a great challenge still [78]. The extent to which walking can be of a
light, moderate or high intensity is arguable due to the extended walking, which might
be more feasible in the urban rather than interior environment.

Several variables can influence walking at the urban level. For instance, street
features are found to shape pedestrians’ leisure walks in cities [79], green space has an
effect on walking as well [80], or that people can get nudged into physical activities
through minor changes to the urban landscape [81]. This is a non-exhaustive list of
potential variables that we argue in this paper to be a necessary agent for increasing
walking as necessary for releasing BDNF in the human brain.

At the interior level, we argue that certain design features can play an important
role in influencing walking as well depending on the building type and the layout
design. Different types of utilitarian walking such as walking to other activities, to front
entry and so forth are influenced by design features but marginally influenced by the
number of stories of the building [82], which we explore subsequently. A systematic
review found that increasing opportunities for walkable spaces and reducing physical
barriers can result in higher levels of physical activity among the elderly [83].

Regarding residential buildings, increasing the area through the spatial layout
design may not be merely effective for promoting physical activity. For instance, in a
study done on rodents, merely increasing the housing size is proven not to increase
physical activity [84]. This is in line with research on humans, where a study found that
apart from house size, families spend the majority of their time at home in the same
space [85]. The antidote to promote walking is argued to be through the spatial layout. A
recent study also shows that residential buildings with traditional house layout patterns
appear to have an advantage over modern or Western styles regarding spending the
least time on sedentary activity due to the fact that traditional houses are designed with
the separation of living and sleeping areas from kitchens, toilets, and bathrooms through
the presence of courtyards and corridors, unlike western modern houses that are
designed with integrated areas [86]. Therefore, architectural design needs to critically
consider how to encompass environmental affordance for physical activity through
layout design in order to increase step count inside homes, workspaces, and other
building uses in order to meet at least the minimum METs for walking, especially that
counterbalancing the effect of sedentary behaviours at home is mainly explored through
the lens of exercise equipment [87].

Last but not least, a recent study has found that employees in workplaces with
linear layouts tend to have more physical activity than those in radial layouts, which is
also found to affect mental health [88].

5.2. Climbing stairs
Using the stairs was quantified as of light, moderate, or heavy intensity with MET

values of 4, 6, and 8, respectively [73]. The distinction between the three forms of
intensity is similar to how it is explained in the previous section.

There are no studies in the literature regarding neuroplasticity or BDNF release
after immediate or long-term use of climbing staircases, but several studies indicate that
there is a gap rather than a lack of evidence. For instance, studies indicate that short
bouts of stair climbing in a naturalistic setting and brief stair-climbing interventions can
induce cognitive benefits and mood states [89,90], which suggests that it is an effective
means for environmental affordance for physical activity, and in this paper, we argue
that climbing staircases can have a greater effect than walking given the higher MET
values. A study discussed that exercises of ≤1-min bouts throughout the day can
improve cardiorespiratory fitness and reduce the negative impact of sedentary
behaviours, relying on more evidence on the benefits of climbing stairs that aligns with



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this argument [91]. Most recently, a randomised controlled crossover trial demonstrate
that interval stair climbing can confer immediate psychological benefits [92], providing
further evidence that climbing stairs is a promising means to address physical inactivity
issues, which this paper takes as additional support for using stairs as a structural form
of environmental enrichment to satisfy environmental affordance for physical activity to
release BDNF and further promote neuroplasticity.

The MET value through climbing stairs can primarily depend on the heart rate
induced potentially by the frequency of using the staircase in a fixed time and also
arguably the staircase design too. As mentioned above that stair climbing has low,
moderate and high intensities that result in various METs, we explained that it is
dependent on indicators such as breathing which is well studied through, for instance,
heart rate [93-96]. This method should help with identifying the mean value of MET to
be used to predict the change in BDNF levels, which will be explained later in this
article.

Regarding the influence on the use of vertical circulation, evidence suggests that
once the destination was in sight, regardless of whether it had high or bare visibility,
participants made an instantaneous decision to switch floors and move up toward the
destination [97], which we argue can be a promoter for staircase use to release BDNF by
meeting the MET values. However, it is crucial to consider that the interaction between
visibility and prior background expectations affects wayfinding efficiency and strategy
during vertical navigation tasks [98], which we suggest to be taken into consideration in
the experiment design process when people are familiar with the environment. Those
studies offer valuable insights into initial calls for research and interventions on the
influence of building design and site design on physical activity by considering stairs,
layout, and building form [99]. Authors discussed the need to provide staircases in
homes as a requirement for MET-based physical activity [78]. Hence, this paper
concludes that the design of the layout both horizontally and vertically may lead to
various extents of overcoming sedentary behaviours by increasing environmental
affordance for physical activity to release BDNF in the human brain.

5.3. Environmental agents
Table 1 synthesises key findings from the previous section regarding the design and

quantification of environmental affordance for physical activity. We explained that the
intensity of physical activity can be identified through heart rate measures and can be
influenced by several built environment factors at the architectural and urban levels.

Certain environmental agents can drive the use of the environment, after its
affordance for physical activity through structural enrichment, but through visual cues
rather than merely the structural enrichment per se. For example, certain aesthetic
variables (such as hominess or fascination) may affect environmental use differently
[100,101]. We expand the exploration of environmental agents to include elements in the
environment that may drive environmental use and may or may not be associated with
the aesthetic variables per se. For example, if natural stimuli influence environmental
use rather than artificial ones, it may or may not be associated with an aesthetic variable
such as hominess or fascination. In that regard, Figure 4 illustrates the linear relationship
expected between environmental agents (natural or artificial), aesthetic variables, and
increase in frequency depending on the dynamics between the two former variables. It
also explains potential methods either using likert scales and core effect as found to be
effective in recent studies [101], or through combined Mobile/EEG and eye tracking that
can be more insightful [102-104]. Testing this model should be feasible through
real-world experimentations or virtual reality [105,106].



Brain Sci. 2024, 14, x FOR PEER REVIEW 12 of 23

Table 1. Environmental affordance for physical activity through metabolic equivalents (METs).

Structural enrichment

METs per Intensity Built environment agents

Light Moderate High Architectural Urban

Walking 3 km/h 3 4 5
e.g., division of space,
zoning, long corridors,

linear layouts…etc

e.g., street
features, green
space, routes

Climbing stairs 4 6 8
e.g., staircase type, floor

visibility, novelty.
N/A

Combined METsmean 3.5 5 6.5

Figure 4. Framework and potential mixed methods for exploring visual environmental agents.

While this paper does not intend to limit the breadth of potential environmental
agents, some examples are given to guide future research at this stage. At the broader
level, environmental agents can be natural or artificial yet both can be aesthetic in
essence. Visual cues found in nature can feature variables such as dynamism,
movement, rhythm, unpredictability, and restorativeness, while human-made variables
can have a greater depth of meaning, such as artwork with an unlimited breadth of
interpretations. Within those two categories individuals can have various responses to
the perceived hominess or fascination, for instance, which may drive the use of a layout
with environmental affordance for physical activity. This is an interesting open-ended
area of exploration.

6. Assessment tool
There are various ways to test if the urban or architectural design has the potential

to hold environmental affordance for physical activity in order to promote
neurosustainability through BDNF release. Some studies will be able to isolate the effect
of walking from the effect of climbing stairs depending on the scale (urban and



Brain Sci. 2024, 14, x FOR PEER REVIEW 13 of 23

architectural) and also depending on the building type. However, at the architectural
level, the effect of the layout design on the extent to which a design holds a potential for
environmental affordance for physical activity will rely on the combined effect of
intermittent use of walking and climbing stairs. In that regard, equations 1-3 explain the
assessment tool based on the expected constant (α) relating METs and time (t) to the
increase of BDNF based on each case and if combined together.

(1)𝐵𝐷𝑁𝐹
𝑠𝑡𝑎𝑖𝑟𝑠

 = α× 𝑀𝐸𝑇
𝑚𝑒𝑎𝑛 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦

 ×𝑡 

(2)𝐵𝐷𝑁𝐹
𝑤𝑎𝑙𝑘𝑖𝑛𝑔

 = α× 𝑀𝐸𝑇
𝑚𝑒𝑎𝑛 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦

 ×𝑡  

(3)𝐵𝐷𝑁𝐹
𝑐𝑜𝑚𝑏𝑖𝑛𝑒𝑑

 = α×( ∑  (𝑀𝐸𝑇
𝑚𝑒𝑎𝑛 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦

 ×𝑡))  

Equation 4 aims to help with understanding the effect size of an urban or
architectural design on the increase of BDNF from the baseline compared to a control
group. However, it is important to note that BDNF posttest varies from the immediate
effect with intervals up to one hour [5]. Testing change in BDNF may be most effective at
the immediate level but it is important to generalise time at which blood samples are
taken from all participants. The study showed that 35 minutes of physical activity did
not yield much difference from cognitive stimulation or mindfulness training [5], which
can help with isolating the effect of environmental affordance for physical activity on
BDNF change.

(4)𝐵𝐷𝑁𝐹
𝑎𝑑𝑗𝑢𝑠𝑡𝑒𝑑

 = 𝐵𝐷𝑁𝐹
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒

 + 𝐵𝐷𝑁𝐹
𝑝𝑜𝑠𝑡𝑡𝑒𝑠𝑡

Regarding expected time of exposure, two studies report that 20 to 35 minutes of
physical activity of low to average intensity is sufficient to cause changes to BDNF levels
[5,6], which facilitates taking the mean value and conducting experiments with control
and experiment groups without time-consuming exposure.

7. Future research directions
The developed methodological means, theoretical framework and assessment tool

for environmental affordances for physical activity are promising to be of interest to
researchers studying the impact of physical activity on public health. This is because
engaging with the environment can sustain adult hippocampal neurogenesis, which
continues into a person's eighth and even tenth decade [107,108].

Testing neurogenesis in humans is less feasible than in animals due to
methodological ethics, which makes shifting focus on boosting the release of BDNF in
humans through environmental enrichment of utmost importance. BDNF is known to
mediate physical activity-dependent neurogenesis [109,110]. The contribution of this
paper is in line with the increasing interest in the relationship between BDNF and
sedentary behaviours. Among multiple studies, BDNF was recently found to be
associated with sedentary patterns in patients with type 2 diabetes mellitus [111], and is
currently being reviewed as inversely associated with such sedentary behaviours among
children and adolescents [112], which makes the contribution of this paper with a model
for an integrative framework as a critically needed antidote for the modern environment
to ensure the neurosustainability of the human brain [113].

This paper provides a stepping stone for future research aiming to counterbalance
the adverse effects of modern environments on the human brain, where sedentary
behaviours are among other factors imposing a dead end for neuroplasticity [114-122].

The theoretical model developed in this paper supports the need for intuitive
innovation that may not be yet fully recognised as a formal area of scientific research but
is considered as critically needed to address complex global challenges through a more



Brain Sci. 2024, 14, x FOR PEER REVIEW 14 of 23

open, interdisciplinary approach to scientific inquiry through the exploration of
unconventional forms of knowledge generation [123]. Despite the promising approach
of every theoretical innovation, some challenges are worth noting at this point:

1. Age differences correlate with neurogenesis rate variances and potentially
variant impact on BDNF change rates. For instance, several studies reported
an age-related decline in adult hippocampal neurogenesis in humans despite
the quantified rate per day, and that this decline varies between healthy
individuals and patients with Alzheimer’s disease [108,124,125]. Therefore,
controlling for age-group variances should be considered in future research.

2. BDNF does not solely respond to physical activity but to many biological and
lifestyle confounding variables. Besides ageing and neurodegeneration, sleep
[126], stress [127,128], and diet [129] are factors that can have confounding
effects. In a recent study, participants were required to be fasting for 9 hours
before blood sampling prior to starting the 20-minute gardening activity [6],
which can be an appropriate way to control diet-related factors in addition to
adequate sleep.

3. Measuring BDNF in real-world settings may be sensitive to temperature, heat
and seasonal variations. Seasonality variations and heat exposure were
reported to affect BDNF levels, as observed in several studies [113].
Therefore, it is essential to control for such external confounding effects.

4. Longitudinal effects of BDNF changes on neurogenesis and brain structure
using MRI brain scans after an average of 3 to 6 months, while recent trends
lean towards the analysis of the postmortem tissue as an alternative means
depending on the population and ethical considerations [130,131].

5. Salivary BDNF methods should be treated cautiously. BDNF results were not
reliable in saliva in three different commercial ELISA kits [132].

6. It is feasible to test changes in BDNF release in serum or plasma, with
concentrations in the former about 100 folds higher than the latter [54].

7. Ethical approvals for blood samples to test BDNF changes may only limit
non-interdisciplinary experimental efforts without collaboration with at least
one researcher with a background in biology or medicine. This encourages
interdisciplinary collaborations or otherwise relies on proxy measures such
as physical activity-dependent heart rate and skin conductance changes
through wearable devices [133].

8. This article highlights that while determining the factor (α) is a preliminary
step before attempting to test the impact of spatial layouts with walking and
climbing affordances, the factor itself for stairs, for instance, may vary
depending on the type of staircase (i.e., straight, with intermediate landing,
l-shaped, double l-shaped, u-shaped, 90 winder, 180 winder, curved, and
spiral stairs), the number of flights, and the riser’s height. Such variability can
affect the intensity that METs already acknowledge, but having a constant (α)
for each staircase type may be a limitation that may be overcome to save time
replicating the same experiment. The same concept applies to layouts with
various areas and spatial division approaches. Unless no combined effect of
walking and climbing is to be studied, the constant (α) may not pose a
limitation.

9. Individual differences, personality traits and lifestyle variability may
influence the interaction with a layout with environmental affordance for
physical activity and the interaction with visual environment agents due to
the meaning-making variability as part of any aesthetic experience [134].
Overcoming this limitation can be achieved through controlling cultural and
social differences.

Those challenges are seen to open more paths to additional research efforts to
bridge methodological, environmental, and individual differences, which can speed the



Brain Sci. 2024, 14, x FOR PEER REVIEW 15 of 23

process of exemplifying environmental affordance for physical activity towards lifelong
neurosustainability.

This paper also follows up on recent evidence suggesting that spending extensive
time inside built environments, specifically homes, has adverse effects on cognition
[137], suggesting that environmental affordance for physical activity can reduce the
negative impact of built environments on brain health. This paper adds another
dimension to the recent evidence showing that natural environments perform better
than built environments in response to stress [138,139], stressing that physical activity
can be another critical variable to consider in the built environment, along with recent
suggestions about biophilia integration. Environmental neuroscience, interested in
understanding how physical environment ingredients impact mental health [140], can
highly benefit from the approach introduced in this article.

8. Conclusion
This paper proposes environmental affordance for physical activity, as summarised

in Figure 5, as a sustainable model for regulating hippocampal neurogenesis and
plasticity processes in the human brain by meeting MET values through the spatial
layout’s structural enrichment in buildings by architectural design. Knowing that the
process of neurogenesis persists till the tenth decade of life and that measuring
neurogenesis in humans is difficult, testing environmental affordance for physical
activity and easily measuring BDNF in serum or plasma immediately after a single bout
of using the enriched environment is highly promising. The developed equations,
framework and methodological guidelines facilitate the use of this assessment tool to tell
if the environment, urban or architectural, is designed with the ability to stimulate
BDNF release in the human brain. This should help overcome not only sedentary
behaviours’ related health issues but also various negative psychiatric and neurological
problems in the modern era associated with the hippocampus function, such as pattern
separation, depression, anxiety, and impaired cognition.

Figure 5. Summary of environmental affordance for physical activity mechanisms for adult
hippocampal neurosustainability.



Brain Sci. 2024, 14, x FOR PEER REVIEW 16 of 23

Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.

Funding: Open access publishing for this article is funded by Cambridge Trust in Partnership with
Jameel Education Foundation

References
1. de Sousa Fernandes, M. S., Ordônio, T. F., Santos, G. C. J., Santos, L. E. R., Calazans, C. T., Gomes, D. A., &

Santos, T. M. (2020). Effects of physical exercise on neuroplasticity and brain function: a systematic review in
human and animal studies. Neural plasticity, 2020(1), 8856621.

2. Firth, J., Stubbs, B., Vancampfort, D., Schuch, F., Lagopoulos, J., Rosenbaum, S., & Ward, P. B. (2018). Effect of
aerobic exercise on hippocampal volume in humans: a systematic review and meta-analysis. Neuroimage, 166,
230-238.

3. Killgore, W. D., Olson, E. A., & Weber, M. (2013). Physical exercise habits correlate with gray matter volume of
the hippocampus in healthy adult humans. Scientific reports, 3(1), 3457.

4. Lauretta, G., Ravalli, S., Maugeri, G., D’Agata, V., Rosa, M. D., & Musumeci, G. (2022). The impact of physical
exercise on the hippocampus in physiological condition and ageing-related decline: current evidence from
animal and human studies. Current Pharmaceutical Biotechnology, 23(2), 180-189.

5. Håkansson, K., Ledreux, A., Daffner, K., Terjestam, Y., Bergman, P., Carlsson, R., ... & Mohammed, A. K. H.
(2017). BDNF responses in healthy older persons to 35 minutes of physical exercise, cognitive training, and
mindfulness: associations with working memory function. Journal of Alzheimer's Disease, 55(2), 645-657.

6. Park, S. A., Lee, A. Y., Park, H. G., & Lee, W. L. (2019). Benefits of gardening activities for cognitive function
according to measurement of brain nerve growth factor levels. International journal of environmental research and
public health, 16(5), 760.

7. Berkemeier, L. R., Winslow, J. W., Kaplan, D. R., Nikolics, K., Goeddel, D. V., & Rosenthal, A. (1991).
Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron, 7(5), 857-866.

8. Hallböök, F., Ibáñez, C. F., & Persson, H. (1991). Evolutionary studies of the nerve growth factor family reveal
a novel member abundantly expressed in Xenopus ovary. Neuron, 6(5), 845-858.

9. Bothwell, M. N. G. F. (2014). Ngf, bdnf, nt3, and nt4. Neurotrophic factors, 3-15.
10. Lippi, G., Mattiuzzi, C., & Sanchis-Gomar, F. (2020). Updated overview on interplay between physical

exercise, neurotrophins, and cognitive function in humans. Journal of sport and health science, 9(1), 74-81.
11. Ribeiro, D., Petrigna, L., Pereira, F. C., Muscella, A., Bianco, A., & Tavares, P. (2021). The impact of physical

exercise on the circulating levels of BDNF and NT 4/5: a review. International Journal of Molecular Sciences,
22(16), 8814.

12. Dadkhah, M., Saadat, M., Ghorbanpour, A. M., & Moradikor, N. (2023). Experimental and clinical evidence of
physical exercise on BDNF and cognitive function: a comprehensive review from molecular basis to therapy.
Brain Behavior and Immunity Integrative, 100017.

13. Zarza-Rebollo, J. A., López-Isac, E., Rivera, M., Gómez-Hernández, L., Pérez-Gutiérrez, A. M., & Molina, E.
(2024). The relationship between BDNF and physical activity on depression. Progress in
Neuro-Psychopharmacology and Biological Psychiatry, 111033.

14. Phillips, C. (2017). Physical activity modulates common neuroplasticity substrates in major depressive and
bipolar disorder. Neural Plasticity, 2017(1), 7014146.

15. Deng, W., Aimone, J. B., & Gage, F. H. (2010). New neurons and new memories: how does adult hippocampal
neurogenesis affect learning and memory?. Nature reviews neuroscience, 11(5), 339-350.

16. Babcock, K. R., Page, J. S., Fallon, J. R., & Webb, A. E. (2021). Adult hippocampal neurogenesis in aging and
Alzheimer's disease. Stem cell reports, 16(4), 681-693.

17. Boldrini, M., Santiago, A. N., Hen, R., Dwork, A. J., Rosoklija, G. B., Tamir, H., ... & John Mann, J. (2013).
Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated
major depression. Neuropsychopharmacology, 38(6), 1068-1077.

18. Lucassen, P. J., Stumpel, M. W., Wang, Q., & Aronica, E. (2010). Decreased numbers of progenitor cells but no
response to antidepressant drugs in the hippocampus of elderly depressed patients. Neuropharmacology, 58(6),
940-949.



Brain Sci. 2024, 14, x FOR PEER REVIEW 17 of 23

19. Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., & Arango, V. (2009).
Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology, 34(11),
2376-2389.

20. Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000). Chronic antidepressant treatment increases
neurogenesis in adult rat hippocampus. Journal of Neuroscience, 20(24), 9104-9110.

21. Milne, A. M., MacQueen, G. M., & Hall, G. B. (2012). Abnormal hippocampal activation in patients with
extensive history of major depression: an fMRI study. Journal of Psychiatry and Neuroscience, 37(1), 28-36.

22. Déry, N., Pilgrim, M., Gibala, M., Gillen, J., Wojtowicz, J. M., MacQueen, G., & Becker, S. (2013). Adult
hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and
depression. Frontiers in neuroscience, 7, 66.

23. Moreno-Jiménez, E. P., Flor-García, M., Terreros-Roncal, J., Rábano, A., Cafini, F., Pallas-Bazarra, N., ... &
Llorens-Martín, M. (2019). Adult hippocampal neurogenesis is abundant in neurologically healthy subjects
and drops sharply in patients with Alzheimer’s disease. Nature medicine, 25(4), 554-560.

24. Numakawa, T., Odaka, H., & Adachi, N. (2018). Actions of brain-derived neurotrophin factor in the
neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases.
International journal of molecular sciences, 19(11), 3650.

25. Li, Y., Wei, C., Wang, W., Li, Q., & Wang, Z. C. (2023). Tropomyosin receptor kinase B (TrkB) signalling:
targeted therapy in neurogenic tumours. The Journal of Pathology: Clinical Research, 9(2), 89-99.

26. Zoladz, J. A., & Pilc, A. (2010). The effect of physical activity on the brain derived neurotrophic factor: from
animal to human studies. Journal of physiology and pharmacology : an official journal of the Polish Physiological
Society, 61(5), 533–541.

27. Huang, T., Larsen, K. T., Ried‐Larsen, M., Møller, N. C., & Andersen, L. B. (2014). The effects of physical
activity and exercise on brain‐derived neurotrophic factor in healthy humans: A review. Scandinavian journal
of medicine & science in sports, 24(1), 1-10.

28. Feter, N., Alt, R., Dias, M. G., & Rombaldi, A. J. (2019). How do different physical exercise parameters
modulate brain-derived neurotrophic factor in healthy and non-healthy adults? A systematic review,
meta-analysis and meta-regression. Science & Sports, 34(5), 293-304.

29. Walsh, E. I., Smith, L., Northey, J., Rattray, B., & Cherbuin, N. (2020). Towards an understanding of the
physical activity-BDNF-cognition triumvirate: A review of associations and dosage. Ageing research reviews,
60, 101044.

30. Zhou, B., Wang, Z., Zhu, L., Huang, G., Li, B., Chen, C., ... & Liu, T. C. (2022). Effects of different physical
activities on brain-derived neurotrophic factor: A systematic review and bayesian network meta-analysis.
Frontiers in aging neuroscience, 14, 981002.

31. Rotondo, R., Proietti, S., Perluigi, M., Padua, E., Stocchi, F., Fini, M., ... & De Pandis, M. F. (2023). Physical
activity and neurotrophic factors as potential drivers of neuroplasticity in Parkinson’s Disease: A systematic
review and meta-analysis. Ageing Research Reviews, 102089.

32. Rodríguez-Gutiérrez, E., Torres-Costoso, A., Pascual-Morena, C., Pozuelo-Carrascosa, D. P., Garrido-Miguel,
M., & Martínez-Vizcaíno, V. (2023). Effects of resistance exercise on neuroprotective factors in middle and late
life: a systematic review and meta-analysis. Aging and disease, 14(4), 1264.

33. Farrukh, S., Habib, S., Rafaqat, A., Sarfraz, A., Sarfraz, Z., & Tariq, H. (2023). Association of exercise,
brain-derived neurotrophic factor, and cognition among older women: A systematic review and
meta-analysis. Archives of Gerontology and Geriatrics, 114, 105068.

34. Herrera, S. G. R., & Leon-Rojas, J. E. (2024). The Effect of Aerobic Exercise in Neuroplasticity, Learning, and
Cognition: A Systematic Review. Cureus, 16(2).

35. Balbim, G. M., Boa Sorte Silva, N. C., Ten Brinke, L., Falck, R. S., Hortobágyi, T., Granacher, U., ... &
Liu-Ambrose, T. (2024). Aerobic exercise training effects on hippocampal volume in healthy older individuals:
a meta-analysis of randomized controlled trials. Geroscience, 46(2), 2755-2764.

36. Frodl, T., Strehl, K., Carballedo, A., Tozzi, L., Doyle, M., Amico, F., ... & O’Keane, V. (2020). Aerobic exercise
increases hippocampal subfield volumes in younger adults and prevents volume decline in the elderly. Brain
imaging and behavior, 14, 1577-1587.



Brain Sci. 2024, 14, x FOR PEER REVIEW 18 of 23

37. Nauer, R. K., Dunne, M. F., Stern, C. E., Storer, T. W., & Schon, K. (2020). Improving fitness increases dentate
gyrus/CA3 volume in the hippocampal head and enhances memory in young adults. Hippocampus, 30(5),
488-504.

38. Cherednichenko, A., Miró-Padilla, A., Adrián-Ventura, J., Monzonís-Carda, I., Beltran-Valls, M. R.,
Moliner-Urdiales, D., & Ávila, C. (2024). Physical activity and hippocampal volume in young adults. Brain
Imaging and Behavior, 1-10.

39. Firth, J., Stubbs, B., Rosenbaum, S., Vancampfort, D., Malchow, B., Schuch, F., ... & Yung, A. R. (2017). Aerobic
exercise improves cognitive functioning in people with schizophrenia: a systematic review and meta-analysis.
Schizophrenia bulletin, 43(3), 546-556.

40. Feter, N., Penny, J. C., Freitas, M. P., & Rombaldi, A. J. (2018). Effect of physical exercise on hippocampal
volume in adults: Systematic review and meta-analysis. Science & Sports, 33(6), 327-338.

41. Behrad, S., Dezfuli, S. A. T., Yazdani, R., Hayati, S., & Shanjani, S. M. (2024). The effect of physical exercise on
circulating neurotrophic factors in healthy aged subjects: A meta-analysis and meta-regression. Experimental
Gerontology, 196, 112579.

42. Heemskerk, V. H., Daemen, M. A., & Buurman, W. A. (1999). Insulin-like growth factor-1 (IGF-1) and growth
hormone (GH) in immunity and inflammation. Cytokine & growth factor reviews, 10(1), 5-14.

43. Laron, Z. (2001). Insulin-like growth factor 1 (IGF-1): a growth hormone.Molecular Pathology, 54(5), 311.
44. Lewitt, M. S., & Boyd, G. W. (2019). The role of insulin-like growth factors and insulin-like growth

factor–binding proteins in the nervous system. Biochemistry insights, 12, 1178626419842176.
45. Dyer, A. H., Vahdatpour, C., Sanfeliu, A., & Tropea, D. (2016). The role of Insulin-Like Growth Factor 1

(IGF-1) in brain development, maturation and neuroplasticity. Neuroscience, 325, 89-99.
46. Williams, H. C., Carlson, S. W., & Saatman, K. E. (2022). A role for insulin-like growth factor-1 in hippocampal

plasticity following traumatic brain injury. In Vitamins and Hormones(Vol. 118, pp. 423-455). Academic Press.
47. Yuan, T., Ying, J., Jin, L., Li, C., Gui, S., Li, Z., ... & Zhang, Y. (2020). The role of serum growth hormone and

insulin-like growth factor-1 in adult humans brain morphology. Aging (Albany NY), 12(2), 1377.
48. Weissleder, C., Webster, M. J., Barry, G., & Shannon Weickert, C. (2021). Reduced insulin-like growth factor

family member expression predicts neurogenesis marker expression in the subependymal zone in
schizophrenia and bipolar disorder. Schizophrenia Bulletin, 47(4), 1168-1178.

49. Nuñez, A., Zegarra-Valdivia, J., Fernandez de Sevilla, D., Pignatelli, J., & Torres Aleman, I. (2023). The
neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states. Molecular
Psychiatry, 28(8), 3220-3230.

50. Jiang, Q., Lou, K., Hou, L., Lu, Y., Sun, L., Tan, S. C., ... & Pang, S. (2020). The effect of resistance training on
serum insulin-like growth factor 1 (IGF-1): a systematic review and meta-analysis. Complementary therapies in
medicine, 50, 102360.

51. de Alcantara Borba, D., da Silva Alves, E., Rosa, J. P. P., Facundo, L. A., Costa, C. M. A., Silva, A. C., ... & de
Mello, M. T. (2020). Can IGF-1 serum levels really be changed by acute physical exercise? A systematic review
and meta-analysis. Journal of Physical Activity and Health, 17(5), 575-584.

52. Berg, U., & Bang, P. (2004). Exercise and circulating insulin-like growth factor I. Hormone research, 62(Suppl. 1),
50-58.

53. Polacchini, A., Metelli, G., Francavilla, R., Baj, G., Florean, M., Mascaretti, L. G., & Tongiorgi, E. (2015). A
method for reproducible measurements of serum BDNF: comparison of the performance of six commercial
assays. Scientific reports, 5(1), 17989.

54. Steventon, J. J., Chandler, H. L., Foster, C., Dingsdale, H., Germuska, M., Massey, T., ... & Murphy, K. (2021).
Changes in white matter microstructure and MRI-derived cerebral blood flow after 1-week of exercise
training. Scientific reports, 11(1), 22061.

55. Colucci-D’Amato, L., Speranza, L., & Volpicelli, F. (2020). Neurotrophic factor BDNF, physiological functions
and therapeutic potential in depression, neurodegeneration and brain cancer. International journal of molecular
sciences, 21(20), 7777.

56. Yang, T., Nie, Z., Shu, H., Kuang, Y., Chen, X., Cheng, J., ... & Liu, H. (2020). The role of BDNF on neural
plasticity in depression. Frontiers in cellular neuroscience, 14, 82.



Brain Sci. 2024, 14, x FOR PEER REVIEW 19 of 23

57. Gourgouvelis, J., Yielder, P., & Murphy, B. (2017). Exercise promotes neuroplasticity in both healthy and
depressed brains: an fMRI pilot study. Neural plasticity, 2017(1), 8305287.

58. Fakhoury, M., Eid, F., El Ahmad, P., Khoury, R., Mezher, A., El Masri, D., ... & Stephan, J. S. (2022). Exercise
and dietary factors mediate neural plasticity through modulation of BDNF signaling. Brain Plasticity, 8(1),
121-128.

59. Cattaneo, A., Cattane, N., Begni, V., Pariante, C. M., & Riva, M. A. (2016). The human BDNF gene: peripheral
gene expression and protein levels as biomarkers for psychiatric disorders. Translational psychiatry, 6(11),
e958-e958.

60. Pruunsild, P., Kazantseva, A., Aid, T., Palm, K., & Timmusk, T. (2007). Dissecting the human BDNF locus:
bidirectional transcription, complex splicing, and multiple promoters. Genomics, 90(3), 397-406.

61. Je, H. S., Yang, F., Ji, Y., Potluri, S., Fu, X. Q., Luo, Z. G., ... & Lu, B. (2013). ProBDNF and mature BDNF as
punishment and reward signals for synapse elimination at mouse neuromuscular junctions. Journal of
Neuroscience, 33(24), 9957-9962.

62. Lu, B. (2003). Pro-region of neurotrophins: role in synaptic modulation. Neuron, 39(5), 735-738.
63. Chao, M. V. (2003). Neurotrophins and their receptors: a convergence point for many signalling pathways.

Nature Reviews Neuroscience, 4(4), 299-309.
64. Hua, Z., Gu, X., Dong, Y., Tan, F., Liu, Z., Thiele, C. J., & Li, Z. (2016). PI3K and MAPK pathways mediate the

BDNF/TrkB-increased metastasis in neuroblastoma. Tumor Biology, 37, 16227-16236.
65. Sun, Y., Liu, W. Z., Liu, T., Feng, X., Yang, N., & Zhou, H. F. (2015). Signaling pathway of MAPK/ERK in cell

proliferation, differentiation, migration, senescence and apoptosis. Journal of Receptors and Signal Transduction,
35(6), 600-604.

66. Yu, J. S., & Cui, W. (2016). Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in
pluripotency and cell fate determination. Development, 143(17), 3050-3060.

67. Levy, M. J., Boulle, F., Steinbusch, H. W., van den Hove, D. L., Kenis, G., & Lanfumey, L. (2018). Neurotrophic
factors and neuroplasticity pathways in the pathophysiology and treatment of depression.
Psychopharmacology, 235, 2195-2220.

68. Ying, S. W., Futter, M., Rosenblum, K., Webber, M. J., Hunt, S. P., Bliss, T. V., & Bramham, C. R. (2002).
Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement
for ERK activation coupled to CREB and upregulation of Arc synthesis. Journal of Neuroscience, 22(5),
1532-1540.

69. Pan, W., Banks, W. A., Fasold, M. B., Bluth, J., & Kastin, A. J. (1998). Transport of brain-derived neurotrophic
factor across the blood–brain barrier. Neuropharmacology, 37(12), 1553-1561.

70. Poduslo, J. F., & Curran, G. L. (1996). Permeability at the blood-brain and blood-nerve barriers of the
neurotrophic factors: NGF, CNTF, NT-3, BDNF.Molecular Brain Research, 36(2), 280-286.

71. Azevedo, K. P. M. D., de Oliveira, V. H., Medeiros, G. C. B. S. D., Mata, Á. N. D. S., García, D. Á., Martínez, D.
G., ... & Piuvezam, G. (2020). The effects of exercise on BDNF levels in adolescents: a systematic review with
meta-analysis. International Journal of Environmental Research and Public Health, 17(17), 6056.

72. Tarassova, O., Ekblom, M. M., Moberg, M., Lövdén, M., & Nilsson, J. (2020). Peripheral BDNF response to
physical and cognitive exercise and its association with cardiorespiratory fitness in healthy older adults.
Frontiers in physiology, 11, 1080.

73. Jetté, M., Sidney, K., & Blümchen, G. (1990). Metabolic equivalents (METS) in exercise testing, exercise
prescription, and evaluation of functional capacity. Clinical cardiology, 13(8), 555-565.

74. Park, S. A., Son, S. Y., Lee, A. Y., Park, H. G., Lee, W. L., & Lee, C. H. (2020). Metabolite profiling revealed that
a gardening activity program improves cognitive ability correlated with BDNF levels and serotonin
metabolism in the elderly. International journal of environmental research and public health, 17(2), 541.

75. Varma, V. R., Chuang, Y. F., Harris, G. C., Tan, E. J., & Carlson, M. C. (2015). Low‐intensity daily walking
activity is associated with hippocampal volume in older adults. Hippocampus, 25(5), 605-615.

76. Sandroff, B. M., Wylie, G. R., Baird, J. F., Jones, C. D., Diggs, M. D., Genova, H., ... & Motl, R. W. (2021). Effects
of walking exercise training on learning and memory and hippocampal neuroimaging outcomes in MS: a
targeted, pilot randomized controlled trial. Contemporary Clinical Trials, 110, 106563.



Brain Sci. 2024, 14, x FOR PEER REVIEW 20 of 23

77. Bergman, F., Matsson-Frost, T., Jonasson, L., Chorell, E., Sörlin, A., Wennberg, P., ... & Boraxbekk, C. J. (2020).
Walking time is associated with hippocampal volume in overweight and obese office workers. Frontiers in
human neuroscience, 14, 307.

78. Baker, N., & Steemers, K. (2019). Healthy homes: designing with light and air for sustainability and wellbeing. Riba
Publishing.

79. Gath-Morad, M., O. Plaut, P., & Kalay, Y. E. (2024). Attract or repel: how street features shape pedestrians’
leisure walks in cities. Journal of Urban Design, 29(3), 342-362.

80. Zhang, X., Melbourne, S., Sarkar, C., Chiaradia, A., & Webster, C. (2020). Effects of green space on walking:
Does size, shape and density matter?. Urban studies, 57(16), 3402-3420.

81. Boldina, A., Hanel, P. H., & Steemers, K. (2023). Active urbanism and choice architecture: encouraging the use
of challenging city routes for health and fitness. Landscape research, 48(3), 276-296.

82. Lu, Z., Rodiek, S., Shepley, M. M., & Tassinary, L. G. (2015). Environmental influences on indoor walking
behaviours of assisted living residents. Building Research & Information, 43(5), 602-615.

83. Gharaveis, A. (2020). A systematic framework for understanding environmental design influences on physical
activity in the elderly population: A review of literature. Facilities, 38(9/10), 625-649.

84. Funabashi, D., Tsuchida, R., Matsui, T., Kita, I., & Nishijima, T. (2023). Enlarged housing space and increased
spatial complexity enhance hippocampal neurogenesis but do not increase physical activity in mice. Frontiers
in Sports and Active Living, 5, 1203260.

85. Khajehzadeh, I., & Vale, B. (2015). How do people use large houses. In Living and Learning: Research for a Better
Built Environment: Proceeding of the 49th International Conference of the Architectural Science Association 2015 (pp.
153-162).

86. Ezezue, A., Ibem, E., Uzuegbunam, F., Odum, C., & Omatsone, M. (2021). Influence of Spatial Layout of
Residential Buildings on Sedentary Behaviour of Residents in Enugu, Nigeria. Civil Engineering and
Architecture, 9(4), 1123-1136.

87. Kaushal, N., & Rhodes, R. E. (2014). The home physical environment and its relationship with physical
activity and sedentary behavior: a systematic review. Preventive medicine, 67, 221-237.

88. Ali, J. S., & Mustafa, F. A. (2023). Active workplace–Association between workplace layout and physical
activity among employees: A cross-sectional study. Al-Qadisiyah Journal for Engineering Sciences, 16(1), 14-20.

89. Stenling, A., Moylan, A., Fulton, E., & Machado, L. (2019). Effects of a brief stair-climbing intervention on
cognitive performance and mood states in healthy young adults. Frontiers in Psychology, 10, 2300.

90. Nasrollahi, N., Quensell, J., & Machado, L. (2021). Effects of a brief stair-climbing intervention on cognitive
functioning and mood states in older adults: A randomized controlled trial. Journal of Aging and Physical
Activity, 30(3), 455-465.

91. Islam, H., Gibala, M. J., & Little, J. P. (2022). Exercise snacks: a novel strategy to improve cardiometabolic
health. Exercise and sport sciences reviews, 50(1), 31-37.

92. Stenling, A., Quensell, J., Kaur, N., & Machado, L. (2024). Stair Climbing Improves Cognitive Switching
Performance and Mood in Healthy Young Adults: A Randomized Controlled Crossover Trial. Journal of
Cognitive Enhancement, 1-15.

93. Caballero, Y., Ando, T. J., Nakae, S., Usui, C., Aoyama, T., Nakanishi, M., ... & Tanaka, S. (2020). Simple
prediction of metabolic equivalents of daily activities using heart rate monitor without calibration of
individuals. International journal of environmental research and public health, 17(1), 216.

94. Donath, L., Faude, O. L. I. V. E. R., Roth, R. A. L. F., & Zahner, L. (2014). Effects of stair‐climbing on balance,
gait, strength, resting heart rate, and submaximal endurance in healthy seniors. Scandinavian journal of
medicine & science in sports, 24(2), e93-e101.

95. Nakanishi, M., Izumi, S., Nagayoshi, S., Kawaguchi, H., Yoshimoto, M., Shiga, T., ... & Tanaka, S. (2018).
Estimating metabolic equivalents for activities in daily life using acceleration and heart rate in wearable
devices. Biomedical engineering online, 17, 1-18.

96. Pan, G., Peng, M., Zhou, T., Wan, Z., & Liang, Z. (2023). Research on Safety Design Strategy of Evacuation
Stairs in Deep Underground Station Based on Human Heart Rate and Ascending Evacuation Speed.
Sustainability, 15(13), 10670.



Brain Sci. 2024, 14, x FOR PEER REVIEW 21 of 23

97. Gath-Morad, M., Thrash, T., Schicker, J., Hölscher, C., Helbing, D., & Aguilar Melgar, L. E. (2021). Visibility
matters during wayfinding in the vertical. Scientific reports, 11(1), 18980.

98. Gath-Morad, M., Grübel, J., Steemers, K., Sailer, K., Ben-Alon, L., Hölscher, C., & Aguilar, L. (2024). The role
of strategic visibility in shaping wayfinding behavior in multilevel buildings. Scientific Reports, 14(1), 3735.

99. Zimring, C., Joseph, A., Nicoll, G. L., & Tsepas, S. (2005). Influences of building design and site design on
physical activity: research and intervention opportunities. American journal of preventive medicine, 28(2),
186-193.

100.Coburn, A., Vartanian, O., Kenett, Y. N., Nadal, M., Hartung, F., Hayn-Leichsenring, G., ... & Chatterjee, A.
(2020). Psychological and neural responses to architectural interiors. Cortex, 126, 217-241.

101.Gregorians, L., Velasco, P. F., Zisch, F., & Spiers, H. J. (2022). Architectural experience: clarifying its central
components and their relation to core affect with a set of first-person-view videos. Journal of Environmental
Psychology, 82, 101841.

102.Djebbara, Z., Fich, L. B., & Gramann, K. (2021). The brain dynamics of architectural affordances during
transition. Scientific reports, 11(1), 2796.

103.Ladouce, S., Mustile, M., Ietswaart, M., & Dehais, F. (2022). Capturing cognitive events embedded in the real
world using mobile electroencephalography and eye-tracking. Journal of Cognitive Neuroscience, 34(12),
2237-2255.

104.Ren, J. (2024). A study on visual perception of traditional residential architectural decoration using eye
tracking and electroencephalogram (EEG) experiments. EVOLUTIONARY STUDIES IN IMAGINATIVE
CULTURE, 731-739.

105.Ergan, S., Radwan, A., Zou, Z., Tseng, H. A., & Han, X. (2019). Quantifying human experience in architectural
spaces with integrated virtual reality and body sensor networks. Journal of Computing in Civil Engineering,
33(2), 04018062.

106.Taherysayah, F., Malathouni, C., Liang, H. N., & Westermann, C. (2024). Virtual reality and
electroencephalography in architectural design: A systematic review of empirical studies. Journal of Building
Engineering, 108611.

107.Boldrini, M., Fulmore, C. A., Tartt, A. N., Simeon, L. R., Pavlova, I., Poposka, V., ... & Mann, J. J. (2018). Human
hippocampal neurogenesis persists throughout aging. Cell stem cell, 22(4), 589-599.

108.Tobin, M. K., Musaraca, K., Disouky, A., Shetti, A., Bheri, A., Honer, W. G., ... & Lazarov, O. (2019). Human
hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell stem cell, 24(6),
974-982.

109.Liu, P. Z., & Nusslock, R. (2018). Exercise-mediated neurogenesis in the hippocampus via BDNF. Frontiers in
neuroscience, 12, 52.

110.Rossi, C., Angelucci, A., Costantin, L., Braschi, C., Mazzantini, M., Babbini, F., ... & Caleo, M. (2006).
Brain‐derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis
following environmental enrichment. European Journal of Neuroscience, 24(7), 1850-1856.

111.Júdice, P. B., Magalhães, J. P., Hetherington-Rauth, M., Correia, I. R., & Sardinha, L. B. (2021). Sedentary
patterns are associated with BDNF in patients with type 2 diabetes mellitus. European Journal of Applied
Physiology, 121, 871-879.

112.de Oliveira Segundo, V. H., de Azevedo, K. P. M., de Medeiros, G. C. B. S., Mata, Á. N. D. S., & Piuvezam, G.
(2024). Association between sedentary behavior and Brain-Derived Neurotrophic Factor (BDNF) in children
and adolescents: A protocol for systematic review and meta-analysis. Plos one, 19(3), e0299024.

113.Khalil, M. H. (2024). Neurosustainability. Frontiers in Human Neuroscience, 18, 1436179.
114.Collins, A. M., Molina-Hidalgo, C., Aghjayan, S. L., Fanning, J., Erlenbach, E. D., Gothe, N. P., ... & Erickson,

K. I. (2023). Differentiating the influence of sedentary behavior and physical activity on brain health in late
adulthood. Experimental Gerontology, 180, 112246.

115.Falck, R. S., Hsu, C. L., Best, J. R., Li, L. C., Egbert, A. R., & Liu-Ambrose, T. (2020). Not just for joints: The
associations of moderate-to-vigorous physical activity and sedentary behavior with brain cortical thickness.
Medicine & Science in Sports & Exercise, 52(10), 2217-2223.

116.Khalil, M. H. (2024). From Cave to Cage? The Evolution of Housing Complexity and the Contemporary Dead
End for the Human Brain. Housing, Theory and Society, 1-19.



Brain Sci. 2024, 14, x FOR PEER REVIEW 22 of 23

117.Khalil, M. H. (2024). Environmental enrichment: a systematic review on the effect of a changing spatial
complexity on hippocampal neurogenesis and plasticity in rodents, with considerations for translation to
urban and built environments for humans. Frontiers in Neuroscience, 18, 1368411.

118.Maasakkers, C. M., Weijs, R. W., Dekkers, C., Gardiner, P. A., Ottens, R., Rikkert, M. G. O., ... & Claassen, J. A.
(2022). Sedentary behaviour and brain health in middle-aged and older adults: A systematic review.
Neuroscience & Biobehavioral Reviews, 140, 104802.

119.Maharjan, R., Bustamante, L. D., Ghattas, K. N., Ilyas, S., Al-Refai, R., & Khan, S. (2020). Role of lifestyle in
neuroplasticity and neurogenesis in an aging brain. Cureus, 12(9).

120.Voss, M. W., Carr, L. J., Clark, R., & Weng, T. (2014). Revenge of the “sit” II: does lifestyle impact neuronal and
cognitive health through distinct mechanisms associated with sedentary behavior and physical activity?.
Mental Health and Physical Activity, 7(1), 9-24.

121.Zavala-Crichton, J. P., Esteban-Cornejo, I., Solis-Urra, P., Mora-Gonzalez, J., Cadenas-Sanchez, C.,
Rodriguez-Ayllon, M., ... & Ortega, F. B. (2020). Association of sedentary behavior with brain structure and
intelligence in children with overweight or obesity: the ActiveBrains project. Journal of clinical medicine, 9(4),
1101.

122.Zou, L., Herold, F., Cheval, B., Wheeler, M. J., Pindus, D. M., Erickson, K. I., ... & Owen, N. (2024). Sedentary
behavior and lifespan brain health. Trends in Cognitive Sciences.

123.Peter, S., & Ibrahim, B. (2024). Intuitive Innovation: Unconventional Modeling and Systems Neurology.
Mathematics, 12(21), 3308.

124.Mathews, K. J., Allen, K. M., Boerrigter, D., Ball, H., Shannon Weickert, C., & Double, K. L. (2017). Evidence
for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers. Aging cell, 16(5),
1195-1199.

125.Spalding, K. L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H. B., ... & Frisén, J. (2013).
Dynamics of hippocampal neurogenesis in adult humans. Cell, 153(6), 1219-1227.

126.Schmitt, K., Holsboer-Trachsler, E., & Eckert, A. (2016). BDNF in sleep, insomnia, and sleep deprivation.
Annals of medicine, 48(1-2), 42-51.

127.Giese, M., Unternaehrer, E., Brand, S., Calabrese, P., Holsboer-Trachsler, E., & Eckert, A. (2013). The interplay
of stress and sleep impacts BDNF level. PloS one, 8(10), e76050.

128.Notaras, M., & van den Buuse, M. (2020). Neurobiology of BDNF in fear memory, sensitivity to stress, and
stress-related disorders.Molecular psychiatry, 25(10), 2251-2274.

129.Gravesteijn, E., Mensink, R. P., & Plat, J. (2022). Effects of nutritional interventions on BDNF concentrations in
humans: a systematic review. Nutritional neuroscience, 25(7), 1425-1436.

130.Moreno-Jiménez, E. P., Terreros-Roncal, J., Flor-García, M., Rábano, A., & Llorens-Martín, M. (2021).
Evidences for adult hippocampal neurogenesis in humans. Journal of Neuroscience, 41(12), 2541-2553.

131.Terstege, D. J., Addo-Osafo, K., Campbell Teskey, G., & Epp, J. R. (2022). New neurons in old brains:
implications of age in the analysis of neurogenesis in post-mortem tissue.Molecular brain, 15(1), 38.

132.Vrijen, C., Schenk, H. M., Hartman, C. A., & Oldehinkel, A. J. (2017). Measuring BDNF in saliva using
commercial ELISA: Results from a small pilot study. Psychiatry research, 254, 340-346.

133.Fuller, D., Colwell, E., Low, J., Orychock, K., Tobin, M. A., Simango, B., ... & Taylor, N. G. (2020). Reliability
and validity of commercially available wearable devices for measuring steps, energy expenditure, and heart
rate: systematic review. JMIR mHealth and uHealth, 8(9), e18694.

134.Chatterjee, A., & Vartanian, O. (2014). Neuroaesthetics. Trends in cognitive sciences, 18(7), 370-375.
135.Cho, H. C., Kim, J., Kim, S., Son, Y. H., Lee, N., & Jung, S. H. (2012). The concentrations of serum, plasma and

platelet BDNF are all increased by treadmill VO2max performance in healthy college men. Neuroscience letters,
519(1), 78-83.

136.Hohn, A., Leibrock, J., Bailey, K., & Barde, Y. A. (1990). Identification and characterization of a novel member
of the nerve growth factor/brain-derived neurotrophic factor family. Nature, 344(6264), 339-341.

137.McCormick, B. P., Brusilovskiy, E., Snethen, G., Klein, L., Townley, G., & Salzer, M. S. (2022). Getting out of
the house: The relationship of venturing into the community and neurocognition among adults with serious
mental illness. Psychiatric Rehabilitation Journal, 45(1), 18.



Brain Sci. 2024, 14, x FOR PEER REVIEW 23 of 23

138.Sudimac, S., Sale, V., & Kühn, S. (2022). How nature nurtures: Amygdala activity decreases as the result of a
one-hour walk in nature.Molecular psychiatry, 27(11), 4446-4452.

139.Sudimac, S., & Kühn, S. (2024). Can a nature walk change your brain? Investigating hippocampal brain
plasticity after one hour in a forest. Investigating Hippocampal Brain Plasticity After One Hour in a Forest.

140.Kühn, S., & Gallinat, J. (2024). Environmental neuroscience unravels the pathway from the physical
environment to mental health. Nature Mental Health, 2(3), 263-269.

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