WILLIAMSON, JON W.1; QUERRY, ROSS2; MCCOLL, RODDERICK3; MATHEWS, DANA3
An exercise bout of sufficient duration and intensity can lead to a temporary decrease in blood pressure (BP) termed postexercise hypotension (PEH). Although PEH is more pronounced in hypertensive individuals (13), others may show only minimal or even no decrease in BP after exercise (19,30). For those individuals experiencing PEH, the magnitude of BP decrease tends to be greater shortly after exercise, reaching its nadir within 5-15 min (21). This decrease is then followed by a slower increase toward preexercise BP levels (21). BP responses during the period of PEH result from alterations in peripheral conductance, mediated by changes in both central neural (8,10,16,17,30) and peripheral mechanisms (9,18,23,24).
Postexercise hypotension is characterized by reductions in sympathetic nerve activity (SNA) (8,9,16) coupled with alterations in vascular vasoconstrictor responsiveness (9) and release of local metabolic factors; specifically histamines (18,23) and kinins (24). The involvement of histaminergenic mechanisms is important in that it can more directly link the central neural and peripheral components involved in PEH; decreases in sympathetic outflow can trigger histamine release in skeletal muscle (4). Histamine blockade can reduce postexercise vasodilation and blunt PEH (18). Additionally, PEH can be attenuated with application of a cold pressure stimulus (8,17). Because the cold pressor is a potent sympathetic stimulus, it is likely that the cold pressor response can restore BP by increasing sympathetic outflow (8). The increase in SNA may also decrease histamine release or otherwise override the local vasodilation. This information suggests that the central neural component of PEH, specifically responsible for reductions in SNA, may be driving the PEH response by affecting histamine release.
The central neural changes during PEH involve alterations within the arterial baroreflex network, such that it is temporarily reset to a lower operating point, effectively reducing sympathetic outflow (7,9). During PEH, there is modulation of barosensitive neurons within the medulla, involving the nucleus tractus solitarius (NTS) (5) and the rostral ventrolateral medulla (RVLM) (12). Of note, blockade of substance P receptors in the rat NTS (5) can attenuate PEH. There is also decreased neural activity within higher brain centers, including the inferior thalamic and insular regions (17,30). These regions of the insular cortex (IC) are involved in autonomic regulation (3) and baroreflex modulation (33) in the rat. The IC, via neural connections through the lateral hypothalamic area (LHA) and RVLM (3), is capable of modulating SNA (3,27). Hanamori (11) has identified neurons within the posterior IC showing discharge patterns correlated with BP changes. In humans, these same IC regions show reduced neural activity after exercise, but only when PEH is present (17,30). During PEH, there exists a good correlation between changes in IC activity and BP (30), but this relationship has only been assessed shortly after exercise. It is not known if regional cerebral blood flow (rCBF) reductions in the IC and other regions persist throughout the period of PEH.
The purpose of this investigation was to determine whether exercise-induced decreases in IC neural activity are sustained throughout PEH and if the changes in IC regional cerebral blood flow (rCBF) are associated with BP changes postexercise. It was hypothesized that there would be decreases in rCBF for IC and thalamic regions as long as PEH persisted and that there would be strong association between the magnitude of change in IC rCBF and BP during PEH. The rCBF distributions were assessed for several cerebral cortical regions of interest (ROI) using single-photon emission computed tomography (SPECT) as an index of changes in neuronal activity (26).
All 10 study participants provided written, informed consent before participating in this study, which was approved by the University of Texas Southwestern Medical Center Institutional Review Board and Radiation Safety Committee. The study group included six women and four men (aged 23 ± 5 yr). All study participants were healthy and normotensive (resting BP <140/90 mm Hg), and none reported any history of neurological or cardiovascular disease. Female participants had a negative pregnancy test on all test days. Further, none reported being involved in a regular exercise program, but all did perform some type of aerobic exercise (e.g., walking, stationary cycling) at least once or twice per week. All had abstained from exercise and caffeine for at least 12 h before testing, and none were taking any prescription medications at the time of the investigation. They were familiarized with all procedures and measurements before any data collection. The participants completed three tests performed in a random order on separate days. Poststudy medical examination of individual magnetic resonance scans showed no significant abnormalities.
Instrumentation and procedures
A primary goal of this investigation was to compare patterns of rCBF and BP at different time points during PEH. As subjects could only be administered three doses of the retained blood flow tracer to measure rCBF (per institutional review board guidelines), each participated in three of the four test conditions. All subjects were tested at baseline (nonexercise control; n = 10) and then during two of the three possible postexercise periods (i.e., 10, 30, or 60 min). The three trials were performed on different days by each subject in random order such that n = 6 for 10 min, n = 7 for 30 min, and n = 7 for 60 min. After familiarization procedures and before testing, a venipuncture was made and capped with an injectable site to facilitate the innocuous administration of a retained blood flow tracer well in advance of data collection.
For the nonexercise control (baseline) condition, the participants remained upright for 30 min walking and standing in the laboratory with the treadmill running. After walking/standing, subjects were placed in a supine position with their right hand positioned at the level of the heart for BP assessment using a Finapres (Ohmeda 2300, Madison, WI). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) data were used to derive mean BP values [(1/3)(SBP − DBP) + DBP]. Finapres data were verified with standard upper arm auscultation. Subjects were asked to remain quiet with their eyes closed so that they were unaware of the exact time of the injection of the brain blood flow tracer. HR and BP data were recorded every 2 min throughout the 60-min postexercise period.
A moderate exercise intensity was used similar to that previously reported (17) to elicit PEH. Participants jogged on a motorized treadmill (Quinton, Model 8500) for 20 min at approximately 60-70% of their maximal HR reserve using the American College of Sports Medicine (ACSM) training HR index for the HR reserve method (1). All subjects rated the exercise at 15-16 Borg units by the 20th minute of exercise using the 6-20 scale (2). Exercise was preceded by a 5-min walking warm-up and followed by a 5-min walking cool down (30 min total time). After exercise cool down, participants were placed on the bed in a supine position. Cardiovascular measurements were recorded at 2-min intervals, and injection of the retained blood flow tracer was initiated at minutes 10, 30, or 60 postexercise. Although PEH can last for hours in some cases, the time frame for injections at minutes postexercise was selected to correspond with reported times for peak changes in postexercise BP (20,21) and also to previous PEH studies reporting data for minutes 30 and 60 postexercise (18-20,22).
To determine the rCBF distributions during each testing condition, 20 mCi of freshly reconstituted Tc-99m ECD (Neurolite, DuPont Pharma, Billerica, MA) was injected intravenously. This retained brain blood flow tracer is a photon emitter with a physical half-life of 6 h. Once in the brain, its distribution is related to brain blood flow patterns. Increases or decreases in rCBF to a particular region of the brain are related to increases or decreases in neuronal activity, respectively. Therefore, any changes in neuronal activity for a specific region can be detected by comparing changes in rCBF to a baseline condition (26). The retained brain blood flow tracer uptake is rapid and is basically completed within 2 min of injection. The reported rCBF distributions represent a 2-min window of time for minutes 10-12, 30-32, and 60-62 postexercise. Participants were asked to remain quiet with their eyes closed, but not to sleep. A technician administered the blood flow tracer and flushed the catheter with normal saline. Participants were unaware of the exact time of injection and reported no noticeable side effects. With the tracer uptake completed and bound in brain tissue, subjects rested for an additional 20 min before rCBF was assessed. The SPECT scanning was completed within 45 min of injection for all subjects. The specifics of brain scanning procedures have been previously reported (28).
Each individual's brain images were aligned in three dimensions by computer using an automated volume coregistration algorithm widely used for positron emission tomography coregistration (31). Once the three SPECT scans for a given subject were coregistered to each other, normalization of total radioactive count variability was obtained by rescaling each volume so that total counts were equal for all volumes. The SPECT magnetic resonance imaging (MRI) coregistration for each individual was performed using an interactive coregistration algorithm (22) implemented on a computer workstation. After the SPECT voxel size was made to match the MRI voxel size, the absolute and the percentage count differences for each pixel was obtained between scans. These differences were then displayed, for each selected slice within the volume, as a color overlay superimposed on the MRI.
Specific brain regions and structures were located using the coregistered magnetic resonance scans as an anatomical reference. Once identified, ROI were drawn around these areas, as seen on the MRI slice. This procedure was repeated on contiguous transaxial slices until the entire brain region/structure had been assessed across all slices. The number of 1.5 mm slices assessed varied by specific region and subject but was consistent for all trials within subjects.
On the basis of the findings from prior human studies involving the IC (6,15,17,25,29,30) and the spatial resolution of the SPECT methodology, the relatively large insular regions were divided into four smaller divisions for analysis consistent with prior studies (17,30). The insular quadrants served as ROI for analysis and were termed anterior superior (rostral dorsal), anterior inferior (rostral ventral), posterior superior (caudal dorsal), and posterior inferior (caudal ventral) for the right and left sides. Similarly, ROI were formed from the two halves of the thalamus divided into two equal superior (dorsal) and inferior (ventral) regions. Other regions/structures analyzed, with corresponding Brodmann's areas (BA) approximated when applicable, included leg sensorimotor regions (BA 1-4), anterior cingulate cortex (BA 24 and 32), a white matter region encompassing the anterior corpus callosum, and a gray matter region (BA 44 and 45) involved in speech (not involved in exercise or BP modulation).
The total number of radioactive SPECT counts within each ROI were then compared between conditions, for each subject, as absolute counts and as a percent change from the baseline condition. The SPECT data were corrected using white matter rCBF from the baseline condition to negate the possibility that differences in global cerebral blood flow between conditions accounted for any observed rCBF changes. During the processing and rCBF data assessment, data were coded such that the researchers performing these analyses were blinded with regard to subject identity and order of experimental conditions.
A univariate analysis was used to assess normality. Data were normally distributed, and a one-way ANOVA was used to compare differences in dependent variables across the baseline period and the three postexercise time points (10, 30, and 60 min). A general linear model was used to account for difference in sample sizes across conditions. HR and BP data were averaged over the 2-min window during rCBF assessment at rest and reported at the 2-min periods when rCBF data were assessed postexercise (i.e., minutes 10-12, 30-32, and 60-62). For rCBF, the raw counts recorded for each ROI were used for data analyses. A Bonferroni correction was used to account for multiple comparisons. If significance was detected, a Tukey post hoc analysis was performed to determine specific differences for pairwise comparisons. A Pearson correlation was performed using the percent change in rCBF and percent change in mean BP for individual data points at 10, 30, and 60 min postexercise to determine the coefficient of determination (r2). The alpha level was set at P < 0.05 for all analyses.
After 20 min of exercise, the HR was 147 ± 8 bpm as averaged over the three tests for all subjects. There were no significant differences for exercise HR between tests. Subjects reported average RPE values of 15 ± 2 U during the last minute of exercise over the three tests. There were no significant differences for RPE between tests. Postexercise data (mean ± SD) for mean BP (mm Hg) and HR (bpm) are reported for minutes 10, 30, and 60 during the periods when rCBF assessments were made (Fig. 1). There were significant decreases in mean BP from baseline at minutes 10 and 30, but not at minute 60. The HR was elevated during minutes 10 and 30, with no significant difference from baseline at minute 60.
FIGURE 1-Changes in ...Image Tools
In making comparisons of rCBF, statistical analyses were performed on raw counts, and data are also presented as percent changes in rCBF for specific brain regions to allow for comparison with other related studies (Table 1). The rCBF activity shown corresponds to the 10-, 30-, and 60-min periods reported in Figure 1. As compared with the baseline condition, at minute 10 postexercise, there were significant deceases in the leg sensorimotor area, the anterior cingulate cortex, the right inferior thalamus, the left inferior thalamus, the right inferior anterior IC, the right inferior posterior IC, and the left inferior anterior IC. At minute 30, there were significant decreases for thalamic and right insular regions as shown in Figure 2. There were no significant differences for the brain regions assessed from baseline measures at 60 min. For those regions showing significant decreases in rCBF at minute 10 postexercise, correlations between percent changes in rCBF and percent changes in mean BP for individual data across the three postexercise periods were assessed: leg sensorimotor (BA 1-4), r2 = 0.07, ns; anterior cingulate (BA 24 and 32), r2 = 0.10, ns; right inferior thalamus, r2 = 0.42, P < 0.05; left inferior thalamus, r2 = 0.31, P < 0.05); and right inferior anterior IC, r2 = 0.38, P < 0.05. The strongest correlation was found for the right inferior posterior IC (r2 = 0.74; P < 0.05) as shown in Figure 3.
There are exercise-induced decreases in rCBF (or neural activity) within the IC shortly after exercise (10-min time frame), but only when PEH is present (30). However, because PEH typically lasts longer than 10 min, the potential role of changes in IC neural activity in relation to postexercise BP over time has not been well defined. The goal of this investigation was to determine whether the exercise-induced decreases in IC rCBF were sustained over the period of PEH and if the changes in IC rCBF were associated with the BP changes during PEH. The main finding from this study was that exercise-induced rCBF changes within the right IC and thalamic regions were sustained during PEH. Although there were no differences in rCBF from baseline at 60 min postexercise for these regions, BP was not significantly decreased at that point in time. Of note, changes in thalamic and IC rCBF were correlated with BP changes over the postexercise period; the strongest association (r2 = 0.74) was found for the right inferior posterior IC.
The IC is a well-defined cerebral cortical site of autonomic integration (3,11,25,27) and baroreflex modulation (33). It represents a central source of sympathetic outflow (3) with direct projections to the lateral hypothalamic area (LHA), which in turn synapse with the rostral ventrolateral medulla (RVLM). Because the RVLM is critical in modulating sympathetic outflow, this suggests that changes in neural activity within the IC are likely capable of altering sympathetic outflow in humans, as shown by Cechetto and Saper (3) in the rat. Although decreases in RVLM neuronal activity have been shown to contribute to PEH in the rat (12), the spatial resolution of the SPECT technique does not allow us to determine whether there were concomitant decreases in neural activity within the human RVLM. However, the present study does show decreases in insular and thalamic activity at 10 and 30 min during PEH, consistent with the time frame for observed BP decreases. The BP decreases during PEH are typically coupled with reductions in SNA (8,16).
Decreases in SNA are a key factor in driving the PEH response (8,16). Floras et al. (8) used a cold pressor stimulus to counter PEH and to elevate BP via increases in SNA. Using this potent sympathetic stimulus, Lamb et al. (17) applied the cold pressor to counter BP decreases during PEH and recorded changes in rCBF. They found that those regions of the IC and thalamus showing decreases in neural activity during PEH were activated during application of the cold pressor and that these rCBF changes were coupled with BP elevations. This observation is consistent with findings from Hanamori (11), who reported that fluctuations in neuronal activity within the posterior IC of the rat are correlated with BP changes. Data presented in Figure 3 also show a strong association between changes in right IC rCBF and BP postexercise. Oppenheimer et al. (24) have previously noted an association between the right IC and the sympathetic activity. These data support the notion that decreased IC activity postexercise is likely involved in reductions in SNA and BP.
Interestingly, other regions of the brain showed alterations in rCBF after exercise, but the magnitude and the time course of changes were not associated with BP changes. Although there were significant decreases in the leg sensorimotor area (BA 1-4) and regions of the anterior cingulate cortex (BA 24 and 32) at minute 10 postexercise, there were no changes from baseline for either region after 30 min. The rCBF decrease at minute 10 is consistent with prior findings (17,30,33). Zanette et al. (33) also found that cortical activity was depressed in motor regions for approximately 30 min after small muscle exercise. This transient depression of cortical activity was only evident for those cortical regions representing the muscles involved in the exercise. In line with the concept that more active brain regions during exercise may show greater postexercise decreases in neural activity, there were no rCBF changes for Broca's area (BA 44 and 45) after exercise because it is primarily involved in language processing. Because both Broca's area and IC regions receive their primary blood supply from the middle cerebral artery, postexercise differences in rCBF between these areas are most likely related to differences in neuronal activity. In sum, these findings support the notion that exercise-induced changes in rCBF to various regions of the brain can vary in magnitude and duration postexercise. However, the underlying mechanisms related to these rCBF differences have not been clearly defined.
The cerebral cortical regions identified in this study may not be inclusive of all brain regions involved in postexercise rCBF changes; the IC regions were preselected based on prior data showing their involvement in BP modulation. Additionally, the spatial limitations of the SPECT technique (∼10 mm3) do not allow us to assess, with confidence, smaller regions that may also play an important role in cardiovascular regulation, such as specific nuclei of the thalamus or other subcortical structures. The rCBF distributions reported reflect the changes from the baseline or control condition but do not define the specific type of neural activity (i.e., excitatory or inhibitory) associated with the rCBF changes. Changes in PCO2 that can affect global CBF were not directly measured. However, assessment of white matter blood flow, which is reflective of global cerebral blood flow, was not significantly different across conditions. Both men and women were involved in the present study; however, there are data showing sex-related differences in brain activity as related the autonomic regulation of cardiovascular function (14). Although the magnitude of response may differ between sexes, the potential impact of this difference was reduced in the present study as each participant served as their own control. As noted previously, PEH involves both central neural and peripheral vascular components, and the role of peripheral vasodilators (e.g., histamines, kinins) was not directly investigated. It remains unclear if there is interaction between reductions in SNA and histaminergic mechanisms during PEH. Studies examining the relationship between sympathetic outflow and histamine release after exercise could provide more insight as to their potential interaction and relative roles in PEH.
Exercise-induced reductions rCBF within insular and thalamic regions appear to be sustained for approximately 30 min after exercise and are further associated with the magnitude of BP change. These findings extend current knowledge (17,30) by providing new information regarding the timeframe and impact of reductions in rCBF (as an index of neural activity) for posterior insular and thalamic regions on BP regulation after exercise. Although implicated in the overall postexercise response, possible mechanisms of interaction between these cerebral cortical regions and the brain stem nuclei involved in PEH can only be postulated based on prior animal studies (5,12). Further, the specific mechanisms responsible for this exercise-related cortical depression have not been clearly defined but could have significant impact toward understanding the effects of exercise on a variety of brain functions from BP modulation to cognition and memory. In support of the hypothesis underlying this study, findings show that exercise-induced decreases in right posterior IC rCBF may be a significant neural factor in BP modulation during, at least the first 30 min of, postexercise hypotension.
The authors thank the subjects for their cooperation and acknowledge the expert technical assistance provided by Shawn Shotzman, Amber Shepherd, and Rhea Anne Campbell as well as the cooperation of Zale Lipshy University Hospital, Dallas, Texas. These results of this study do not constitute endorsement by the ACSM.
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