Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

High-intensity exercise does not protect against orthostatic intolerance following bedrest in 55- to 65-yr-old men and women.

Prolonged bedrest provokes orthostatic hypotension and intolerance of upright posture. Limited data are available on the cardiovascular responses of older adults to head-up tilt following bedrest, with no studies examining the potential benefits of exercise to mitigate intolerance in this age group. This randomized controlled trial of head-down bedrest (HDBR) in 55- to 65-yr-old men and women investigated if exercise could avert post-HDBR orthostatic intolerance. Twenty-two healthy older adults (11 female) underwent a strict 14-day HDBR and were assigned to either an exercise (EX) or control (CON) group. The exercise intervention included high-intensity, aerobic, and resistance exercises. Head-up tilt-testing to a maximum of 15 minutes was performed at baseline (Pre-Bedrest) and immediately after HDBR (R1), as well as 6 days (R6) and 4 weeks (R4wk) later. At Pre-Bedrest, three participants did not complete the full 15 minutes of tilt. At R1, 18 did not finish, with no difference in tilt end time between CON (422 ± 287 s) and EX (409 ± 346 s). No differences between CON and EX were observed at R6 or R4wk. At R1, just 1 participant self-terminated the test with symptoms, while 12 others reported symptoms only after physiological test termination criteria were reached. Finishers on R1 protected arterial pressure with higher total peripheral resistance relative to Pre-Bedrest. Cerebral blood velocity decreased linearly with reductions in arterial pressure, end-tidal CO2, and cardiac output. High-intensity interval exercise did not benefit post-HDBR orthostatic tolerance in older adults. Multiple factors were associated with the reduction in cerebral blood velocity leading to intolerance.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Cardiac-Related Pulsatility in the Insula Is Directly Associated With Middle Cerebral Artery Pulsatility Index.

BACKGROUND: Arterial stiffness in large arteries is a risk factor for cerebral small vessel disease and neurodegeneration. The challenge of accessing intracranial pulsatility noninvasively is one reason few studies provide empirical insight on the relationship between large artery and tissue pulsatility in the human brain. PURPOSE: To investigate the association between the functional magnetic resonance imaging (fMRI)-derived cardiac-related pulsatility in the insular cortex and the ultrasound-derived pulsatility index in the middle cerebral artery (MCA-PI). STUDY TYPE: Cross-sectional. POPULATION: Younger adults (11; 25 ± 4 years) and older adults with and without cardiovascular risk factors (44; 70 ± 6 years). FIELD STRENGTH/SEQUENCE: T1 -weighted, fluid attenuated inversion recovery, and T2 *-weighted blood oxygenation level-dependent (BOLD) sequences at 3T. ASSESSMENT: MCA-PI and cardiac-related pulsatility were assessed at rest by transcranial Doppler ultrasound and BOLD fMRI, respectively. STATISTICAL TESTS: Multivariate analyses of covariance between MCA-PI and cardiac-related pulsatility. Analysis of variance was used to assess regional differences. RESULTS: MCA-PI was associated with cardiac-related insular pulsatility (P = 0.037), but not whole-brain pulsatility (P = 0.81). Left insular pulsatility was higher than right insular pulsatility (P < 0.01) and was associated with diastolic blood pressure (P = 0.028). DATA CONCLUSION: We show a correlation between ultrasound and fMRI measures of cerebrovascular pulsatility. This association provides insight into the transmission of pulsatile energy from large basal arteries at the Circle of Willis to downstream cerebrovascular beds and has implications for the utility of cardiac-related pulsatility as a potential marker for cerebral small vessel disease. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1454-1462.

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study.

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Acute reduction in cerebral blood velocity on supine-to-stand transition increases postural instability in young adults.

We tested the hypothesis that transient deficits in cerebral blood flow are associated with postural sway. In 19 young, healthy adults, we examined the association between the drop in cerebral blood flow during supine-to-stand transitions, indexed by transcranial Doppler ultrasound [middle cerebral artery blood velocity at diastole (MCAdv)] and near-infrared spectroscopy [tissue saturation index (TSI)] and the center of pressure displacement while standing. Participants performed transitions under three conditions aimed at progressively increasing the drop in MCAdv, in a randomized order: 1) a control transition (Con); 2) a transition that coincided with deflation of bilateral thigh cuffs; and 3) a transition that coincided with both thigh-cuff deflation and 90 s of prior hyperventilation (HTC). The deficit in diastolic blood velocity (MCAdv deficit) was quantified as the difference between MCAdv and its preceding baseline value, summed over 10 s, beginning at the MCAdv nadir. Compared with Con, HTC led to greater drops in MCAdv (P = 0.003) and TSI (P < 0.001) at nadir. The MCAdv deficit was positively associated with the center of pressure displacement vector-average using repeated-measures correlation (repeated-measures correlation coefficient = 0.56, P < 0.001). An a posteriori analysis identified a sub-group of participants that showed an exaggerated increase in MCAdv deficit and greater postural instability in both the anterior-posterior (P = 0.002) and medial-lateral (P = 0.021) directions in response to the interventions. These findings support the theory that individuals who experience greater initial cerebral hypoperfusion on standing may be at a greater risk for falls.NEW & NOTEWORTHY Dizziness and risk for falls after standing might link directly to reduced delivery of oxygen to the brain. By introducing challenges that increased the drop in brain blood flow in healthy young adults, we have shown for the first time a direct link to greater postural instability. These results point to a need to measure cerebral blood flow and/or oxygenation after postural transitions in populations, such as older adults, to assist in fall risk assessment.

Increased postflight carotid artery stiffness and inflight insulin resistance resulting from 6-mo spaceflight in male and female astronauts.

Removal of the normal head-to-foot gravity vector and chronic weightlessness during spaceflight might induce cardiovascular and metabolic adaptations related to changes in arterial pressure and reduction in physical activity. We tested hypotheses that stiffness of arteries located above the heart would be increased postflight, and that blood biomarkers inflight would be consistent with changes in vascular function. Possible sex differences in responses were explored in four male and four female astronauts who lived on the International Space Station for 6 mo. Carotid artery distensibility coefficient (P = 0.005) and ß-stiffness index (P = 0.006) reflected 17-30% increases in arterial stiffness when measured within 38 h of return to Earth compared with preflight. Spaceflight-by-sex interaction effects were found with greater changes in ß-stiffness index in women (P = 0.017), but greater changes in pulse wave transit time in men (P = 0.006). Several blood biomarkers were changed from preflight to inflight, including an increase in an index of insulin resistance (P < 0.001) with a spaceflight-by-sex term suggesting greater change in men (P = 0.034). Spaceflight-by-sex interactions for renin (P = 0.016) and aldosterone (P = 0.010) indicated greater increases in women than men. Six-month spaceflight caused increased arterial stiffness. Altered hydrostatic arterial pressure gradients as well as changes in insulin resistance and other biomarkers might have contributed to alterations in arterial properties, including sex differences between male and female astronauts.

'Under pressure': is there a link between orthostatic hypotension and cognitive impairment in α-synucleinopathies?

Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.

Automated removal of spurious intermediate cerebral blood flow volumes improves image quality among older patients: A clinical arterial spin labeling investigation.

PURPOSE: To evaluate the impact of rejecting intermediate cerebral blood flow (CBF) images that are adversely affected by head motion during an arterial spin labeling (ASL) acquisition. MATERIALS AND METHODS: Eighty participants were recruited, representing a wide age range (14-90 years) and heterogeneous cerebrovascular health conditions including bipolar disorder, chronic stroke, and moderate to severe white matter hyperintensities of presumed vascular origin. Pseudocontinuous ASL and T1 -weigthed anatomical images were acquired on a 3T scanner. ASL intermediate CBF images were included based on their contribution to the mean estimate, with the goal to maximize CBF detectability in gray matter (GM). Simulations were conducted to evaluate the performance of the proposed optimization procedure relative to other ASL postprocessing approaches. Clinical CBF images were also assessed visually by two experienced neuroradiologists. RESULTS: Optimized CBF images (CBFopt ) had significantly greater agreement with a synthetic ground truth CBF image and greater CBF detectability relative to the other ASL analysis methods (P < 0.05). Moreover, empirical CBFopt images showed a significantly improved signal-to-noise ratio relative to CBF images obtained from other postprocessing approaches (mean: 12.6%; range 1% to 56%; P < 0.001), and this improvement was age-dependent (P = 0.03). Differences between CBF images from different analysis procedures were not perceptible by visual inspection, while there was a moderate agreement between the ratings (κ = 0.44, P < 0.001). CONCLUSION: This study developed an automated head motion threshold-free procedure to improve the detection of CBF in GM. The improvement in CBF image quality was larger when considering older participants.

Exercise intensity modulates the change in cerebral blood flow following aerobic exercise in chronic stroke.

The mechanisms supporting functional improvement by aerobic exercise following stroke remain incompletely understood. This study investigated how cycling intensity and aerobic fitness influence cerebral blood flow (CBF) following a single exercise session. Thirteen community-living stroke survivors performed 20 min of semi-recumbent cycling at low and moderate intensities (40-50 and 60-70 % of heart rate reserve, respectively) as determined from an exercise stress test. CBF was quantified by arterial spin labeling MRI at baseline, as well as 30 and 50 min post-exercise. An intensity-dependent effect was observed in the right post-central and supramarginal gyri up to 50 min after exercise (uncorrected p < 0.005, cluster size ≥10). Regional CBF was increased 18 ± 17 % and reduced 8 ± 12 % following moderate- and low-intensity cycling, respectively. In contrast, CBF changes were similar between sessions in the right lentiform nucleus and mid-frontal gyrus, as well as the left temporal and parietal gyri. Aerobic fitness was directly related to posterior cingulate and thalamic CBF, and inversely related to precuneal CBF at rest (R (2) ≥ 0.75); however, no relationship between fitness and the post-exercise change in CBF was observed. Divergent changes in regional CBF were observed in the right parietal cortex following low- and moderate-intensity exercise, which suggests that intensity of prescribed exercise may be useful in optimizing rehabilitation.

Assessing cerebrovascular autoregulation from critical closing pressure and resistance area product during upright posture in aging and hypertension.

Static cerebral autoregulation (sCA) is believed to be resistant to aging and hypertensive pathology. However, methods to characterize autoregulation commonly rely on beat-by-beat mean hemodynamic measures and do not consider within-beat pulse wave characteristics that are impacted by arterial stiffening. We examined the role of critical closing pressure (CrCP) and resistance area product (RAP), two measures derived from the pulse wave, across supine lying, sitting, and standing postures in young adults, normotensive older adults, and older adults with controlled and uncontrolled hypertension (N = 80). Traditional measures of sCA, using both intracranial and extracranial methods, indicated similar efficiency across all groups, but within-beat measures suggested different mechanisms of regulation. At rest, RAP was increased in hypertension compared with young adults (P < 0.001), but CrCP was similar. In contrast, the drop in CrCP was the primary regulator of change in cerebrovascular resistance upon adopting an upright posture. Both CrCP and RAP demonstrated group-by-posture interaction effects (P < 0.05), with older hypertensive adults exhibiting a rise in RAP that was absent in other groups. The posture-related swings in CrCP and RAP were related to changes in both the pulsatile and mean components of arterial pressure, independent of age, cardiac output, and carbon dioxide. Group-by-posture differences in pulse pressure were mediated in part by an attenuated heart rate response in older hypertensive adults (P = 0.002). Examination of pulsatile measures in young, elderly, and hypertensive adults identified unique differences in how cerebral blood flow is regulated in upright posture.

Patient-reported outcomes for psoriasis patients with clear versus almost clear skin in the clinical setting.

BACKGROUND: There is little evidence to guide the establishment of treatment goals for moderate to severe psoriasis in the clinical setting. OBJECTIVE: We sought to compare Dermatology Life Quality Index scores and prescription topical medication use between patients with clear versus almost clear skin. METHODS: This was a multicenter cross-sectional study of 97 patients with clear skin and 441 patients with almost clear skin receiving current systemic therapy or phototherapy for a primary indication of plaque psoriasis evaluated at 1 of 10 US outpatient dermatology sites participating in the Dermatology Clinical Effectiveness Research Network. RESULTS: In adjusted analyses, patients with clear versus almost clear skin were more likely to report no impact of psoriasis on quality of life (relative risk 1.60; 95% confidence interval 1.37-1.86). Patients with clear versus almost clear skin were also more likely to report no prescription topical medication use in the preceding week (relative risk 2.08; 95% confidence interval 1.73-2.49). LIMITATIONS: Cross-sectional design prohibits longitudinal assessment of outcomes. CONCLUSIONS: Clinically important differences in quality of life and prescription topical medication use exist between patients with clear versus almost clear skin. Collectively, our results indicate that achievement of clear skin may be an important clinical distinction among patients with moderate to severe psoriasis.

Palmoplantar psoriasis is associated with greater impairment of health-related quality of life compared with moderate to severe plaque psoriasis.

BACKGROUND: The impact of palmoplantar psoriasis on health-related quality of life (QoL) is largely unknown. OBJECTIVE: We sought to compare clinical characteristics and patient-reported outcomes between patients with palmoplantar psoriasis and moderate to severe plaque psoriasis. METHODS: We conducted a cross-sectional study of patients with plaque psoriasis (N=1153) and palmoplantar psoriasis (N=66) currently receiving systemic or light treatment for psoriasis. RESULTS: Patients with palmoplantar psoriasis were more likely to report Dermatology Life Quality Index scores that correspond to at least a moderate impact on QoL (odds ratio [OR] 2.08; 95% confidence interval [CI] 1.20-3.61); problems with mobility (OR 1.98; 95% CI 1.10-3.58), self-care (OR 3.12; 95% CI 1.24-7.86), and usual activities (OR 2.47; 95% CI 1.44-4.22) on the European Quality of Life-5 Dimensions questionnaire; and heavy topical prescription use of at least twice daily in the preceding week (OR 2.81; 95% CI 1.63-4.85) than those with plaque psoriasis. LIMITATIONS: Our assessment tools may not account for all dimensions of health-related QoL affected by palmoplantar disease, and these results may not be generalizable to patients with milder forms of psoriasis. CONCLUSION: Patients with palmoplantar psoriasis experience greater health-related QoL impairment and are more likely to report heavy use of topical prescriptions than those with moderate to severe plaque psoriasis.

Comparative effectiveness of less commonly used systemic monotherapies and common combination therapies for moderate to severe psoriasis in the clinical setting.

BACKGROUND: The effectiveness of psoriasis therapies in real-world settings remains relatively unknown. OBJECTIVE: We sought to compare the effectiveness of less commonly used systemic therapies and commonly used combination therapies for psoriasis. METHODS: This was a multicenter cross-sectional study of 203 patients with plaque psoriasis receiving less common systemic monotherapy (acitretin, cyclosporine, or infliximab) or common combination therapies (adalimumab, etanercept, or infliximab and methotrexate) compared with 168 patients receiving methotrexate evaluated at 1 of 10 US outpatient dermatology sites participating in the Dermatology Clinical Effectiveness Research Network. RESULTS: In adjusted analyses, patients on acitretin (relative response rate 2.01; 95% confidence interval [CI] 1.18-3.41), infliximab (relative response rate 1.93; 95% CI 1.26-2.98), adalimumab and methotrexate (relative response rate 3.04; 95% CI 2.12-4.36), etanercept and methotrexate (relative response rate 2.22; 95% CI 1.25-3.94), and infliximab and methotrexate (relative response rate 1.72; 95% CI 1.10-2.70) were more likely to have clear or almost clear skin compared with patients on methotrexate. There were no differences among treatments when response rate was defined by health-related quality of life. LIMITATIONS: Single time point assessment may result in overestimation of effectiveness. CONCLUSIONS: The efficacy of therapies in clinical trials may overestimate their effectiveness as used in clinical practice. Although physician-reported relative response rates were different among therapies, absolute differences were small and did not correspond to differences in patient-reported outcomes.

Seated Elliptical Exercise, But Not Periodic Standing, Alleviates Sitting-Induced Changes to Arterial Wave Reflections.

PURPOSE: Sedentary behavior may contribute to increased central wave reflection due to associated peripheral vasoconstriction, yet its impact on central hemodynamics and the mitigating effects of interventional strategies have not been thoroughly investigated. We tested whether standing or seated elliptical breaks alleviate the deleterious effects of prolonged sitting on central wave reflections. METHODS: Eighteen healthy adults (9 9 females, 25 ± 3 yr) completed three 3-h protocols on separate days: uninterrupted sitting, sitting with periodic standing, and sitting with periodic seated elliptical activity. Central wave reflection, central pulse wave velocity, and lower-limb pulse wave velocity were measured before and after each intervention. RESULTS: Central relative wave reflection magnitude (RM) increased during sitting (0.31 ± 0.05 to 0.35 ± 0.05; P < 0.01) but did not change after standing (0.30 ± 0.05 to 0.32 ± 0.04; P = 0.19) or elliptical protocols (0.30 ± 0.05 to 0.30 ± 0.04; P > 0.99). The change in RM during prolonged sitting (ΔRM) was attenuated with elliptical activity (0.04 ± 0.05 vs 0.00 ± 0.03; P = 0.02) but not with periodic standing (0.04 ± 0.04 vs 0.02 ± 0.05; P = 0.54). In addition, augmentation index and central pulse wave velocity increased after sitting (both P < 0.01) and periodic standing (both P < 0.01) but were unchanged after elliptical activity. Lower limb pulse wave velocity did not change after sitting ( P = 0.73) or standing ( P = 0.21) but did decrease after elliptical activity ( P = 0.03). CONCLUSIONS: Prolonged sitting without interruptions increased central wave reflection, whereas elliptical but not standing interruptions were able to ameliorate multiple sitting-induced vascular consequences. More work is required to examine the long-term effectiveness of interruption strategies, as well as the optimal type, frequency, and duration for reducing vascular risk associated with sedentary behaviors.

Characterization of internal jugular vein region-specific distension and flow patterns during progressive volume shifting.

Blood volume shifts during postural adjustment lead to irregular distension of the internal jugular vein (IJV). In microgravity, distension may contribute to flow stasis and thromboembolism, though the regional implications and associated risk remain unexplored. We characterized regional differences in IJV volume distension and flow complexity during progressive head-down tilt (HDT) (0°, -6°, -15°, -30°) using conventional ultrasound and vector flow imaging. We also evaluated low-pressure thigh cuffs (40 mmHg) as a fluid shifting countermeasure during -6° HDT. Total IJV volume expanded 139 ± 95% from supine position (4.6 ± 2.7 mL) to -30° HDT (10.3 ± 5.0 mL). Blood flow profiles had greater vector uniformity at the cranial IJV region (P < 0.01) and became more dispersed with increasing tilt (P < 0.01). Qualitatively, flow was more uniform throughout the IJV during its early flow cycle phase and more disorganized during late flow phase. This disorganized flow was accentuated closer to the vessel wall, near the caudal region, and during greater HDT. Low-pressure thigh cuffs during -6° HDT decreased IJV volume at the cranial region (-12 ± 15%; P < 0.01) but not the caudal region (P = 0.20), although flow uniformity was unchanged (both regions, P > 0.25). We describe a distensible IJV accommodating large volume shifts along its length. Prominent flow dispersion was primarily found at the caudal region, suggesting multidirectional blood flow. Thigh cuffs appear effective for decreasing IJV volume but effects on flow complexity are minor. Flow complexity along the vessel length is likely related to IJV distension during chronic volume shifting and may be a precipitating factor for flow stasis and future thromboembolism risk.NEW & NOTEWORTHY The internal jugular vein (IJV) facilitates cerebral outflow and is sensitive to volume shifts. Concerns about IJV expansion and fluid flow behavior in astronauts have surfaced following thromboembolism reports. Our study explored regional volume distension and blood flow complexity in the IJV during progressive volume shifting. We observed stepwise volume distension and increasing flow dispersion with head-down tilting across all regions. Flow dispersion may pose a risk of future thromboembolism during prolonged volume shifts.

Heating-induced peripheral limb microvascular vasodilation reduces arterial wave reflection.

Arterial wave reflection augments cardiac afterload increasing myocardial demands. Mathematical models and comparative physiology suggest that the lower limbs are the primary source of reflected waves; however, in vivo human evidence corroborating these observations is lacking. This study was designed to determine whether the vasculature of the lower or upper limbs contributes more to wave reflection. We hypothesized that lower limb heating will result in larger reductions in central wave reflection compared with upper limb heating due to local vasodilation of a larger microvascular bed. Fifteen healthy adults (8 females, 24 ± 3.6 yr) completed a within-subjects experimental crossover protocol with a washout period. The right upper and lower limbs were heated in a randomized order using 38°C water-perfused tubing with a 30-min break between protocols. Central wave reflection was calculated using pressure-flow relationships derived from aortic blood flow and carotid arterial pressure at baseline and after 30 min of heating. We observed a main effect of time for reflected wave amplitude (12.8 ± 2.7 to 12.2 ± 2.6 mmHg; P = 0.03) and augmentation index (-7.5 ± 8.9% to -4.5 ± 9.1%; P = 0.03). No significant main effects or interactions were noted for forward wave amplitude, reflected wave arrival time, or central relative wave reflection magnitude (all P values >0.23). Unilateral limb heating reduced reflected wave amplitude; however, the lack of a difference between conditions does not support the hypothesis that the lower limbs are the primary source of reflection. Future investigations should consider alternative vascular beds, such as splanchnic circulation.NEW & NOTEWORTHY Lower limb contributions to central wave reflections have been theorized without direct evidence in humans. In this study, mild passive heating was used to locally vasodilate either the right arm or leg to control local wave reflection sites. Heating in general reduced the reflected wave amplitude, but there were no differences between the arm or leg heating intervention, failing to provide support for the lower limbs as a primary contributor to wave reflection in humans.

Effect of High-Intensity Interval Training and Moderate-Intensity Continuous Training in People With Poststroke Gait Dysfunction: A Randomized Clinical Trial.

Background The exercise strategy that yields the greatest improvement in both cardiorespiratory fitness (V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$) and walking capacity poststroke has not been determined. This study aimed to determine whether conventional moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) have different effects on V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6-minute walk distance (6MWD). Methods and Results In this 24-week superiority trial, people with poststroke gait dysfunction were randomized to MICT (5 days/week) or HIIT (3 days/week with 2 days/week of MICT). MICT trained to target intensity at the ventilatory anaerobic threshold. HIIT trained at the maximal tolerable treadmill speed/grade using a novel program of 2 work-to-recovery protocols: 30:60 and 120:180 seconds. V̇O2 and heart rate was measured during performance of the exercise that was prescribed at 8 and 24 weeks for treatment fidelity. Main outcomes were change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6MWD. Assessors were blinded to the treatment group for V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ but not 6MWD. Secondary outcomes were change in ventilatory anaerobic threshold, cognition, gait-economy, 10-meter gait-velocity, balance, stair-climb performance, strength, and quality-of-life. Among 47 participants randomized to either MICT (n=23) or HIIT (n=24) (mean age, 62±11 years; 81% men), 96% completed training. In intention-to-treat analysis, change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ for MICT versus HIIT was 2.4±2.7 versus 5.7±3.1 mL·kg-1·min-1 (mean difference, 3.2 [95% CI, 1.5-4.8]; P<0.001), and change in 6MWD was 70.9±44.3 versus 83.4±53.6 m (mean difference, 12.5 [95% CI, -17 to 42]; P=0.401). HIIT had greater improvement in ventilatory anaerobic threshold (mean difference, 2.07 mL·kg-1·min-1 [95% CI, 0.59-3.6]; P=0.008). No other between-group differences were observed. During V̇O2 monitoring at 8 and 24 weeks, MICT reached 84±14% to 87±18% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ while HIIT reached 101±22% to 112±14% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ (during peak bouts). Conclusions HIIT resulted in more than a 2-fold greater and clinically important change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ than MICT. Training to target (ventilatory anaerobic threshold) during MICT resulted in ~3 times the minimal clinically important difference in 6MWD, which was similar to HIIT. These findings show proof of concept that HIIT yields greater improvements in cardiorespiratory fitness than conventional MICT in appropriately screened individuals. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03006731.

Ambulatory Monitoring of Cerebrovascular Responses to Upright Posture and Walking in Older Adults With Heart Failure.

Background: Insufficient cardiac output in individuals with heart failure (HF) limits daily functioning and reduces quality of life. Although lower cerebral perfusion, secondary to limitations in cardiac output, has been observed during moderate-intensity efforts, individuals with HF also may be at risk for lower perfusion during even low-intensity ambulatory activities. Methods: We determined whether HF is associated with an altered cerebrovascular response to low-intensity activities representative of typical challenges of daily living. In this study, we monitored central hemodynamics and middle cerebral artery blood velocity (MCAv) and cerebral tissue oxygenation (near-infrared spectroscopy) in 10 individuals with HF (aged 78 ± 4 years; left ventricular ejection fraction 20%-61%) and 13 similar-aged controls (79 ± 8 years; 52%-73%) during 3 randomized transitions, as follows: (i) supine-to-standing; (ii) sitting-to-slow-paced over-ground walking; and (iii) sitting-to-normal-paced over-ground walking. Results: Throughout supine, sitting, standing, and both walking conditions, individuals with HF had lower cardiac index and cerebral tissue oxygenation than controls (P < 0.05), and MCAv was lower across the range of blood pressure in HF patients (P = 0.051) and during walking only (P = 0.011). Individuals with HF had an attenuated increase in stroke volume index and cardiac index during normal-paced walking, compared to controls (P < 0.01). Conclusions: The indices of cerebral perfusion from MCAv and cerebral oxygenation were lower during ambulatory activities in individuals with HF; however, relationships between MCAv and blood pressure were not different between those with HF and controls, indicating no difference in static cerebral autoregulation.

Contexte: Un débit cardiaque insuffisant chez les personnes atteintes d'insuffisance cardiaque limite les activités quotidiennes et affecte la qualité de vie. Par exemple, des efforts d'intensité modérée ont été associés à une perfusion cérébrale affaiblie chez ces personnes. Or, il semble que même des activités ambulatoires de faible intensité soient susceptibles d'avoir les mêmes conséquences. Méthodologie: Nous voulions déterminer si l'insuffisance cardiaque est associée à une altération de la réponse cérébrovasculaire à des activités de faible intensité qui sont typiques de la vie quotidienne. Dans le cadre de cette étude, nous avons surveillé l'hémodynamique centrale et la vitesse du sang dans l'artère cérébrale moyenne (VACM), ainsi que l'oxygénation tissulaire cérébrale (par spectroscopie dans le proche infrarouge) chez 10 personnes atteintes d'insuffisance cardiaque (âge : 78 ± 4 ans; fraction d'éjection du ventricule gauche de 20 à 61 %) et 13 témoins d'âge similaire (79 ± 8 ans; de 52 à 73 %) lors de 3 transitions réparties de façon aléatoire, soit : i) de la position couchée à debout; ii) de la position assise à une marche lente et iii) de la position assise à une marche à vitesse normale. Résultats: En position couchée, assise ou debout et avec les deux vitesses de marche, l'index cardiaque et l'oxygénation tissulaire cérébrale étaient plus faibles chez les personnes atteintes d'insuffisance cardiaque que chez les témoins (p < 0,05); la VACM était plus faible dans toutes les plages de pression artérielle chez les personnes atteintes d'insuffisance cardiaque (p = 0,051) et durant la marche seulement (p = 0,011). Les personnes atteintes d'insuffisance cardiaque présentaient une plus faible augmentation du volume d'éjection systolique et de l'index cardiaque durant la marche à vitesse normale, comparativement aux témoins (p < 0,01). Conclusions: Les indices de la perfusion cérébrale selon la VACM et l'oxygénation cérébrale étaient réduits durant les activités ambulatoires chez les personnes atteintes d'insuffisance cardiaque; cependant, les relations entre la VACM et la pression artérielle n'étaient pas différentes entre les personnes atteintes d'insuffisance cardiaque et les témoins, ce qui indique que l'autorégulation cérébrale statique n'est pas un facteur de différenciation.