Does breaking up prolonged sitting improve cognitive functions in sedentary adults? A mapping review and hypothesis formulation on the potential physiological mechanisms

Glucose is the primary fuel source for brain metabolism and function. Brain blood glucose transport and neural activity are significantly reduced after exposure to postprandial hyperglycemia [32]. Further, hyperglycemia and insulin resistance can be anticipated as causes for poor cognitive skills. Hyperglycemia and insulin resistance in individuals without clinically apparent diabetes, is found to be associated with reduced cognitive measures, with an atrophy of the hippocampus [33]. Contemporary evidence claims that prolonged uninterrupted sitting elevates postprandial hyperglycemia, proportional hyperinsulinemia and subsequent insulin resistance [34]. Nevertheless, the above metabolic derangements negatively affect brain glucose metabolism that would result in reduced cognitive performance (memory impairment) and cognitive decline [21] as depicted in Fig. 2.

Explicit episodic memory and attention is associated with medial temporal lobe (MTL) activity [35]. Moreover, decreased posterior cingulate and precuneus activity is found to be correlated with better episodic memory [35]. Given that the MTL, specifically the hippocampus, is one of the primary targets of physical activity effects in the rodent brain [36, 37] and age-related neurodegeneration (and Alzheimer disease) in humans [38, 39], prolonged sitting is speculated to reduce the MTL density and activity [40]. Figure 3. shows the cortical regions (medial temporal lobe, posterior cingulate cortex and posterior precuneus) associated with attention and working memory that might be influenced by sedentary behavior.

Sedentary behavior has been associated with poor posterior cingulate gyrus and medial temporal lobe (MTL) density and the future risk of neurodegenerative disorders [41]. In a fairly recent cross-sectional study, Siddharth et al. (2018) found an inverse correlation between sitting hours/day and MTL thickness (parahippocampal [r = − 0.45, p = 0.007], entorhinal [r = − 0.33, p = 0.05] and subiculum [r = − 0.36, p = .04] regions) which may negatively impact cognitive functions [40]. In a fairly recent randomized controlled trial (Inphact Treadmill study), Bergman et al. compared long term effects of treadmill desks in a group of 40 overweight and obese office workers to conventional education alone on magnetic resonance imaging of the brain volume for 13 months [42]. Longitudinal mediation analysis revealed non-significant reduction in hippocampal volume (− 33 mm³) and anterior cingulate cortex (− 0.02 mm) in control group compared to treadmill desk group at 13 months. Further hippocampal volume was positively correlated with the walking time [β = 1.448] and negatively correlated with total sitting time [β = − 0.462] [42]. Thus, excessive sitting may be detrimental to the medial temporal lobe, posterior precuneus and posterior cingulate cortex density which may be speculated due to reduced neuronal potentiation, cerebral blood flow and synaptic plasticity. This reduction in structural cortical density is postulated to the early cognitive decline and dementia risk [43].

A decline in peripheral arterial function (predominantly endothelial shear and flow mediated dilation) is perceived to compromise the cardiovascular function and alter the cortical hemodynamics. It is speculated that excessive sitting may modify the anatomy of the lower limb arteries and form unprecedented changes to hemodynamics (e.g. increased venous pooling, stasis and blood viscosity), thereby compromising preload volume to heart [44]. Further, excessive sitting for > 6 h is found to be associated with reduced shear stress in the lower limb blood vessels which may alter endothelial integrity and consecutively result in endothelial dysfunction in the lower limbs [45]. Venous pooling, loss of endothelial integrity and viscous blood flow in the lower limbs may compromise the central hemodynamics and cortical circulation [46]. Recently, Paterson et al. (2020) systematically reviewed 17 studies that investigated the effects of prolonged sitting compared to interrupted sitting strategies (standing, walking or calisthenics) on peripheral vascular functions in adults [47]. Lower limb flow mediated dilation was found to be reduced by 2.12% (95% CI − 2.66 to − 1.59) during sitting bouts lasting more than 1 h [47]. Another speculated mechanism for cerebral hypoperfusion is hyperglycemia, that causes endothelial damage and reduce shear stress; however, based on the recent review such evidence exists only for animal models [21]. Thus, prolonged poor cerebral perfusion may reduce oxygen supply to the brain, and disrupt neuronal metabolism, and damage astrocytes and microglial cells leading to an impairment in learning and working memory [48].

Compromised respiratory functions may hamper the optimal alveolar recruitment and available alveolar oxygen (P_AO₂) necessary for cortical oxygenation and, subsequently, affect cognitive function [49] following prolonged sitting. Prolonged sitting for more than an hour was found to increase slouched posture and forward leaning which are found to cause fatigue in rectus abdominis, internal oblique, transversus abdominis and iliocostalis muscles in office workers [50]. The thoracolumbar core muscles fatigue in turn may reduce lung volumes and capacities [51] resulting in reduced alveolar ventilation. The above speculation can be confirmed from the findings of a fairly recent systematic review by Katz et al. (2018) [52]. The authors found an average increase of 0.21 L in forced expiratory volume in 1 sec (FEV₁) and forced vital capacity (FVC) with standing than sitting from a pooled analysis of 43 studies with only 26 studies involving healthy participants [52]. In a large stratified study involving 51,338 Canadian healthy adults and patients with lung disease, sitting time was negatively associated with FEV₁ and FVC (β = − 0.32, CI: − 0.2, − 0.54) [53]. In addition, the sitting posture was found to reduce vital capacity, functional residual capacity and peak expiratory flow (PEF) compared to the standing posture in brass players [54]. In another study, prolonged sitting for 1 h in a chair with backrest compared to that without backrest is found to significantly reduce dynamic lung volumes (PEF = − 0.29 L/min; FEV1 = − 0.15 L; FVC = − 0.10 L) in 24 Korean adults [55]. Thus, reduction in dynamic lung volumes in sitting may reduce the alveolar recruitment and reduce the availability of continuous oxygen supply to the brain.

Hormones such as Brain Derived Neurotrophic Factor (BDNF), Dihydroxy Phenyl Alanine (DOPA) and Dihydroxy Phenyl Glycol (DHPG) are found to improve sympathetic activity resulting in higher frontal lobe functions [56]. In an experimental trial, Wennberg et al. (2016) demonstrated that increased fatigue is associated with a decrease in heart rate (r = − 0.60, p = 0.007) and plasma level of DOPA (r = − 0.59, p = 0.009) and an increased level of plasma dihydroxyphenyl glycol (DHPG; r = 0.73, p < 0.001) at first 4 h of uninterrupted sitting [13] in 19 sedentary desk-based Australian workers. The central fatigue due to increased cortisol levels seems to be negatively associated with cognitive function (primarily executive functions) [13]. In contrary, Sperlich et al. (2018) found no difference in plasma cortisol levels between prolonged sitting for 3 h and sitting interrupted with high intensity interval training for 6 min after 1 h of sitting in 12 young adults [30]. Hence, there are inconsistent findings to substantiate that prolonged sitting will affect salivary cortisol and stress hormones.

Based on the physiological mechanisms presented above, we hypothesize that prolonged sitting is likely to affect cognitive functions. Figure 4 demonstrates the hypothetical model of possible interactions of the physiological mechanisms linked to excessive sitting. Therefore, breaking up prolonged sitting is viewed as an imperative strategy for improving cognitive functions.

Emerging evidence claims the direct influence of breaking up prolonged sitting seems conflicting. In an experimental trial, Schwartz et al. (2017) assessed the reaction time (Stroop test), working speed (text editing task) and attention (d2R test of attention) in 45 students (aged 25.4 ± 3.3 years) in two alternating postures (sitting and standing) [16]. The authors found no significant difference in cognitive functions between sitting and standing postures. Similarly, a recent crossover experimental trial by Vincent et al. (2018) investigated the effects of prolonged sitting and breaking up sitting periods in six males on three consecutive sleep restricted days [60]. The average reaction time on the psychomotor vigilance test and digital symbol substitution tests did not differ between prolonged sitting and sitting interrupted with breaks. However, another crossover trial by Christmas et al. (2019) compared attention, episodic memory and executive functions between the conditions of breaking up sitting (3 min of treadmill walk every 30 min for 5 h) and uninterrupted sitting (5 h) in 11 sedentary Qatari females [12]. The authors found quicker reaction times (~ 210 ms) in Stroop incongruent task test following breaking up sitting compared to uninterrupted sitting [12]. Moreover, Wheeler et al. (2019) administered three behavioral interventions: 1) uninterrupted (SIT); 2) moderate exercise for 1 h before uninterrupted sitting (SIT+Ex) and 3) combined exercise and scheduled breaks every 30 min (SIT+Break) in 67 Australian community dwelling adults and found a significant improvement in working memory and executive functions in SIT+Break and SIT+Ex than SIT groups [61].

Breaking up prolonged sitting seems to improve or regulate certain indirect physiological mechanisms that might influence cognition. The plausible physiological mechanisms are modulating: 1) cardiometabolic risk markers, 2) glucose metabolism, 3) adipose tissue metabolism, 4) energy expenditure and metabolic preference, 5) neuroendocrine functions, 6) muscular system and 7) central and peripheral vascular functions. Figure 5. depicts the direct and indirect effects of breaking up sitting on cognitive functions.

Breaking up prolonged sitting may reduce postprandial hyperglycemia, insulin resistance and endothelial damage, thereby improving hemodynamics and cardiovascular health [18]. A recent meta-analysis by Hadgraft et al. (2020) of ≤33 studies revealed a significant change in both anthropometric measures (weight [− 0.6 kg], waist circumference [− 0.7 cm] and body fat percentages [− 0.3%]) and cardiometabolic risk factors (blood pressure [− 1.1 mmHg], plasma insulin [− 1.4 pM] and increased high-density lipoprotein cholesterol [+ 0.04 mM]) following interventions targeting sedentary behavior reduction with or without an increase in physical activity [18]. Another meta-analysis (of ≤24 studies) by Mulchandani et al. (2019) found that worksite based physical activity interventions (interrupting prolonged sitting) have significantly reduced body weight (− 2.61 kg), BMI (− 0.42 kg/m²) and waist circumference (− 1.92 cm); however, the analysis did not find a significant change in blood pressure, lipid profile and blood glucose levels [62]. The significant reduction in lipid profile and blood glucose in the review by Hadgraft et al. (2020) may be due to stringent search criteria, larger number of studies and sensitivity analysis. It could be hypothesized that breaking up sitting bouts may improve postprandial glucose metabolism, insulin resistance, lipid profile and other cardiometabolic risk biomarkers such as inflammatory markers. Though the reduction in cardiometabolic risk factors associated with the breaking sedentary behavior is perceived to regulate endothelial integrity, cortical perfusion and thus may improve cognitive functions [21], early experimental mechanistic studies failed to establish the relation between cardiometabolic risk factors, endothelial functions and cognitive functions [63, 64].

Brain metabolism depends entirely on glucose as energy source with 100–150 mg/day which constitutes nearly 20% of body glucose stores, although the brain accounts for only 2% of the body weight [65]. Glucose Transporter 1 (GLUT1) in the luminal and abluminal surfaces of blood brain barrier are responsible for active transport of glucose molecules across the tight blood brain barrier and cortical blood glucose utilization by the parenchymal cells which is facilitated by the concentration gradient [65]. Sedentary behavior including excessive sitting may result in reduced concentration gradient, and plasma hyperglycemia can alter the permeability of blood brain barrier and reduce the sensitivity of GLUT1 transporters which can lead to brain hypoglycemia [21]. Hence, breaking sitting can be viewed as an imperative solution to improve GLUT1 sensitization for improving glucose transport across blood-brain barrier, in turn central utilization of glucose and speculated to improve cognitive functions. Increased muscle contraction mediated glucose metabolism with acute standing [66] or walking bouts [67] has been perceived to improve brain glucose metabolism and cognitive functions [21, 61].

Prolonged sedentary bouts may be associated with cerebral hypoperfusion and this in turn is associated with neuroglycopenia, neural astrocyte and microglial damage resulting in poor cognitive functions [68]. Intermittent standing (e.g. every 20 min) is found to reduce postprandial glucose and insulin through upregulation of glucose transporters (GLUT1 and Glucose Transporter 2 in brain; Glucose Transporter 4 in muscle) [20, 21]. A recent systematic review by Loh et al. (2020) found a significant reduction in glucose (effect size, d = − 0.56; 95 CI -0.70, − 0.30) and insulin (d = − 0.56; 95% CI − 0.74, − 0.38) after physical activity at 40–70% of VO2max or self-selected walk breaks every 30 min to 1 h for 2 min to 30 min over a 7–9 h typical working hours [19]. Even so, another systematic review by Sauders et al. (2018) found that breaking up prolonged sitting has reduced postprandial glucose (d = − 0.36) and insulin levels (d = − 0.37), but not plasma triglyceride levels (d = 0.06) [69]. Therefore, we postulate breaking-up prolonged sitting can facilitate glucose metabolism and may provide sufficient glucose to the brain and subsequently improve cognitive functions [70]. Thus, improved cortical glucose utilization and peripheral glucose regulation with the microbreaks may be viewed as imperative mechanisms for cognitive functions improvement.

In a counterbalanced crossover trial, perivascular adipose tissue inflammation was hypothesized to be linked with the incidence of vascular diseases [71]. The study found a significant reduction in adipose tissue mRNA expression for several inflammatory genes including but not limited to interleukin 6, leptin, adiponectin, pyruvate dehydrogenase kinase and insulin receptor [71]. In a randomized controlled trial, Grace et al. (2019) demonstrated the metabolic effects of breaking up prolonged sitting on the adipose tissue transcriptional changes [72]. Breaking up prolonged sitting has been found to be positively associated with the regulation of lipid metabolism and inflammatory pathways [72], increased insulin signaling and adipocyte cell cycle regulation [18]. The above physiological changes may be associated with a reduction in inflammatory markers such as interleukin-6 (IL-6) and free radicals. Therefore, breaking up sitting could significantly reduce the proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 which in turn may reduce macrophages formation in the subendothelial space, forming foam cells, and resulting atherogenesis and cerebral vascular functions [73]. However, further studies based on robust randomized clinical trials are warranted to evaluate the long-term effects of breaking up sitting with appropriate interventions on inflammation or vascular functions [18].

Brain metabolism accounts for 20% of total resting metabolism of the body [21]. Dynamic changes in brain glucose metabolism are of paramount importance for neuronal activation, neural plasticity and cognitive functions [21]. During thought process, an increase in neuronal metabolism depends on the availability of substrates and overall glucose metabolism of the body. Also, cerebral mitochondrial functioning depends on the cerebral glucose and neurometabolic-vascular coupling [48].

Oxidative stress is linked with over nutrition, obesity and reduced energy expenditure [74]. Reduced energy expenditure is associated with changes in cellular oxidative state (mitochondrial enzymes and glycolytic pathway changes), especially an increase in reactive oxygen species or hypoxia, that induce cellular stress and damage [74]. Furthermore, orexin, an excitatory hypothalamic neuropeptide, which increases with voluntary physical activity, is found to increase brain metabolism, facilitate serotonin secretion from brainstem, and improve daytime wakefulness [75]. Orexin is argued to be reduced in obese and elderly populations and, claimed to be associated with poor cognitive functions which is depicted in Fig. 6.

Reduced energy expenditure is argued to be negatively associated with cognitive functions [76]. Individuals with obesity/overweight have been found to have worse cognitive outcomes compared to their lean counterparts, mainly those related to executive functions [77]. Middleton et al. (2013) investigated the relationship between cognitive functions (based on mini mental state examination) and energy expenditure (estimated by double labelled water technique) in 323 community dwelling older adults through a prospective cohort study [78]. The older adults with a high energy expenditure had lower odds of cognitive impairment incidence (odds ratio [OR]: 0.09; 95% CI 0.01–0.79) compared to those with a low energy expenditure. In another (cross-sectional) study of 123 community dwelling, non-demented adults, energy expenditure independently accounted for a 2% variance in verbal learning and the delayed verbal recall on the Rey Auditory Verbal Learning Test [76]. Thus increased energy expenditure and improved glucose metabolism could be speculated to improve the executive functions such as response inhibition and information processing speed among adults [58] but the convincing evidence has still yet to be investigated.

Though facilitation of the sympathetic nervous system and neural hormones such as epinephrine and norepinephrine during postural change have been investigated for decades [79], its role in arousal and cognitive functions have not been substantiated. Chronic fatigue following excessive sitting may be associated with impaired autonomic nervous system functions [13]. In a crossover trial, intermittent walks have been found to improve the fatigue (visual analog scale – VAS-F) and cognitive functions – episodic memory (face-name association test), inhibition (Eriksen flanker and Stroop tests) and executive function updating (n-back and letter memory test) as compared with uninterrupted sitting in a 7-h experimental condition [13]. The probable causative mechanism through which breaking up prolonged sitting strategies reduce the fatigue is through autonomic nervous system regulation. Increased sympathetic nervous system facilitation, increased release of adrenalin, norepinephrine and increased metabolism and continuous brain glucose supply are hypothesized to reduce central fatigue and improve cognition [13].

Breaking up prolonged sitting or exercise may increase the dopamine, catecholamine levels in the brain [59]. Consequently, the brain catecholamines might increase arousal by activating the reticular formation [80]. Further, the interaction between hypothalamic-pituitary-adrenal cortex (HPA) axis hormones and BDNF is found to be significantly associated with cognitive functions [80]. Though the brain is the major source of BDNF, the circulatory enzymes secreted by muscles such as irisin, cathepsin B, or liver-derived β-hydroxybutyrate during exercise/physical activity are also postulated to positively influence BDNF which is found to be associated with learning and memory related cognitive functions [61].

In a pilot crossover trial by Wennberg et al. (2016), the participants underwent either uninterrupted sitting for 7 h or sitting interrupted with a 3-min walk every 30 min for 2 days with a wash-out period of 6 days in-between [13]. The authors found a significant reduction in fatigue levels and improvement in composite cognitive scores from the Face-Name Association, Eriksen Flanker test, Stroop color test, N-back and letter memory test at 4 h and 7 h of sitting. Also, fatigue scores over time correlated with a decrease in heart rate and plasma DOPA and an increase in plasma DHPG [13]. In the three arm cross over trial by Wheeler et al. (2020), 8 h serum BDNF was found significantly higher in two intervention days among 65 Australian sedentary obese office workers [61]. Their participants received morning exercise with breaks every 30 min (EX+BR) or without breaks for the next 6.5 h (EX+SIT) [171 (− 449 to + 791) ng/mL·hour] compared to uninterrupted sitting (SIT) day for 8 h [− 227 (− 851 to + 396) ng/mL·hour] [61]. However, the authors did not find significant difference between the intervention groups either EX+SIT or EX+break [61]. Despite of the growing anecdotal evidence, empirical evidence seems to remain equivocal regarding the beneficial effects of breaking up prolonged sitting on neuroendocrine functions.

Disrupting monotonous muscle activity with scheduled breaks is postulated to regulate isokinetic peak torque and power. These physiological changes are considered to reverse reduced motor unit potentiation and neuromuscular fatigue associated with prolonged sitting (Fig. 5) [14]. However, the current empirical evidence does not favor the (neuromuscular) effects of breaking up sitting, especially, on skeletal muscle twitch amplitude and fatigue accrued during the typical work hours [81].

Breaking up sitting bouts with short bouts of physical activity is postulated to improve endothelial functions, regulating peripheral, cerebral blood flow, improving venous return (Fig. 7) and viewed as a prophylactic strategy to mitigate impaired cognitive functions associated with prolonged sitting [57]. In a recent systematic review, Paterson et al. (2020) analyzed the effects of interrupted bouts with aerobics, resistance exercises or standing on flow mediated dilation of brachial, femoral and posterior tibial arteries from 6 studies [47]. The review found significantly higher flow mediated dilation (1.91%; 95% CI 0.40–3.42%) during interrupted sitting bouts compared to uninterrupted sitting [47]. However, the dose response relationship of the interventions targeting reducing sitting or improving physical activity on the cerebral flow velocity remains unclear.

In a crossover trial, 15 middle-aged adults underwent three interventions: uninterrupted sitting for 4 h, sitting interrupted with a 2-min walk every 30 min and sitting with a 8-min walk every 2 h [57]. The study found a significant decline of cerebral flow velocity in uninterrupted sitting (− 3.2 ± 1.2 cm/s) compared to 2-min walk breaks (0.6 ± 1.5 cm/s) but not 8-min walk breaks (− 1.2 ± 1.0 cm/s). In contrary to earlier studies, Maasakkers et al. (2020) failed to find a significant difference in cerebral flow velocity or cerebral vasomotor functions between uninterrupted (3 h) and interrupted sitting bouts (2 min walk break every 30 min for 3 h) combined with or without mental tasks in 22 elderly adults (78 years) [63]. The aforementioned inconsistent findings regarding the effects of interrupted sitting bouts on the cerebral flow velocity and perfusion makes it difficult to extrapolate the effects of such interventions on cognitive functions.

Few promising controlled trials have succeeded in observing a change in peripheral blood vessels shear stress and flow mediated dilation percentage after an acute exposure of breaking up sitting with different doses of physical activity (low intensity walks to moderate intensity exercises) [82, 83]. Thosar et al. (2015) interrupted 3 h of sitting with active breaks which prevented a decline in superficial femoral artery dilation (0.24–1.74% from the baseline) with no reduction in shear rates in 12 non-obese men [82]. In addition, Carter et al. (2019) in an experimental study investigated the effects of two different break strategies (2-min walking breaks every 30 min of sitting and 8-min walking breaks every 2 h) on superficial femoral artery endothelial function in 15 healthy desk-based office workers. They found an increase in SFA blood flow (by 0.45 ± 17.7 mL·min) after 8-min breaks compared to 2-min breaks [83]. The observed increase in blood flow and arterial dilation is perceived as a necessary mechanism for reducing the risk of atherosclerosis and future cardiovascular diseases [44]. This improved vasodilation is probably due to improved nitric oxide (endothelium-derived relaxing factor), prostaglandin and increased venous return which in turn may improve the cortical perfusion [84]. In a recent study, Carter et al. (2020) assessed the effects of an e-health intervention on vascular function, amongst other outcomes, in 14 heathy office workers for 8 weeks. In spite of perceived interruption to the routine workflow, vascular functions improved (d = 0.88) and total daily sitting time (d = 0.92) decreased with the scheduled breaks delivered through the e-health intervention [85].