Before you skip another workout, you might think about your brain. A provocative new study finds that some of the benefits of exercise for brain health may evaporate if we take to the couch and stop being active, even just for a week or so. 
 
 I have frequently written about how physical activity, especially endurance exercise like running, aids our brains and minds. Studies with animals and people show that working out can lead to the creation of new neurons, blood vessels and synapses and greater overall volume in areas of the brain related to memory and higher-level thinking. 
 
 Presumably as a result, people and animals that exercise tend to have sturdier memories and cognitive skills than their sedentary counterparts. 
 
 Exercise prompts these changes in large part by increasing blood flow to the brain, many exercise scientists believe. Blood carries fuel and oxygen to brain cells, along with other substances that help to jump-start desirable biochemical processes there, so more blood circulating in the brain is generally a good thing. ||||| Physically fit, healthy older adults who stopped exercising for only 10 days showed signs of significant decreases in blood flow to parts of the brain that are important for thinking, learning, and memory - such as the hippocampus. 
 
 
 
 The researchers found significant reductions in resting brain blood flow in eight brain regions in fit older adults who stopped exercising. The researchers found significant reductions in resting brain blood flow in eight brain regions in fit older adults who stopped exercising. 
 
 This was the key finding of a new study - led by the University of Maryland (UMD) School of Public Health and recently published in the journal Frontiers in Aging Neuroscience - that adds to growing evidence of links between physical fitness and cognitive health. 
 
 In their study paper, the researchers discuss how evidence shows endurance exercise training improves cerebrovascular health and has positive effects on the hippocampus, but what happens to these benefits if exercise ceases is somewhat unclear. 
 
 Lead author J. Carson Smith, associate professor of kinesiology at UMD says we know that the hippocampus is important for learning and memory. 
 
 He explains that studies of mice and rats have shown exercise increases growth of new blood vessels and brain cells. Also, research shows that in older people, exercise can protect the hippocampus from shrinking. He notes: 
 
 "So, it is significant that people who stopped exercising for only 10 days showed a decrease in blood flow to brain regions that are important for maintaining cognitive health." 
 
 Significant reductions in brain blood flow 
 
 Using magnetic resonance imaging (MRI) brain scans, the team measured brain blood flow in healthy, physically fit older adults aged from 50-89 years (average 61) before and after a 10-day period during which they stopped all exercise. 
 
 Fast facts about the hippocampus Named after its shape, the word "hippocampus" comes from old Greek via Latin for "seahorse" 
 
 Recent research finds the human brain stores time and place of memories in the hippocampus 
 
 The hippocampus is one the first parts of the brain to suffer damage in people with Alzheimer's disease. 
 
 From the brain scans, the researchers were able to assess the velocity of blood flow while the participants were at peak fitness and then again after 10 days of no exercise. 
 
 The results showed significant reductions in resting brain blood flow in eight brain regions - including the right and left hippocampus. 
 
 The other regions included parts of the "default mode network" - a brain structure that is known to deteriorate quickly in people with Alzheimer's disease. 
 
 However, the researchers found no significant change in cognitive function - measured using verbal fluency tests - in the participants from before to after they stopped exercising. 
 
 The participants who volunteered for the study were all "master athletes" whom the researchers describe as "a unique population and should not be considered equivalent to older adults who engage in regular moderate to vigorous intensity leisure-time physical activity." 
 
 The researchers were not surprised to find these senior athletes scored high for their age on aerobic fitness. Their VO2 max was in the top 10 percent for their age group (above the 90th percentile). VO2 max is the volume of oxygen a person consumes while exercising at their maximum capacity. 
 
 With an average continuous endurance training history of around 29 years, the volunteers regularly took part in national and regional events. 
 
 Just before taking part in the study, they were running an average of 59 kilometers a week and training on 5 days a week. 
 
 "We know that if you are less physically active, you are more likely to have cognitive problems and dementia as you age. However, we did not find any evidence that cognitive abilities worsened after stopping exercising for just 10 days. But the take home message is simple - if you do stop exercising for 10 days, just as you will quickly lose your cardiovascular fitness, you will also experience a decrease in blood brain flow." Prof. J. Carson Smith 
 
 The researchers say their findings point to a need for further research to discover how fast the brain blood flow changes occur, what their long-term effects could be, and whether they can be reversed by taking up exercise again. 
 
 Learn how any type of exercise appears to dramatically reduce risk of developing Alzheimer's disease. ||||| We all know regular exercise comes with numerous brain health benefits, like improving memory and thinking skills, helping to ward away cognitive decline in old age. However, hitting pause on our workout routine could weigh heavy on our conscious — literally. A recent study published in the journal Frontiers in Aging Neuroscience found stopping exercise for just 10 days can significantly reduce blood flow to several brain regions, including the hippocampus. 
 
 "We know that the hippocampus plays an important role in learning and memory and is one of the first brain regions to shrink in people with Alzheimer's disease," said Dr. J. Carson Smith, lead author of the study and associate professor of kinesiology at University of Maryland School of Public Health (UMD), in a statement. 
 
 Typically, the hippocampus shrinks in late adulthood, which is what leads to impaired memory and increased risk for dementia. Previous research has found the hippocampus responds to exercise training by increasing in volume, and leading to improvements in spatial memory. Aerobic exercise training can be effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function. 
 
 In the UMD study Smith and his colleagues observed ‘master athletes” who were between the ages of 50 and 80 (average age was 61), who had at least 15 years history of participating in endurance exercise, and who have recently competed in an endurance event. The participants' exercise routines included at least four hours of high intensity endurance training each week. On average, they were running ~36 miles each week or the equivalent of a 10K run a day. This group also had a VO2 max — the maximum amount of oxygen the body is capable to use of in one minute — above 90 percent for their age. 
 
 An MRI scan was used to measure the velocity of blood flow in the brain while the athletes were following their regular training routine, specifically at peak fitness, and again after 10 days of no exercise. The researchers noted resting cerebral blood flow significantly decreased in eight brain regions, including the areas of the left and right hippocampus, and other regions known to be part of the brain's "default mode network" — a neural network known to deteriorate quickly with Alzheimer's disease. It's important to note these significant changes were regionally specific. 
 
 “[T]he take home message is simple - if you do stop exercising for 10 days, just as you will quickly lose your cardiovascular fitness, you will also experience a decrease in blood brain flow” said Smith, about the findings. 
 
 A similar study published in the journal Neurology found less fit middle-aged adults saw loss of brain volume after 20 years. Participants performed treadmill tests to estimate their “exercise capacity,” which was measured by monitoring the amount of time they could exercise before their heart rate passed a threshold. The researchers found for every The researchers found those who saw their blood pressure and heart rate surge the most during the treadmill test were “more likely to have smaller brain volumes two decades later,” they wrote. In other words, there was a direct correlation between poor fitness levels and brain volume decades later, which indicates accelerated brain aging. 
 
 Stopping exercise for awhile, or the lack of exercise, has important implications on our brain health. More research is needed to confirm how fast these changes occur, and what the long term effects could be. Researchers will also need to look into if these brain changes could be reversed with the resumption of exercise. 
 
 Source: Alfini AJ, Weiss LR, Leitner BP et al. Hippocampal and Cerebral Blood Flow after Exercise Cessation in Master Athletes. Front. Aging Neurosci. 2016. ||||| While endurance exercise training improves cerebrovascular health and has neurotrophic effects within the hippocampus, the effects of stopping this exercise on the brain remain unclear. Our aim was to measure the effects of 10 days of detraining on resting cerebral blood flow (rCBF) in gray matter and the hippocampus in healthy and physically fit older adults. We hypothesized that rCBF would decrease in the hippocampus after a 10-day cessation of exercise training. Twelve master athletes, defined as older adults (age ≥ 50 years) with long-term endurance training histories (≥15 years), were recruited from local running clubs. After screening, eligible participants were asked to cease all training and vigorous physical activity for 10 consecutive days. Before and immediately after the exercise cessation period, rCBF was measured with perfusion-weighted MRI. A voxel-wise analysis was used in gray matter, and the hippocampus was selected a priori as a structurally defined region of interest (ROI), to detect rCBF changes over time. Resting CBF significantly decreased in eight gray matter brain regions. These regions included: (L) inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, (R) cerebellar tonsil, lingual gyrus, precuneus, and bilateral cerebellum (FWE p < 0.05). Additionally, rCBF within the left and right hippocampus significantly decreased after 10 days of no exercise training. These findings suggest that the cerebrovascular system, including the regulation of resting hippocampal blood flow, is responsive to short-term decreases in exercise training among master athletes. Cessation of exercise training among physically fit individuals may provide a novel method to assess the effects of acute exercise and exercise training on brain function in older adults. 
 
 Introduction 
 
 Endurance exercise training (exercise) produces physiological adaptations that enhance aerobic fitness and cardiovascular health (Brooks et al., 1996). Consistent exercise effectively augments the maximal rate of oxygen consumption ( V ⋅ O 2max ) centrally, by increasing cardiac output, and/or peripherally by widening the arterial-venous oxygen (A- V ⋅ O 2 ) difference (Seals et al., 1981). V ⋅ O 2max is the gold-standard index of cardiorespiratory fitness and is highly correlated with both morbidity and mortality (Hoekstra et al., 2008; Sawada et al., 2012), with greater fitness status associated with a reduced risk of chronic disease and a longer lifespan. In addition to enhancing the function of the cardiovascular system, exercise has been shown to increase bone density, improve muscle quality, and protect against metabolic dysfunction (Brooks et al., 1996). Conversely, when the exercise stimulus is removed many of these systemic adaptations rapidly dissipate (Mujika and Padilla, 2000a, 2001a,b), thereby increasing the potential for adverse health effects. For example, 20 days of bed rest immobilization resulted in a substantial 28% decrease in V ⋅ O 2max (Saltin et al., 1968); a prolonged detraining period reduced muscle fiber capillarization and oxidative enzyme activity (Klausen et al., 1981); and a 10-day period of physical inactivity was related to the development of impaired glucose tolerance and insulin resistance (Rogers et al., 1990). 
 
 A growing body of empirical evidence supports the notion that exercise also robustly affects the human brain. Multimodal neuroimaging studies, including both structural and functional MRI, have helped elucidate the brain's complex neurobiological response to exercise. These exercise-induced effects include cytoarchitectonic modifications (Erickson et al., 2009; Smith et al., 2014; ten Brinke et al., 2015); altered patterns of neural activity (Smith et al., 2013); and improved performance across the cognitive domains (Tomporowski, 2003; Kramer et al., 2005; Davranche and McMorris, 2009; Chapman et al., 2013). The hippocampus, a subcortical brain structure well known for its role in learning and memory, has shown neurotrophic effects as the result of exercise training in humans and animal models (van Praag et al., 1999; Pereira et al., 2007; Erickson et al., 2009). Exercise interventions in humans have been shown to affect hippocampal-dependent cognition and to increase hippocampal blood perfusion (Pereira et al., 2007) and volume (Erickson et al., 2009). While the effects of detraining have been reported in peripheral physiological systems, the effects of detraining on brain function, and on cortical and hippocampal blood flow, have not been reported. 
 
 A key unanswered question, and the primary aim of this study, was to determine how short-term exercise cessation impacts cerebrovascular function in healthy highly physically active and physically fit older adults. To accomplish this goal we measured the resting cerebral blood flow (rCBF) of master athletes both before and immediately after 10 days of exercise cessation. To quantify rCBF we employed pseudo-continuous arterial spin labeling (pCASL), a perfusion-weighted MRI technique. Our hypotheses were twofold. We predicted (1) that 10 days of physical inactivity would alter rCBF in areas known to be susceptible to age-related decline (Greicius et al., 2004; Buckner et al., 2005), and (2) that detraining would decrease hippocampal blood flow, which we chose as an a priori region of interest (ROI). 
 
 Methods 
 
 Participants 
 
 Our unique study sample consisted entirely of master athletes, which were defined as a sub-group of highly trained healthy older adults who regularly engaged in endurance exercise. Master athletes ranged in age between 50 and 80, and were recruited from local Washington D.C. area running clubs. These individuals had an endurance exercise history of at least 15 years and had recently competed in regional and national endurance events. Personalized training regimens must have entailed at least 4 h of high intensity endurance training per week. 
 
 This study was approved by the Institutional Review Board, and written informed consent was obtained from all participants, in accordance with the Helsinki declaration. A telephone screen was used to determine eligibility. Those who met inclusion/exclusion criteria (see below) and agreed to participate completed the following: anthropometric measurement, a maximal intensity treadmill/electrocardiography test, DEXA (Dual-energy X-ray absorptiometry) body composition assessment, neuropsychological testing, and fMRI scanning (Table 1 shows descriptive data for variables examined at baseline only). 
 
 TABLE 1 
 
 Table 1. Descriptive participant data collected at baseline. 
 
 Inclusion and Exclusion Criteria 
 
 Individuals were excluded if they had a BMI ≥ 30, reported being a smoker (within the past 5 years), or had a history of heart attack, stroke, lung disease, chronic obstructive pulmonary disease, peripheral vascular disease, heart disease, liver disease, kidney disease, anemia, or diabetes. Individuals taking prescription medication for hypertension were also deemed ineligible. Women participants must have been post-menopausal for at least 2 years and must not have used hormone therapy during the previous year. Additionally, individuals were excluded if they presented any absolute contraindications to MRI. During the initial telephone screening 21 persons were deemed ineligible to participate in this study. Of the 12 individuals who qualified for participation, nine (7 men, ~89% Caucasian) were included in the final analysis. One individual was removed due to irregular ECG activity during the graded treadmill test; another because of dental work that severely distorted the MR signal; and a third for failure to achieve V ⋅ O 2max during the graded treadmill exercise test. 
 
 Neuropsychological Testing 
 
 Prior to the baseline MRI scan, all participants were administered the Mini Mental State Exam (MMSE) (Folstein et al., 1975), which is a 30-point questionnaire used to screen for global cognitive impairment and dementia. Additionally, after both the baseline and follow-up MRI scan all participants were administered the semantic verbal fluency test (Monsch et al., 1992). This test required participants to list as many words as possible from a given category in 60-s (fruits and animals, order counterbalanced). 
 
 V ⋅ O 2max Testing 
 
 Cardiorespiratory fitness was determined by assessing V ⋅ O 2max during a graded treadmill test with indirect calorimetry (Quark, Cosmed USA). Exercise tests were conducted utilizing a protocol we have used numerous times previously in older athletes, and included standard ECG monitoring (Rogers et al., 1990; Brooks et al., 1996). The exercise test continued until maximal effort or exhaustion was achieved. For exercise tests to be considered maximal, participants had to reach both a plateau in V ⋅ O 2max with increasing workload and a respiratory exchange ratio >1.1. The highest V ⋅ O 2 attained during the test was recorded as V ⋅ O 2max . The maximal exercise test was conducted several hours after the baseline MRI scan. 
 
 Body Composition Assessment 
 
 Body composition was measured using dual energy x-ray absorptiometry (DEXA) (DXA; Prodigy, LUNAR Radiation Corp). 
 
 Exercise Cessation Period 
 
 MRI scanning occurred at two time points, baseline and immediately after the 10-day exercise cessation. Participants were asked to refrain from exercise during the 12 h preceding the baseline assessment. The exercise cessation commenced 72 h after the baseline scan, at which time all exercise training was stopped. During this period participants were asked to refrain from exercise and all other forms of vigorous physical activity. The abstention from exercise during the 10-day period was verified frequently by telephone conversations with the participants and during their final testing. The second MRI scanning session occurred on the morning after the last day of the exercise cessation period, and before participants resumed their training regimens. 
 
 MRI Acquisition 
 
 All MRI data were acquired with a Siemens 3.0 Tesla MR system (Magnetom Trio Tim Syngo, Munich, Germany). A 32-channel head coil was used for radio frequency (RF) transmission and reception. Foam padding was positioned within the head coil to minimize patient motion. A high-resolution T1-weighted anatomical image was acquired for co-registration with the following sequence parameters: Magnetization Prepared Rapid Acquisition of Gradient Echo (MPRAGE), matrix = 256, field-of-view (FOV) = 230 mm, voxel size = 0.9 × 0.9 × 0.9 mm, slices = 192 (sagittal plane, acquired right to left), slice thickness = 0.9 mm, repetition time (TR) = 1900 ms, echo time (TE) = 2.32 ms, inversion time (TI) = 900 ms, flip angle = 9°, sequence duration = 4:26 min. The pCASL data were acquired using the following sequence parameters: single-shot gradient echo planar images, matrix = 64, FOV = 210 mm, voxel size = 3.28 × 3.28 × 6.0 mm, slices = 20 (axial plane, acquired in ascending order), slice thickness = 5.0 mm, gap between slices = 1 mm, single slice acquisition time = 48 ms, label duration = 1500 ms, post-label delay = 1000–1912 ms, TR/TE = 4000/19 ms, volumes = 140, number of label/control pairs = 70, flip angle = 90°, RF blocks = 80, RF pulses = 20, gap between pulses = 360 μs, bandwidth = 3004 Hz/Px, and sequence duration = 9:28 min. Additionally, a concatenated series of control volumes stacked in the time dimension was used as the proton density (PD) image for perfusion calibration. 
 
 MRI Data Preprocessing 
 
 The pCASL and PD images were realigned to the first volume of the image time series for motion correction (Cox, 1996). Using pairwise subtraction, a perfusion-weighted image was derived from the motion-corrected interleaved (control—tag) volumes, and this image was corrected for slice-timing delay (Woolrich et al., 2009). 
 
 Using FSL's BASIL (Bayesian Inference for Arterial Spin Labeling, FMRIB Software Library v5.0, Oxford, UK) (Woolrich et al., 2009), a reference mask from the T1-weighted anatomical image was used to isolate and sample the cerebral spinal fluid (CSF) within the ventricles of the PD image. The CSF sample was used to compute the magnetization equilibrium (M0) of tissue, which was further used to obtain the magnetization equilibrium of arterial blood (M0a) (Woolrich et al., 2009). 
 
 Buxton's general model for kinetic inversion was used to estimate absolute CBF (ml/100g/min) (Buxton et al., 1998), and included both Bayesian inferences and the following parameters (Chappell et al., 2009): ΔM (proportional magnetization change represented by the perfusion-weighted image), T1 blood (longitudinal relaxation time of blood = 1650 ms), T1 tissue (longitudinal relaxation time of tissue = 1300 ms), α (labeling efficiency = 0.85), M0 a (magnetization equilibrium of arterial blood), BAT (bolus arrival time = 1300 ms), Bolus (label duration = 1500 ms), PLD (post label delay = 1000 ms), and λ (blood/brain partition coefficient of GM = 0.98 ml/g) (Buxton et al., 1998; Alsop et al., 2014). The rendered CBF map was spatially smoothed using an adaptive technique, which combined neighboring voxel signals on an intensity-dependent basis, while preserving the non-linear kinetics where smoothing was unnecessary (Groves et al., 2009; Chappell, 2014). Due to the inherently low spatial resolution of the perfusion image, partial volume error correction was performed to improve the accuracy of CBF estimation (Chappell et al., 2011; Chappell, 2014). This process effectively calculated separate gray matter and white matter perfusion using tissue specific partial volume estimates in each voxel (Chappell et al., 2011; Chappell, 2014). Co-registration and normalization was performed with SPM8 (Hall and Degenhardt, 2008; SPM, University College, London, UK), using the PD image as the reference to which the CBF map was aligned. The output parameters were used to transform the CBF map and gray matter estimates to standard space, which effectively up-sampled the images to a 2 mm3 isotropic voxel resolution. Normalized gray matter estimates were merged together and used as a mask for the voxel-wise analysis. 
 
 Gray Matter Voxel-Wise Analysis 
 
 A voxel-wise analysis, restricted to voxels within the gray matter mask, was conducted to explore the effect of exercise cessation on rCBF. Statistical parametric maps were produced (Cox, 1996), indicating where rCBF had significantly changed over time. We used AFNI's 3dClustsim program (on the 2 mm3 data) to control for the effects of multiple comparisons and reduce the likelihood of a Type-I error. This analysis tool used Monte Carlo simulations to establish a family-wise error (FWE) corrected probability threshold at both the voxel (p < 0.05) and cluster (α < 0.05) level (Cox, 1996). Using first-order nearest neighbor clustering, we maintained results at a minimum cluster size of ≥480 mm3. To further illustrate the results of the voxel-wise analysis, the mean rCBF from each significant ROI was extracted from all subjects, at both time points. 
 
 Hippocampal Analysis 
 
 To examine the effect of exercise cessation on hippocampal blood flow, we conducted an a priori analysis that was restricted to voxels within the hippocampus. To isolate and examine hippocampal rCBF, we used FreeSurfer's (version 5.3.0) automated subcortical processing stream (Fischl et al., 2002). This procedure segmented the T1-weighted anatomical image and rendered a segmentation map based on both atlas probabilities and subject-specific tissue intensities. The segmentation map was normalized using non-linear transformation to maintain both the accuracy and integrity of the labeled subcortical anatomy. The non-linear transformation parameters were then used to warp the co-registered CBF map to standard space. The normalized bilateral hippocampal regions were extracted, merged together, and used as a mask for the voxel-wise analysis. Using the same clustering procedures as described above, Monte Carlo simulations were run over the hippocampal volume to establish a FWE threshold of p < 0.05 with a minimum cluster size of ≥200 mm3. 
 
 Results 
 
 The Master Athlete Profile 
 
 The master athletes who volunteered for this study are a unique population and should not be considered equivalent to older adults who engage in regular moderate to vigorous intensity leisure-time physical activity. Our participants had a mean continuous endurance training history of ~29 years, and on average were running 59 km per week and training 5 days per week just prior to the baseline testing. They also regularly participated in regional and national endurance competition. Moreover, as a group these master athletes had a V ⋅ O 2max above the 90th percentile for their age and sex. 
 
 Gray Matter rCBF 
 
 Results of the gray matter voxel-wise analysis demonstrated that the 10-day exercise cessation period significantly reduced absolute rCBF in eight brain regions (Figure 1). Of note are the Pre > Post comparisons, shown in blue on the Δ rCBF maps in Figure 1, revealing significantly decreased rCBF in each ROI (total volume = 5,640 mm3) that remained after correction for multiple comparisons using the False Discovery Rate (see Table 2). These regions included: (L) inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, (R) cerebellar tonsil, lingual gyrus, precuneus, and (L/R) cerebellum. No statistically significant change in whole brain absolute CBF in gray matter was detected [mean (±SD) baseline = 69.4 (±10.4 ml/100g/min), post-cessation = 67.2 (±12.6 ml/100g/min)]. 
 
 FIGURE 1 
 
 Figure 1. Results of the gray matter voxel-wise analyses reveal eight brain regions (A–H), which demonstrated significant rCBF changes over time. Adjacent bar graphs represent the mean rCBF difference within each region, and include brain area, LPI coordinates, and cluster volume in mm3. The color bar represents the mean absolute CBF difference (post-detraining minus pre-detraining) within each region, expressed in ml/100g/min. Corrected p-values reflect the contrast between the Pre and Post time points. 
 
 TABLE 2 
 
 Table 2. Cerebral blood flow (CBF) results from gray matter voxel-wise analysis. 
 
 Hippocampal rCBF 
 
 The a priori hippocampal analysis also revealed significantly decreased blood flow in both the left and right hippocampus from before to after the cessation of exercise training (see Figure 2). 
 
 FIGURE 2 
 
 Figure 2. (A) Results of the a priori hippocampal analysis demonstrating significant CBF changes over time in the left and right hippocampus. The color bar represents the mean absolute CBF difference (post-detraining minus pre-detraining) within each ROI, (B) Scatter plots showing hippocampal CBF for each participant at both time points. Additionally, scatter plots indicate LPI coordinates and cluster volume in mm3. Corrected p-values were 0.0011 and 0.0041 for left and right hippocampus, respectively. 
 
 Verbal Fluency 
 
 Verbal fluency performance did not significantly change from before to after the cessation of training period [mean (±SD) baseline = 19.9 (±4.9 words), post-cessation = 17.4 (±5.8 words), t (8) = 0.91, p = 0.39]. 
 
 Discussion 
 
 In the present study, we examined the relationship between short-term exercise cessation and resting rCBF in master athletes. Exercise cessation was associated with reduced rCBF within eight gray matter regions, including bilateral regions of the hippocampus. Importantly, these significant changes were regionally specific, and not the result of global CBF changes after the 10-day period of exercise cessation. 
 
 In one of the first studies of its kind, Saltin et al. (1968) demonstrated the deleterious effects of bed rest immobilization on the cardiovascular system. Comparable to decades of biological aging, this extreme sedentary behavior reduced V ⋅ O 2max ~27% in just 20 days (Mcguire et al., 2001). Using biopsy samples from the vastus lateralis, Klausen examined the effects of exercise cessation on skeletal muscle. After an 8-week detraining period, both muscle fiber capillarization and oxidative enzyme activity declined (Klausen et al., 1981). Finally, in a study of master athletes, Rogers examined the effects of a short-term period without exercise on insulin-regulated glucose metabolism. After 10 days, ~29% of these older adults developed signs of impaired glucose tolerance or insulin resistance (Rogers et al., 1990). Here, we have extended this literature to demonstrate that not only does exercise cessation among physically fit older adults affect markers of peripheral metabolic function, but also appears to affect brain cortical and hippocampal blood flow. 
 
 Exercise training has been shown to robustly affect the structural and functional integrity of the hippocampus in animals and humans, producing neurotrophic effects leading to neurogenesis and angiogenesis in rodents (van Praag et al., 1999; Pereira et al., 2007; Intlekofer and Cotman, 2013), and to increased structural volume in healthy older adults (Erickson et al., 2009). Twelve weeks of exercise training in healthy younger adults was shown to increase the blood volume within the dentate gyrus of the hippocampus and to improve episodic memory performance. Our findings of reduced rCBF bilaterally in the hippocampus suggest that training-induced changes in hippocampal blood flow may be reversed with 10 days of exercise cessation. Our participants, however, did not show any changes in cognitive function over the 10-day cessation of exercise period. Nevertheless, it is not known if cellular adaptations, undetectable using MRI, occur when exercise training is stopped temporarily. 
 
 Although several studies have used perfusion-weighted imaging to probe for exercise-induced alterations in rCBF, differences in exercise intensity, study design, and data analysis methods have likely led to conflicting results. In a randomized controlled trial, Chapman et al. (2013) demonstrated that a 12-week aerobic exercise intervention significantly increased rCBF in the anterior cingulate cortex of previously sedentary older adults (Chapman et al., 2013). Likewise, a cross-sectional study by Thomas showed that master athletes had significantly greater rCBF in the posterior cingulate cortex than age-matched sedentary controls (Thomas et al., 2013). While these findings seem to corroborate one another, the effects of acute exercise on rCBF have proven to be complex. Although Smith et al. found rCBF in the motor cortex to be significantly greater after a session of moderate-intensity exercise (Smith et al., 2010), MacIntosh demonstrated, in a similar study, that acute exercise decreased rCBF in the hippocampus and insula (MacIntosh et al., 2014). 
 
 Until now, the effects of exercise cessation on cerebrovascular function have been virtually unexplored. This study has extended the literature by showing that a short-term period of physical inactivity among master athletes reduces rCBF in the hippocampus and several gray matter regions. While these effects may have implications for brain function in older adults, it is also possible that these effects represent changes in arterial transit time (Buxton, 2005) or cerebral blood volume (Yoshiura et al., 2009), neither of which we were able to measure. A decrease in arterial transit time, for instance, while using the same post-label delay parameter, could result in an apparent decrease in rCBF (Buxton, 2005). In addition, total blood volume has been shown to increase in response to exercise training (Convertino, 1991) and to decrease after detraining (Coyle et al., 1986). These are important points to consider; however, the regional specificity of the effects we observed suggests these changes were not an artifact of a global flux in blood flow or volume. Although increases in blood volume have been documented in the dentate gyrus after 12 weeks of exercise in younger adults (Pereira et al., 2007), the impact of exercise cessation on cerebral blood volume and arterial transit time has not been established. 
 
 Animal research suggests the most viable mechanism for exercise-induced perfusion alterations may be structural modifications to the cerebrovasculature (Swain et al., 2003; Pereira et al., 2007). One such study established these effects by examining the association between increased cerebral blood volume and post-mortem neurogenesis in exercised mice (Pereira et al., 2007). The results indicate that local increases in hippocampal blood volume coincide with the cellular proliferation and reconfiguration within the dentate gyrus. In another investigation, Ryhu provided further support for this proposition by evaluating the effects of both exercise training and exercise cessation on the non-human primate cerebrovascular system (Rhyu et al., 2010). During this study, animals were randomized to either treadmill training or sedentary behavior. After 5 months, a sub-set of primates from the exercise group were subjected to an additional 3 months without exercise. At the 5-month time point, the exercised animals had significantly greater cerebrovascular volumes than their sedentary counterparts. As for the effects of exercise cessation, the increases in vascular volume induced during the exercise-training period were reversed after 3 months of detraining. It is plausible that the cessation of exercise involves a reversal of these effects, which would need to be confirmed in additional animal models. 
 
 There are several limitations to the current study. We had a small (n = 9) and homogeneous (7 men, ~89% Caucasian) study sample, in which all participants exhibited a high level of aerobic fitness, long history of competitive endurance training, and normal BMI, which limits the generalizability of our findings. While our sample was small, the effects we observed were substantial and all in the same direction. We may have lacked statistical power to detect smaller effects and may have underestimated the decreases in CBF that occurred. In addition, because we only measured rCBF at two time points, we do not know the time course of the changes we observed. It is possible reduced rCBF may have been evident prior to day 10. Further, we cannot speculate regarding whether or not these effects would have increased, decreased or remained stable with a longer period of exercise cessation. We made a priori predictions of changes in hippocampal blood flow based on an extensive literature, a method also used by others (Pereira et al., 2007), which avoided adjustment for whole brain voxel-wise comparisons and prevented a possible Type-II error. Nevertheless, future studies should confirm these effects in a larger sample. Additionally, aerobic fitness was assessed only at baseline, so we do not know the magnitude of the fitness change over time. Several studies have documented that in trained individuals substantial decreases in fitness occur after short-term cessation from exercise training (Klausen et al., 1981; Rogers et al., 1990; Mujika and Padilla, 2000b). Finally, the nature of our imaging sequence (single-delay) limited our ability to estimate changes in cerebral blood volume, and possible changes in arterial transit time. Our post label delay values began at 1000 ms and increased at each slice, which does not precisely correspond to the ISMRM Perfusion Study Group recommended guidelines for ASL scanning among older adults (Alsop et al., 2014). This could contribute to CBF quantification challenges, including arterial transit time artifacts. Measuring cerebral blood volume and arterial transit time with multi-delay ASL is an important next step (Alsop et al., 2014). 
 
 Approximately two-thirds of the ROIs that showed altered rCBF after exercise cessation are considered part of the brain's default mode network (DMN), which is known to be disrupted with age-related cognitive decline and Alzheimer's disease (Raichle et al., 2001; Sheline et al., 2010; Petrella et al., 2011). Exercise training in older adults has been shown to augment functional connectivity within the DMN in healthy older adults (Voss et al., 2010). While our findings suggest that short-term cessation from endurance training in highly trained older adults may lead to decreased rCBF within the DMN, there was no indication that these effects were detrimental to cognitive function, as measured by a semantic verbal fluency task (which activates brain regions that overlap with the DMN; Binder et al., 2009), or to the integrity of these neural networks. Future exercise detraining studies should examine participants after resuming their training schedules to document whether or not these effects would be reversed. It is also not known if the decreased rCBF we observed solely reflects changes in the rate of blood flow within parenchymal regions, or additionally reflects changes in arterial transit time and/or blood volume. Nevertheless, the exercise cessation paradigm may provide useful information to probe the durability of the effects of exercise training and physical activity on brain function. Just as the effects of long-term endurance exercise training on cardiovascular and metabolic function wane considerably after a short period of detraining (Mujika and Padilla, 2000b), so also may hippocampal and gray matter rCBF be sensitive to exercise cessation. 
 
 Author Contributions 
 
 Substantial contributions to the conception or design of the work (JH, JS). The acquisition, analysis, or interpretation of data for the work (AA, BL, LW, TS, JS, JH). Drafting the work or revising it critically for important intellectual content (AA, JS, BL, LW, TS, JH). 
 
 Funding 
 
 This study was supported by a grant from the National Institutes of Health (HL098810). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. 
 
 Conflict of Interest Statement 
 
 The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 
 
 Acknowledgments 
 
 We thank the participants for abstaining from the exercise that so aptly defines their daily lives. The authors also thank Hyuk Oh, Wang Zhan, and Kate Reiter for their technical and analytical support on this project. 
 
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– Think it's OK to take a week off from working out? Think again ... if you even can. A study published last month in Frontiers in Aging Neuroscience finds the benefits of exercise on the brain can fade after just 10 days. Previous studies have shown that exercise increases blood flow to the brain, which can create new neurons, increase volume in important places, and possibly even improve memory and thought, the New York Times reports. But it was unclear how long that healthy increased blood flow and its benefits would last. Now we know: Less than 10 days. Researchers looked at a dozen "exceedingly fit" seniors—ages 50 to 80—who still ran 35 or more miles per week. After 10 days of doing nothing, the seniors had less blood flow to eight regions of their brain, including significantly less to the hippocampus, which is associated with memory, Medical News Today reports. Medical Daily quotes the study's lead author, Dr. J. Carson Smith, who says the hippocampus is "one of the first brain regions to shrink in people with Alzheimer's disease." The seniors didn't perform any worse on cognitive tests after 10 days of loafing about, and more research is needed to see if a cessation of exercise actually impacts the functioning of the brain. In the meantime, keep on that workout schedule. (Eleven hours of this brain game can cut dementia risk in half.)