Sympathetic regulation of blood pressure (BP) and cerebral blood flow (CBF) is essential for maintaining cerebral perfusion during physiological stress. BP provides a driving force for CBF, and its beat-to-beat regulation is critical for cerebrovascular regulation. Sympathetic-BP transduction is the acute process by which sympathetic nerve activity (SNA) alters mean arterial pressure (MAP). Although age-related differences in BP and CBF control have been reported, it remains unclear whether dysregulation of SNA (i.e., sympathetic transduction) contributes to age-related impairments in cerebral hemodynamics, and if these responses are associated with maximal aerobic capacity (VO2max). To reduce confounding from sedentary behavior, which affects autonomic and vascular function, we restricted our sample to physically active adults. Therefore, the purpose of this study was to examine age-related differences in peak SNA-MAP and SNA-middle cerebral artery velocity (MCAv; an index of CBF) transduction under resting conditions in physically active adults. We hypothesized that older adults would exhibit reduced transduction compared with younger adults. Healthy young (20-35 years; n=17, 9F) and older (55-68 years; n=16, 6F) adults who regularly engaged in physical activity underwent continuous 5-minute recordings of SNA (peroneal microneurography), beat-by-beat MAP (finger photoplethysmography), MCAv (transcranial Doppler ultrasound), and heart rate (HR; 3-lead ECG). Resting muscle SNA was quantified as burst incidence (BI; bursts/100 heartbeats). On a separate visit, VO2max was measured via an incremental cycle ergometer test. Sympathetic transduction was assessed as the maximal change in SNA-MAP and SNA-MCAv, and group differences were analyzed with independent t-tests. Given that cardiac activity and aerobic capacity may influence pressure and flow responses, HR and VO2max were included and analyzed alongside transduction measures using Pearson correlations. Older adults exhibited lower peak SNA-MAP transduction (p< 0.05) and a trend toward lower SNA-MCAv transduction (p=0.07) compared with younger adults. Baseline BI was higher in older adults (p< 0.05), whereas HR and VO2max were higher in younger adults (both p< 0.05). In the combined sample, HR was not related to peak SNA-MAP transduction (r=0.05, p=0.78) but was positively associated with peak SNA-MCAv transduction (r=0.39, p< 0.05). VO2max was not associated with SNA-MAP (r=0.07, p=0.72) or SNA-MCAv transduction (r=0.03, p=0.87). Aging in habitually active adults is therefore associated with reduced sympathetic transduction, reflected by lower translation of muscle SNA into arterial pressure at rest. Despite age-related differences in HR and VO2max, these variables were not meaningfully related to SNA-MAP or SNA-MCAv transduction, suggesting that regular physical activity and higher cardiorespiratory fitness alone may not fully preserve resting sympathetic regulation of BP and cerebral perfusion in older adults. Funding: NIH R00 HL118154; Virginia Horn Henry Research Grant This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Gulf War Illness (GWI) is a chronic, multi-symptom condition characterized by fatigue, cognitive difficulties, pain, and autonomic dysfunction. Veterans with GWI (GWI+) frequently report orthostatic intolerance and symptoms consistent with impaired autonomic and cerebrovascular regulation. Because head-up tilt challenges autonomic control, it provides a physiological assessment to reveal potential impairments. Thus, the objective of this study was to determine whether GWI+ exhibit altered middle cerebral artery velocity (MCAv), blood pressure (BP), and heart rate (HR) responses during graded head-up tilt (HUT) compared with Veterans without GWI (GWI-). We hypothesized that GWI+ group would show greater MCAv reductions and exaggerated HR responses during HUT tests. A total of thirty-nine Veterans participated in the study (GWI-: n=16 and GWI+: n=23). During the laboratory visit, continuous MCAv by transcranial Doppler, mean arterial pressure (MAP) by finger photoplethysmography, and HR by 3-lead electrocardiogram were recorded during supine, 30° HUT, and 60° HUT. Steady-state responses were defined at minute 2-3 of each tilt stage. Percent changes from baseline (%MCAv, %MAP, %HR) were compared between GWI- and GWI+ using ANOVA. The groups were not different in age (60 ± 4 vs. 59 ± 4 yrs; p = 0.324). There were no group differences between GWI- and GWI+ in resting MAP (99 ± 9 vs. 101 ± 10 mmHg, p = 0.398) and resting HR (64 ± 15 vs. 63 ± 10 bpm, p = 0.830). As expected, HUT resulted in significant decreases in steady-state MCAv, and increases in HR in both groups (p < 0.05). There were no significant changes in MAP with HUT. MCAv significantly decreased with HUT in both groups, with a decrease from 30° HUT to 60° HUT in both GWI- and GWI+ Veterans (GWI-: -3.5% to -12.0% and GWI+: -6.6% to -10.1%, both p < 0.05). However, there were no group differences in the change in MCAv at either 30° HUT (GWI-: -3.5% vs. GWI+: -6.6%, p > 0.05) or 60° HUT (GWI-: -12.0% vs. GWI+: -10.1%, p > 0.05), suggesting similar tilt-induced reductions in cerebral blood velocity. There were no group differences in the change in MAP at either 30° HUT (GWI-: -3.5% vs. GWI+: -4.0%) or 60° HUT (GWI-: -3.1% vs. GWI+: -1.8%, p > 0.05). There was a significant group and angle interaction for HR (p < 0.05). HR increased significantly from 30° HUT to 60° HUT in both groups (GWI-: 4.5% to 16.2% and GWI+: 6.0% to 25.2%, both p < 0.05). At 30° HUT, there were no group differences in the magnitude of change in HR (GWI+: 6.0% vs. GWI-: 4.5%, p = 0.69), but at 60° HUT, the change in HR was significantly greater in GWI+ than in GWI- (GWI+: 25.2% vs. GWI-: 16.2%, p < 0.05) Veterans. This HR response in GWI+ reflects heightened cardiac activation despite similar reductions in MCAv. In conclusion, these findings indicate that GWI+ Veterans have enhanced HR responses during orthostatic stress when compared with GWI- Veterans, despite similar MCAv reductions. These findings suggest that autonomic dysfunction rather than impaired cerebral perfusion during HUT in GWI+ Veterans may underlie orthostatic symptoms in GWI. Supported by the Department of Defense: W81XWH1910381 and NIH T32HL007936 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Biological sex modifies cerebrovascular responses to physiological challenges such as chemical stimuli. Yet, the impact of biological sex on cerebrovascular responses to aerobic exercise remain unclear. This uncertainty stems, in part, from the reliance on intracranial blood velocity assessment which does not consider possible sex differences in vasomotor responses. Also, measures are typically made in one vessel, overlooking possible regional variations in cerebrovascular responses. 4D flow magnetic resonance imaging (MRI) enables simultaneous assessment of intracranial vasomotor and hemodynamic responses in multiple arteries. This research leveraged 4D flow MRI to evaluate the impact of biological sex on cerebrovascular responses during light intensity exercise in multiple intracranial arteries. We tested the hypothesis that cerebrovascular responses during light intensity exercise would differ between females and males, and regional variations would be observed. 34 young, healthy adults (31 ± 5 years of age, 18 females) underwent 3T MRI and performed supine exercise at 30-35% [Formula: see text]O 2 max in the MRI bore using an MRI compatible stepper exercise device. 4D flow MRI captured cross-sectional area (CSA), blood flow, and cerebral pulsatility (PI) in the internal carotid arteries (ICA), middle cerebral arteries (MCA), anterior cerebral arteries (ACA), vertebral arteries (VA), basilar artery, and the posterior cerebral arteries (PCA), and cerebrovascular conductance (CVC) was calculated. Biological sex influenced blood flow responses to exercise in the left VA (P = 0.03) and left ACA (P = 0.03). Despite no sex difference in left VA blood flow at baseline (females: 99 ± 39 mL/min, males: 75 ± 19 mL/min, P = 0.06), females demonstrated an increase in left VA blood flow with exercise (P < 0.01) while blood flow did not change in males (P = 0.053), leading to greater left VA blood flow during exercise in females (115 ± 43 mL/min) compared with males (88 ± 22 mL/min; P = 0.02). In the left ACA, no sex differences were observed in blood flow at baseline (P = 0.12); however, males demonstrated a larger increase in left ACA blood flow with exercise (∆16 ± 9 mL/min) compared with females (∆9 ± 7 mL/min; P = 0.03). Biological sex did not influence blood flow responses in other arteries (all P ≥ 0.18) and did not impact CSA responses (all P ≥ 0.07). In contrast, biological sex impacted CVC in the left VA, left and right MCA, and left and right PCA (all P ≤ 0.03) wherein females demonstrated greater CVC than males during baseline and exercise (all P ≤ 0.049). Further, despite no difference in left ICA CVC at baseline (females: 2.8 ± 0.5 mL/min/mmHg, males: 2.5 ± 0.6 mL/min/mmHg, P = 0.06), females demonstrated greater left ICA CVC during exercise (2.6 ± 0.4 mL/min/mmHg) than males (2.3 ± 0.4 mL/min/mmHg; P = 0.03). Lastly, biological sex did not impact PI responses to exercise (all P ≥ 0.13). Overall, modest sex differences were observed in cerebrovascular responses during light intensity exercise with regional variations. Exercise at higher intensities may further provoke sex differences in cerebrovascular responses to aerobic exercise, and further research may aide in intervention implementation in various populations. This research was supported by funding from the NIH (RF1 1NS117746-01 to JNB; T32HL007936 to UW-Madison CVRC and SHAGM), a Virginia Horne Henry Research Grant (AAK1123 to JNB), and the Wisconsin Alumni Research Foundation (to JNB). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Following menopause, cardiovascular disease and hypertension risk increases in females potentially due to impaired autonomic cardiovascular control. However, age at menopause varies, with earlier menopausal onset being associated with higher blood pressure (BP). Thus, it may be important to understand the effect of the timing of menopause onset on autonomic cardiovascular control measures such as baroreflex sensitivity (BRS) and heart rate variability (HRV). This study aimed to examine the impact of age at menopause onset on autonomic cardiovascular control measures. We hypothesized that females with early menopausal onset would have lower BRS and lower HRV compared with females who experienced menopause at a later age. Forty-six postmenopausal females (56-66 years) were categorized into early (≤49 years; n=26) or late (≥53 years; n=20) menopause onset groups. Heart rate (HR) and R-R intervals (RRI) were measured via 3-lead ECG, and beat-to-beat BP was measured using finger plethysmography. Cardiovagal BRS (cvBRS) was measured during phase IV of the Valsalva maneuver using the slope of the relationship between RRI and systolic BP (SBP). HRV was measured during a 5-minute rest and reported as the standard deviation of RRI (SDRR), root mean square of successive differences (RMSSD), low frequency (LF) power, high frequency (HF) power, and LF/HF ratio. Independent sample t-tests were used to compare demographics and autonomic cardiovascular variables. Data are presented as mean ± SD. At baseline, there were no differences between early versus late menopause groups in HR (62±7 bpm vs. 61±9 bpm; P=0.625), SBP (134±14 mmHg vs.124±19 mmHg; P=0.066), or diastolic BP (79±7 mmHg vs. 75±9 mmHg; P=0.083). For cvBRS in early (n=21) versus late onset (n=15) groups, the early onset group had lower cvBRS compared to the late onset group (6.30±2.76 ms/mmHg vs. 9.42±4.68 ms/mmHg; P< 0.05). Regarding HRV, there were no differences observed for SDRR (47.8±25.0 ms vs. 42.0±18.6 ms; P=0.368) and RMSSD (41.4±35.5 ms vs. 31.4±19.0 ms; P=0.230) between early versus late menopause groups. In the early onset group, there was a lower LF (43.2±22.6 nu, 66.6±21.0 nu; P< 0.05), higher HF (55.7±21.1 nu, 32.6±19.9 nu; P< 0.05), and a lower LF/HF ratio (1.32 ± 1.71; 4.48 ± 5.69; P< 0.05) compared to the late onset group. In summary, early menopausal onset females had lower BRS, lower LF, higher HF, and a lower LF/HF ratio compared to late menopausal onset females, which suggests that the age of onset of menopause has complex physiological implications for autonomic cardiovascular control. Future work should examine the mechanisms underlying these differences to clarify how age at menopause influences long-term cardiovascular risk. Funding: AHA (191PLOI34680015) and NIH (T32HL007936) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Approximately 70% of blood flow to the brain is delivered via the internal carotid arteries (ICAs), making regulation of blood flow through these vessels vital. Aerobic exercise challenges this regulation and has been shown to induce increases in ICA flow at light exercise intensities. There is evidence to suggest that regulation of blood flow to the brain may differ between males and females. However, little is known about sex differences in ICA flow responses to aerobic exercise. The purpose of this study was to investigate sex-based differences in ICA flow responses to light intensity aerobic exercise. We hypothesized that males would have greater magnitude of change in ICA flow during light exercise when compared to females. To address this, 33 recreationally active young adults (18 females, 15 males; age: 28 ± 6 yrs; BMI: 23.34 ± 2.35 kg/m 2 ) completed a maximal oxygen uptake (VO2max) cycling test and an experimental study visit on a separate day where they exercised at 30-35% of their VO2max for 10 minutes on a recumbent cycle ergometer. Mean arterial pressure (MAP) was measured via brachial sphygmomanometry during seated rest (BSL) and exercise (EXE). The left ICA was imaged using doppler ultrasound at BSL and EXE, once participants had achieved steady state. ICA diameter and blood velocity were captured, and ICA flow was calculated as velocity x cross sectional area x 60. Cerebrovascular conductance (CVC) was calculated as ICA flow/MAP. In the combined group, ICA flow was higher during EXE when compared to BSL (BSL: 422 ± 122 mL/min, EXE: 447 ± 121 mL/min, P < 0.05). ICA flow was not significantly different between males and females at BSL (males: 436 ± 115 mL/min, females: 411 ± 130 mL/min, P = 0.58) or EXE (males: 482 ± 121 mL/min, females: 418 ± 118 mL/min, P = 0.13). However, there was a trend for sex differences in the change in ICA flow (males: 46 ± 64 mL/min, females: 7 ± 56 mL/min, P = 0.07) with males showing a significant increase in ICA flow during exercise (P < 0.05), while females had no significant difference between conditions (BSL: 411 ± 130 mL/min, EXE: 418 ± 118 mL/min, P = 0.66). In the combined group, there were no significant differences in CVC between BSL and EXE (BSL: 4.8 ± 1.4 mL/min/mmHg, EXE: 4.9 ± 1.5 mL/min/mmHg, P = 0.52). There were also no significant differences in CVC between males and females at BSL (males: 4.9 ± 1.3 mL/min/mmHg, females: 4.8 ± 1.6 mL/min/mmHg, P = 0.77) or EXE (males: 5.2 ± 1.5 mL/min/mmHg, females: 4.7 ± 1.5 mL/min/mmHg P = 0.30), or in the change in CVC from BSL to EXE (males: 0.3 ± 0.7 mL/min/mmHg, females: -0.1 ± 0.8 mL/min/mmHg, P = 0.13). In summary, males, but not females, showed increases in ICA flow during light aerobic exercise. When comparing CVC to account for MAP changes with exercise, there were no sex differences. Taken together, this data suggests that regulation of ICA flow during light steady state aerobic exercise may differ between males and females. Funding Source: Wisconsin Alumni Research Foundation This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Alterations in white matter microstructure (WMM) are associated with reduced cognitive function in patients with Alzheimer’s disease and related dementias, especially of vascular origin. Cardiorespiratory fitness (CRF) and habitual exercise can positively influence brain health; however, the impact on WMM is not clear. The purpose of our study was to assess the relationship between CRF and habitual exercise participation on WMM in healthy older adults. We hypothesized that CRF and habitual exercise would be positively associated with WMM in tracts more susceptible to age-related change or those related to motor function. Older adults free of underlying disease participated in this study (n=23, age=64±5 yrs, M=12, F=11). CRF was assessed using an incremental maximal exercise test on a cycle ergometer (VO2max) and habitual exercise was assessed using the Godin Leisure-Time Exercise Questionnaire (Godin Score). On a separate visit, WMM was measured using neurite orientation dispersion and density imaging (NODDI) MRI scans. Neurite density index (NDI), fraction of isotropic diffusion compartment (FISO), and orientation dispersion index (ODI) were analyzed in twenty-seven white matter tracts defined by the Johns Hopkins Atlas. Associations between VO2max, Godin scores, and WMM in each white matter tract were evaluated using multivariable linear regression while controlling for age and sex. VO2max was a significant predictor of ODI in the genu of the corpus callosum (β=0.714, B=0.001, 95% CI [0.000, 0.002], p=0.007), corticospinal tract (β=0.553, B=0.003, 95% CI [0.000, 0.006], p=0.035), inferior cerebellar peduncle (β=0.558, B=0.001, 95% CI [0.000, 0.003], p=0.024), cerebral peduncle (β=0.566, B=0.001, 95% CI [0.000, 0.002], p=0.040), and uncinate fasciculus (β=0.607, B=0.001, 95% CI [0.000, 0.002], p=0.023). Godin scores significantly predicted ODI in the medial lemniscus (β=0.448, B=0.001, 95% CI [0.000, 0.001], p=0.033). VO2max also significantly predicted FISO of the sagittal striatum (β=0.519, B=0.002, 95% CI [0.000, 0.004], p=0.031). Neither VO2max nor Godin scores were significantly associated with NDI in any of the white matter tracts (p >0.05). Notably, after applying a Benjamini-Hochberg FDR correction for multiple comparisons (q=0.05), neither VO2max nor Godin scores were significantly associated with any WMM variables in any of the white matter tracts. In conclusion, cardiorespiratory fitness was associated with white matter microstructure, especially the orientation dispersion index, in several tracts associated with aging and motor function. However, the significance of these associations depended on the analytical approach. Future studies should examine longitudinal relationships between cardiorespiratory fitness and white matter microstructure to better understand the role of habitual exercise in mitigating risk for Alzheimer’s disease and related dementias. Funding: National Institutes of Health - HL118154 (JNB), HL007936 (KBM) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Vertebral artery hypoplasia (VAH) is one of the most common anomalies of cerebrovascular structure and is present among healthy asymptomatic individuals. The prevalence of VAH is estimated to be between 15% and 35%. Although VAH has been associated with regional hypoperfusion in the brain, less is known about the impact of VAH on cerebrovascular reactivity, which is a sensitive measure of microvascular function and reflects the ability of cerebral arteries to dilate in response to vasoactive stimuli such as carbon dioxide (CO 2 ). Therefore, the purpose of this study was to determine the impact of VAH on cerebrovascular reactivity of regional arteries including the vertebral arteries (VAs) and basilar artery (BA) among cognitively unimpaired middle-aged and older adults. We hypothesized that in response to hypercapnia, individuals with VAH (VAH+) would have lower VA and BA reactivity compared with individuals without VAH (No VAH). Sixty-three cognitively unimpaired middle-aged and older adults underwent 4D flow magnetic resonance imaging (MRI) in a 3T scanner to determine blood flow of the VAs and BA during normocapnia and a stepped hypercapnia protocol (+5 mmHg and +8 mmHg CO 2 ). Individuals were categorized as VAH+ if they met all three criteria: (1) left or right VA diameter < 2.5 mm, (2) left or right VA flow < 50 mL/min, and (3) flow ratio between the hypoplastic and contralateral VAs < 1:2. Mean arterial blood pressure (MAP) and end-tidal CO 2 (ETCO 2 ) were continually monitored during the MRI scan. Cerebrovascular conductance (CVC) was calculated as flow/MAP for each condition. Cerebrovascular reactivity was calculated as the slope of the relationship between the absolute changes in ETCO 2 and CVC of the VAs and BA. In the VAH+ group, paired t-tests were used to evaluate differences between the hypoplastic and contralateral VAs. Independent t-tests were used to evaluate group differences (VAH+ vs. No VAH) in the BA. Twenty participants were categorized as VAH+ (15F/5M, 63 ± 4 years old) and 43 were No VAH (34F/9M, 64 ± 4 years old). As expected, the hypoplastic VA had significantly lower flow than the contralateral VA (32.74 ± 11.85 mL/min vs. 107.45 ± 29.26 mL/min, p < 0.001) among the VAH+ group during normocapnia. Additionally, the hypoplastic VA had significantly lower CVC reactivity than the contralateral VA (0.03 ± 0.02 mL/min/mmHg2 vs. 0.07 ± 0.04 mL/min/mmHg2, p < 0.001) in the VAH+ group. Contrary to our hypothesis, there were no group differences in BA flow during normocapnia between the VAH+ and No VAH groups (123.05 ± 37.93 mL/min vs. 129.71 ± 32.21 mL/min, p = 0.480). There were also no group differences in BA CVC reactivity between the VAH+ and No VAH groups (0.09 ± 0.04 mL/min/mmHg2 vs. 0.08 ± 0.04 mL/min/mmHg2, p = 0.182). Our results suggest that, among cognitively unimpaired middle-aged and older VAH+ adults, although the hypoplastic VA has a lower reactivity, the contralateral VA appears to compensate for this blunted reactivity. This may in part explain why VAH+ and No VAH adults have comparable BA flow and reactivity. Funding Source: National Institute of Neurological Disorders and Stroke Grant (R01NS117746, JNB), National Institute on Aging Grant (K00AG083283, ZZ), and the Alzheimer’s Association Research Fellowship (AARF-22-924325, BGF). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Time-restricted eating (TRE) is a dietary approach that restricts calories within a specific window of time each day. Implementing TRE at midlife, a time in the adult lifespan prior to overt disease, may be beneficial as a preventative strategy against disease later in life. However, there is limited evidence of effects of TRE in humans, especially on autonomic cardiovascular control and at midlife. Thus, the purpose of this study was to identify the effects of TRE on autonomic cardiovascular control measures in healthy middle-aged adults by assessing resting muscle sympathetic nerve activity (MSNA) and circulating catecholamines (norepinephrine, NE; epinephrine, Epi) before and after a 5-week TRE intervention. We hypothesized that MSNA, NE, and Epi would decrease from pre- to post-TRE. Twenty-nine healthy middle-aged adults (12M/17F; age: 54 ± 5 yrs) participated in 5 weeks of TRE where meals were consumed within a 10-hour window and ≥ 2 hours prior to bedtime. Dietary intake was measured 3 days per week via a diet log. Resting heart rate (HR) and blood pressure (BP) were measured using a 3-lead electrocardiogram and an automated brachial cuff, respectively. MSNA was measured via microneurography and reported as burst frequency (BF; bursts/min) and burst incidence (BI; bursts/100 heart beats), and catecholamines were measured following venipuncture. Paired t-tests were used to evaluate differences from pre- and post-TRE. Following 5 weeks of TRE, systolic BP (SBP) was reduced (Pre: 126 ± 10 mmHg; Post: 122 ± 10 mmHg; p = 0.024), however there were no other differences pre- to post-TRE for any other resting vital of interest (p > 0.051). Interestingly, NE decreased post-TRE (Pre: 22.3 ± 15.5 ng/mL; Post: 12.3 ± 6.5 ng/mL; p = 0.004), while Epi (Pre: 1.1 ± 0.5 ng/mL; Post: 0.9 ± 0.6 ng/mL; p = 0.163), MSNA BF (Pre: 29 ± 11 bursts/min; Post: 25 ± 12 bursts/min; p = 0.257), and MSNA BI (Pre: 47 ± 18 bursts/100 heart beats; Post: 42 ± 19 bursts/100 heart beats; p = 0.376) did not change post-TRE. A 5-week TRE intervention reduced circulating NE without observable changes in Epi or MSNA. We observed a reduction in SBP, which could be attributable to reduced NE, but future studies are needed to further investigate TRE and its impact on autonomic cardiovascular control. Funding: AHA (191PLOI34680015) NIH (T32HL007936) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

This research examined the impact of aerobic exercise intensity and dose on acute post-exercise cerebral shear stress and blood flow. Fourteen young adults (27 +/- 5 years of age, eight females) completed a maximal oxygen uptake (VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$) treadmill test followed by three randomized study visits: treadmill exercise at 30% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min, 70% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min and 70% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for a duration that resulted in caloric expenditure equal to that in the 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ visit (EqEE). A venous blood draw and internal carotid artery (ICA) ultrasound were collected before and immediately following exercise. ICA diameter and blood velocity were determined using automated edge detection software, and blood flow was calculated. Using measures of blood viscosity, shear stress was calculated. Aerobic exercise increased ICA shear stress (time: P = 0.005, condition: P = 0.012) and the increase was greater following exercise at 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 4.1 +/- 3.5 dyn/cm2) compared with 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 1.1 +/- 1.9 dyn/cm2; P = 0.041). ICA blood flow remained elevated following exercise (time: P = 0.002, condition: P = 0.010) with greater increases after 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (Delta 268 +/- 150 mL/min) compared with 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 125 +/- 149 mL/min; P = 0.041) or 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ EqEE (triangle 127 +/- 177 mL/min; P = 0.004). Therefore, aerobic exercise resulted in both intensity- and dose-dependent effects on acute post-exercise ICA blood flow whereby vigorous intensity exercise provoked a larger increase in ICA blood flow compared to light intensity exercise when performed at a higher dose. What is the central question of this study? What are the independent and combined effects of exercise intensity and dose on post-exercise internal carotid artery (ICA) haemodynamics? What is the main finding and its importance? The combined effects of exercise intensity and dose evoked the greatest haemodynamic response whereby vigorous intensity exercise for a longer duration resulted in the greatest increase in post-exercise ICA blood flow. Therefore, exercise intensity and dose are important considerations for utilizing exercise to improve cerebrovascular function.

Cerebral blood flow at rest declines with age. However, age-related changes in functional measures of cerebrovascular health including cerebrovascular reactivity and neurovascular coupling are not well understood. Additionally, the effect of apolipoprotein E (APOE) ε4, a strong genetic risk factor for Alzheimer’s disease, on cerebral blood flow and cerebrovascular function remains unclear. APOEε4 positive (APOEε4+; n = 37, age = 63±4y) and APOEε4 negative (APOEε4-; n = 50, age = 63±4y) cognitively unimpaired adults participated in this study. Macrovascular cerebral blood flow and microvascular cerebral perfusion were measured using 4D flow MRI and pseudo-continuous arterial spin labeling MRI, respectively. Cerebrovascular reactivity and neurovascular coupling were assessed by measuring middle cerebral artery blood velocity in response to hypercapnia and the n-back test, respectively. Neurovascular coupling was lower in APOEε4+ compared with APOEε4- adults (P<0.05), despite higher cerebral blood flow and cerebrovascular reactivity to hypercapnia. Alterations in neurovascular coupling may occur early, prior to changes in cognition, in aging APOEε4 carriers.

Changes in white matter microstructure of the genu of the corpus callosum are predictive of cognitive decline in patients with mild cognitive impairment. Cardiorespiratory fitness (CRF) is positively associated with brain health; however, the relationship between cardiorespiratory fitness and white matter microstructure of the genu of the corpus callosum is unknown. Further, a novel diffusion method for assessing white matter microstructure, neurite orientation dispersion and density imaging (NODDI), can detect specific microstructural features that are not observed with conventional diffusion tensor imaging (DTI). Young (n=27, age=25±5, m=12, f=15) and older (n=23, age=64±5, m=12, f=11) adults free of underlying disease participated in this study. CRF was assessed using an incremental maximal exercise test on a cycle ergometer. On a separate visit, white matter microstructure of the genu of the corpus callosum was measured using both DTI and NODDI MRI scans. In young adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured using either DTI or NODDI (p>0.05). In older adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured with DTI. However, in older adults, there was a positive association between CRF and orientation dispersion index of the genu of the corpus callosum measured with NODDI (r=0.47, p=0.02). In conclusion, using conventional DTI, no associations between CRF and white matter microstructure of the genu of the corpus callosum were observed. However, using NODDI, which can detect specific microstructural features, our results suggest that older adults with higher CRF demonstrated enhanced white matter microstructure, specifically orientation dispersion index, of the genu of the corpus callosum. Conventional DTI may underestimate the impact of CRF on age-related changes in white matter microstructure. National Institutes of Health - HL118154 (JNB), HL007936 (KBM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract Platelet activation may contribute to age‐related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. This study evaluated the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular reactivity (CVR) in healthy young (n = 35; 25 ± 4 years; 17 women, 18 men) and older (n = 12; 62 ± 2 years; 8 women, 4 men) adults, who were not daily aspirin users, before and after cyclooxygenase inhibition. Prostacyclin was determined by levels of 6‐keto‐prostaglandin F1α (6‐keto PGF1α) in the blood. CVR was assessed by measuring the middle cerebral artery blood velocity response to hypercapnia using transcranial Doppler ultrasound before (CON) and 90 min after cyclooxygenase inhibition with indomethacin (INDO). In young adults, there were no associations between prostacyclin and middle cerebral artery CVR during CON (r = −0.14, P = 0.415) or INDO (r = 0.27, P = 0.118). In older adults, associations between prostacyclin and middle cerebral artery CVR during CON (r = 0.53, P = 0.075) or INDO (r = –0.45, P = 0.136) did not reach the threshold for significance. We also evaluated the relationship between prostacyclin and the change in CVR between conditions (ΔCVR). We found no association between ΔCVR and prostacyclin in young adults (r = 0.27, P = 0.110); however, in older adults, those with higher baseline prostacyclin levels demonstrated significantly greater ΔCVR (r = –0.74, P = 0.005). In conclusion, older adults with higher serum prostacyclin, a platelet inhibitor, may rely more on cyclooxygenase products for cerebrovascular reactivity to hypercapnia.

Age-related changes in cerebral hemodynamics are controversial and discrepancies may be due to experimental techniques. As such, the purpose of this study was to compare cerebral hemodynamics measurements of the middle cerebral artery (MCA) between transcranial Doppler ultrasound (TCD) and four-dimensional flow MRI (4D flow MRI). Twenty young (25 ± 3 years) and 19 older (62 ± 6 years) participants underwent two randomized study visits to evaluate hemodynamics at baseline (normocapnia) and in response to stepped hypercapnia (4% CO 2 , and 6% CO 2 ) using TCD and 4D flow MRI. Cerebral hemodynamics measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity. Cerebrovascular reactivity was calculated as the linear relationship between cerebrovascular conductance (CVC using 4D flow MRI) or cerebrovascular conductance index (CVCi using TCD) and changes in ETCO 2 at rest and during hypercapnia. MCA velocity between the methods was positively correlated across the conditions (r=0.262; p=0.004). Additionally, cerebral PI of the MCA was significantly correlated between TCD and 4D flow MRI across the conditions (r=0.236; p=0.010). However, there was no association between MCA velocity using TCD and MCA flow using 4D flow MRI across the conditions (r=0.079; p=0.397). When age-associated differences in cerebrovascular reactivity were compared using both methodologies, cerebrovascular reactivity was greater in young adults compared to older adults when using 4D flow MRI (2.11±1.68 ml/min/mmHg/mmHg vs. 0.78±1.68 ml/min/mmHg/mmHg; p=0.019), but not with TCD (0.88±1.01 cm/s/mmHg 2 vs. 0.68±0.94 cm/s/mmHg 2 ; p=0.513). In conclusion, our results demonstrated good agreement between the methods measuring MCA velocity at normocapnia and in response to hypercapnia, but MCA velocity with TCD and MCA flow with MRI were not related. In addition, measurements using 4D flow MRI revealed additional effects of aging on cerebral hemodynamics that were not apparent using TCD. This study was funded by the NIH grants (HL118154, NS117746), the NIH, Ruth L. Kirschstein National Research Service Award T32's from the National Institute on Aging to the University of Wisconsin-Madison Biology of Aging & Age-Related Diseases (AG000213) and the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center (HL007936) as well as the Wisconsin Alumni Research Foundation. This study was also supported by Alzheimer's Association Research Fellowship (AARF-22-924325). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BACKGROUND: Greater cerebral blood flow pulsatility, measured as pulsatility index (PI), has recently been under investigation as a risk factor for cognitive impairment and neurodegenerative diseases. Furthermore, physical activity (PA), which has been associated with improved cognitive function and holds therapeutic effects for cardiovascular function, may be linked with lower cerebral pulsatility, especially in postmenopausal women (PMW). PURPOSE: To investigate the relationship between PA and PI in PMW and determine if these relationships are maintained in age-matched men. We hypothesized that there would be an inverse relationship between PA and PI in PMW, and that this relationship would diminish in age-matched men. METHODS: Fifty-two healthy PMW (age 63 ± 4 years) and 25 age-matched men (63 ± 4 years) were recruited for this study. PA was self-reported via the Godin Questionnaire (Godin Score) and using the metabolic equivalent to exercise in minutes per week (MET-Min). Cerebral blood flow was measured through the internal carotid arteries (ICAs), middle cerebral arteries (MCAs), and the basilar artery using 4D Flow MRI. PI was calculated as (maximum flow – minimum flow)/mean flow. RESULTS: There were no significant differences in PA between groups via Godin Score (PMW: 37 ± 21 vs. Men 37 ± 13, p = 1.00) or MET-Min (PMW: 1586 ± 901 vs. Men: 1831 ± 901, p = 0.28). When combined, there was a significant inverse association between MET-Min and basilar PI (r = -0.24, p = 0.04). In PMW, there was a trend for greater MET-Min to be associated with lower basilar PI (r = -0.24, p = 0.08), however this trend was not observed in men (r = -0.25, p = 0.25). Interestingly, in men, there was a significant positive association between MET-Min and MCA PI (r = 0.46, p = 0.03). There were no significant associations observed between PA and ICA PI. CONCLUSION: Greater PA may be linked to lower PI in PMW, but not in in age-matched men. The influence of regular physical activity on cerebral PI may be specific to certain cerebral vessels. This study was funded by the Virginia Horn Henry Research Grant, NIH grant (AG070469-01), and the Wisconsin Alzheimer's Disease Research Center (P30-AG062715). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Brain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex-specific. 407 cognitively healthy middle-aged and older adults (45-87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid-attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume. PI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P = 0.01, all male P = 0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P = 0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P = 0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (ß = 0.39±0.09 a.u., R2 = 0.13) compared with females (ß = 0.18±0.05 a.u., R2 = 0.05). These data suggest that, among cognitively healthy middle-aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex- and vessel-specific which may contribute to sex-specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

Vertebral artery hypoplasia (VAH) is an anatomical variation that may be associated with lower cerebral blood flow. We demonstrated the prevalence of VAH to be approximately 26% in a pilot study of healthy adults (n = 39). The purpose of this study was to expand on these findings by determining the prevalence of VAH and its impact on cerebral hemodynamics in a larger sample size of middle-aged and older adults. A total of 550 participants (66 ± 9 years; 346 females) underwent 4D flow MRI scans to evaluate the internal carotid arteries (ICA), vertebral arteries, and basilar artery. VAH+ (positive for VAH) was determined from the 4D flow MRI scans using both diameter (<2.5 mm) and flow (<47 mL/min). We identified 152 participants as VAH+ (prevalence of 28%). The prevalence of VAH+ was similar between females (n = 95; 27%) and males (n = 57; 28%). VAH predominantly occurred in the right vertebral artery (n = 102; 67%). As expected within VAH+ participants, the hypoplastic vertebral artery diameter was smaller (2.0±0.2 mm vs. 2.8±0.5 mm; p<0.001), blood flow was lower (29±10 ml/min vs. 100±44 ml/min; p<0.001), and pulsatility index was higher (1.8±0.6 a.u. vs. 1.3±0.3 a.u.; p<0.001) compared to the contralateral artery. There were no differences in ICA diameter (p = 0.875), blood flow (p = 0.553) or pulsatility index (p = 0.984) between VAH+ and no VAH. When evaluating the basilar artery, the diameter was smaller (2.7±0.4 mm vs. 2.8±0.4 mm; p = 0.037) with lower blood flow (105±35 ml/min vs. 116±37 ml/min; p<0.001) in VAH+ compared with no VAH. Males with VAH+ had higher basilar artery pulsatility index compared with males with no VAH (1.4±0.4 a.u. vs. 1.2±0.3 a.u.; p = 0.004), but this was not apparent in females (p = 0.544). When comparing global cerebral blood flow, there was a trend for lower flow in VAH+ compared with no VAH (p = 0.096). We demonstrated VAH prevalence to be around 28%, with similar prevalence in both males and females. VAH was associated with impaired regional flow and with elevated basilar artery cerebral pulsatility in males.

BACKGROUND: Muscle sympathetic nerve activity (MSNA) has been shown to be a predictor of cardiovascular diseases. There are currently disputed findings regarding the effects of exercise training on MSNA at rest. Therefore, this study sought to compare MSNA in young exercise trained and sedentary adults. The purpose of this analysis was to examine associations between MSNA at baseline with VO2max in order to determine if VO2max can be a predictor of MSNA. METHODS: Forty-two young adults were evaluated including 11 resistance trained (RE: age = 24 ± 4 years; BMI = 24 ± 2 kg/m2), 18 aerobically trained (AE: age = 27 ± 5 years; BMI = 24 ± 2 kg/m2), and 13 sedentary controls (CON: age = 28 ± 5 years; BMI = 25 ± 2 kg/m2). Participants underwent a maximal exercise test to exhaustion on a cycle ergometer to measure VO2max. During a separate visit, mean arterial pressure (MAP), heart rate (HR) and MSNA were measured at rest for five minutes. MSNA was assessed using burst frequency, burst incidence, and total activity. One-way ANOVA was performed in order to assess between-group differences in MSNA. Simple linear regression was performed in order to determine the impact of VO2max on MSNA and the relationship between MAP and VO2max. RESULTS: There were significant differences in VO2max across all three groups (RE: 41.4 ± 4.6 ml/kg/min; AE: 46.2 ± 4 ml/kg/min; CON: 35.3 ± 6.7 ml/kg/min; p < 0.01) and between groups (RE vs. AE p < 0.01; RE vs. CON p < 0.02; AE vs. CON p < 0.01). There were no differences in MSNA burst frequency (RE: 15 ± 8 bursts/min; AE: 17 ± 7 bursts/min; CON: 18 ± 5 bursts/min; p = 0.57), MSNA burst incidence (RE: 36 ± 13 bursts/100 cardiac cycles; AE: 34 ± 15 bursts/cardiac cycles; CON: 30 ± 7 bursts/100 cardiac cycles; p = 0.27), and total MSNA (RE: 881 ± 684 B/min; AE: 1361 ± 1092 B/min; CON: 1031 ± 379 B/min; p = 0.29) across the three groups. There were no relationships found between VO2max and MSNA burst frequency (r = 0.23; p = 0.15), VO2max and MSNA incidence (r = 0.06; p = 0.71), or VO2max and total MSNA (r = 0.03; p = 0.89). CONCLUSION: In conclusion, these results demonstrate a disassociation between MSNA and VO2max at rest in young adults. Since this analysis was limited to resting values, future studies could examine the relationship between VO2max and MSNA as a result of an exercise training intervention. Funding: NIH HL118154, Virginia Horne Henry This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased central arterial stiffness is associated with downstream vascular dysfunction. Despite this relationship, our lab has previously demonstrated no association between central arterial stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), and cerebrovascular or mean arterial pressure (MAP) reactivity in habitually active adults. Physical activity level may affect the relationship between cfPWV and cerebrovascular or MAP reactivity, yet these associations have not been evaluated in aerobically trained young adults. Further, the relationship between baseline cfPWV and post-exercise cerebrovascular and MAP reactivity is unknown. PURPOSE: To examine the relationship between baseline cfPWV and pre- and post-exercise cerebrovascular reactivity and MAP reactivity in aerobically trained young adults. METHODS: Thirteen trained runners (age: 27 ± 5 y; VO2max = 54 ± 10 mL/kg/min; men = 6, women = 7) completed a study visit in which they walked for 30 min at 30% VO2max. cfPWV was measured prior to exercise. Cerebrovascular and MAP reactivity to hypercapnia were measured pre- and 30 min post-exercise. Middle cerebral artery velocity (MCAv), MAP, and end-tidal CO2 (ETCO2) were continuously monitored during hypercapnia. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the slope between MCAv, CVCi, or MAP and ETCO2. RESULTS: While cfPWV was not associated with pre-exercise MCAv and CVCi reactivity (p ≥ 0.05 for both), it was associated with MAP reactivity (r = 0.65, p = 0.02). There was no association between cfPWV and post-exercise MCAv, CVCi, or MAP reactivity (p ≥ 0.05 for all). Finally, there was no association between cfPWV and the pre-to-post exercise change in MCAv and CVCi reactivity (p ≥ 0.05 for both), but there was an association between cfPWV and the pre-to-post exercise change in MAP reactivity (r = -0.78, p < 0.01). CONCLUSION: While cfPWV was not associated with pre- or post-exercise cerebrovascular reactivity, it was associated with pre-exercise MAP reactivity and the change from pre-to-post exercise MAP reactivity. These results suggest that in aerobically trained individuals, central arterial stiffness may influence blood pressure reactivity to a vasoactive stimulus. Supported by the Wisconsin Alumni Research Foundation.