The correlation between carotid artery Doppler and stroke volume during central blood volume loss and resuscitation.

BACKGROUND: Using peripheral arteries to infer central hemodynamics is common among hemodynamic monitors. Doppler ultrasound of the common carotid artery has been used in this manner with conflicting results. We investigated the relationship between changing common carotid artery Doppler measures and stroke volume (SV), hypothesizing that more consecutively-averaged cardiac cycles would improve SV-carotid Doppler correlation. METHODS: Twenty-seven healthy volunteers were recruited and studied in a physiology laboratory. Carotid artery Doppler pulse was measured with a wearable, wireless ultrasound during central hypovolemia and resuscitation induced by a stepped lower body negative pressure protocol. The change in maximum velocity time integral (VTI) and corrected flow time of the carotid artery (ccFT) were compared with changing SV using repeated measures correlation. RESULTS: In total, 73,431 cardiac cycles were compared across 27 subjects. There was a strong linear correlation between changing SV and carotid Doppler measures during simulated hemorrhage (repeated-measures linear correlation [Rrm ]=0.91 for VTI; 0.88 for ccFT). This relationship improved with larger numbers of consecutively-averaged cardiac cycles. For ccFT, beyond four consecutively-averaged cardiac cycles the correlation coefficient remained strong (i.e., Rrm of at least 0.80). For VTI, the correlation coefficient with SV was strong for any number of averaged cardiac cycles. For both ccFT and VTI, Rrm remained stable around 25 consecutively-averaged cardiac cycles. CONCLUSIONS: There was a strong linear correlation between changing SV and carotid Doppler measures during central blood volume loss. The strength of this relationship was dependent upon the number of consecutively-averaged cardiac cycles.

Odds and associated factors for thrombosis development among Lebanese COVID-19 patients: a case-control retrospective study.

Background: Thromboembolism is reported to be up to 27% in COVID-19 patients due to SARS-CoV-2 infection. Dysregulated systemic inflammation and various patient traits play a vital role in thrombosis progression. Purpose: To assess odds and associated factors for thrombosis development among Lebanese COVID-19 patients. Methods: This was a case-control retrospective study conducted in January-May 2021. Patients infected with COVID-19 and developed thrombosis were classified as cases and patients who were thrombosis-free identified as control. A questionnaire assessed socio-demographics, clinical parameters, and WHO COVID-19 disease severity. Results: Among 267 patients, 26 (9.7%) developed thrombosis and the majority of thrombosis 34.6% was myocardial infarction, and the least (3.8%) was for catheter-related thrombosis. Results showed that the risk of thrombosis development is higher in patients with previous thromboembolic event (OR = 9.160) and previous intake of anti-hypertensive medications at home (OR = 3.116). However, females (OR = 0.330; CI: 0.118-0.925), intake of anticoagulants during hospital admission (OR = 0.126; CI: 0.053-0.300) and non-severe COVID-19 were at lower thrombosis risk (OR = 0.273). Patients who developed thromboembolic events had longer hospital stay (OR = 0.077). Conclusion: Patients with COVID-19 and thromboembolism were at higher risk of mortality as compared to patients with COVID-19 but without thromboembolism. The use of anticoagulants significantly reduced the risk for thromboembolism.

Inferior Vena Caval Measures Do Not Correlate with Carotid Artery Corrected Flow Time Change Measured Using a Wireless Doppler Patch in Healthy Volunteers.

(1) Background: The inspiratory collapse of the inferior vena cava (IVC), a non-invasive surrogate for right atrial pressure, is often used to predict whether a patient will augment stroke volume (SV) in response to a preload challenge. There is a correlation between changing stroke volume (SV∆) and corrected flow time of the common carotid artery (ccFT∆). (2) Objective: We studied the relationship between IVC collapsibility and ccFT∆ in healthy volunteers during preload challenges. (3) Methods: A prospective, observational, pilot study in euvolemic, healthy volunteers with no cardiovascular history was undertaken in a local physiology lab. Using a tilt-table, we studied two degrees of preload augmentation from (a) supine to 30-degrees head-down and (b) fully-upright to 30-degrees head down. In the supine position, % of IVC collapse with respiration, sphericity index and portal vein pulsatility was calculated. The common carotid artery Doppler pulse was continuously captured using a wireless, wearable ultrasound system. (4) Results: Fourteen subjects were included. IVC % collapse with respiration ranged between 10% and 84% across all subjects. Preload responsiveness was defined as an increase in ccFT∆ of at least 7 milliseconds. A total of 79% (supine baseline) and 100% (head-up baseline) of subjects were preload-responsive. No supine venous measures (including IVC % collapse) were significantly related to ccFT∆. (5) Conclusions: From head-up baseline, 100% of healthy subjects were 'preload-responsive' as per the ccFT∆. Based on the 42% and 25% IVC collapse thresholds in the supine position, only 50% and 71% would have been labeled 'preload-responsive'.

An imaging-based method of mapping multi-echo BOLD intracranial pulsatility.

PURPOSE: Cardiac-related intracranial pulsatility may relate to cerebrovascular health, and this information is contained in BOLD MRI data. There is broad interest in methods to isolate BOLD pulsatility, and the current study examines a deep learning approach. METHODS: Multi-echo BOLD images, respiratory, and cardiac recordings were measured in 55 adults. Ground truth BOLD pulsatility maps were calculated with an established method. BOLD fast Fourier transform magnitude images were used as temporal-frequency image inputs to a U-Net deep learning model. Model performance was evaluated by mean squared error (MSE), mean absolute error (MAE), structural similarity index (SSIM), and mutual information (MI). Experiments evaluated the influence of input channel size, an age group effect during training, dependence on TE, performance without the U-Net architecture, and importance of respiratory preprocessing. RESULTS: The U-Net model generated BOLD pulsatility maps with lower MSE as additional fast Fourier transform input images were used. There was no age group effect for MSE (P > 0.14). MAE and SSIM metrics did not vary across TE (P > 0.36), whereas MI showed a significant TE dependence (P < 0.05). The U-Net versus no U-Net comparison showed no significant difference for MAE (P = 0.059); however, SSIM and MI were significantly different between models (P < 0.001). Within the insula, the cross-correlation values were high (r > 0.90) when comparing the U-Net model trained with/without respiratory preprocessing. CONCLUSION: Multi-echo BOLD pulsatility maps were synthesized from a U-net model that was trained to use temporal-frequency BOLD image inputs. This work adds to the deep learning methods that characterize BOLD physiological signals.

The Correlation between Carotid Artery Corrected Flow Time and Velocity Time Integral during Central Blood Volume Loss and Resuscitation.

Background: Doppler ultrasound of the common carotid artery is used to infer central hemodynamics. For example, change in the common carotid artery corrected flow time (ccFT) and velocity time integral (VTI) are proposed surrogates of changing stroke volume. However, conflicting data exist which may be due to inadequate beat sample size and measurement variability - both intrinsic to handheld systems. In this brief communication, we determined the correlation between changing ccFT and carotid VTI during progressively severe central blood volume loss and resuscitation. Methods: Measurements were obtained through a novel, wireless, wearable Doppler ultrasound system. Sixteen participants (ages of 18-40 years with no previous medical history) were studied across 25 lower body-negative pressure protocols. Relationships were assessed using repeated-measures correlation regression models. Results: In total, 33,110 cardiac cycles comprise this analysis; repeated-measures correlation showed a strong, linear relationship between ccFT and VTI. The strength of the ccFT-VTI relationship was dependent on the number of consecutively averaged cardiac cycles (R1 cycle = 0.70, R2 cycles = 0.74, and R10 cycles = 0.81). Conclusions: These results positively support future clinical investigations employing common carotid artery Doppler as a surrogate for central hemodynamics.

Associations of white matter hyperintensities with networks of gray matter blood flow and volume in midlife adults: A coronary artery risk development in young adults magnetic resonance imaging substudy.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.

An in vivo comparison of wound healing characteristics of two commercial acellular dermal matrices.

OBJECTIVES: Many acellular dermal matrices (ADMs) are available for use in periodontal surgical procedures. However, few studies exist evaluating their in vivo healing properties. The objectives of this study were to compare the wound healing and remodeling of two ADMs used for gingival augmentation procedures in the rat model. MATERIALS AND METHODS: This was a nonrandomized controlled split-mouth study. Envelope flaps were surgically created in the maxillary quadrants of 24 Sprague Dawley rats. Each received either (a) AlloDerm Regenerative Tissue Matrix, or (b) OrACELL. Gingival tissue from one mandibular quadrant served as the untreated control. Six male and six female rats were treated for 7 or 21 days. Biopsies were processed for histologic analysis (H&E, Picro-sirius red, Verhoeff's solution) or RNA analysis (RT-PCR) to analyze the expression of type I collagen (Col1a1), fibronectin (Fn-1) and VEGF-A (Vegf-A). RESULTS: There was a greater density of fibroblasts in OrACELL compared to AlloDerm at both timepoints. There was a greater density of elastin present in AlloDerm compared to OrACELL at 7 days but no differences at 21 days. There were no differences between test groups in the percentage of birefringent collagen or in the expression of Vegf-A or Fn-1. At 7 days, there were significantly more fibroblasts for males in the OrACELL group compared to females. At 21 days, there was a significantly greater expression of Col1a1 for males in the OrACELL group compared to females. CONCLUSIONS: Early wound healing and remodeling of OrACELL appeared to occur more rapidly than AlloDerm and was accelerated in male rats. Whether these results have clinical implications for soft tissue grafting procedures in humans remains to be determined.

Cerebrovascular assessments to help understand brain-related changes associated with aerobic exercise after stroke.

Evidence suggests exercise is "good medicine" after stroke, yet consensus is lacking on the time to initiate, type, exertion level, and duration per session. It remains a challenge to identify outcome measures for stroke-exercise trials that are sufficiently sensitive to intervention parameters. Cerebrovascular assessments, namely cerebral blood flow and intracranial pulsatility, are herein discussed as examples of quantitative brain-specific measures that may be useful to monitor exercise-related brain changes and help to guide stroke rehabilitation interventions. Novelty: Cerebral blood flow and arterial stiffness are potential vascular targets for stroke exercise trials.

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease.

Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.

Lower Thalamic Blood Flow Is Associated With Slower Stride Velocity in Older Adults.

BACKGROUND: Gait deficits are associated with brain atrophy and white matter hyperintensities (WMH) - both markers of underlying cerebral small vessel disease (SVD). Given reduced subcortical cerebral blood flow (CBF) is prevalent in SVD, we tested the hypothesis that regional CBF is positively associated with gait performance among older adults. METHODS: Thirty-two older adults (55-80 years) with at least one vascular risk factor were recruited. We assessed gait during 2 consecutive walking sequences using a GAITRite system: (1) at a self-selected pace, and (2) while performing a serial subtraction dual-task challenge. We quantified CBF using pseudo-continuous arterial spin labeling MRI within 4 regions of interest: putamen, pallidum, thalamus, and hippocampus. We investigated associations between gait characteristics and overall CBF adjusting for age, sex, and height in an omnibus approach using multivariate analysis of variance, followed by regression analysis with each individual region. We also conducted further regression analyses to investigate associations between gait characteristics and frontal lobe CBF. Sensitivity analyses examined how the observed associations were modified by WMH, executive function, and depressive symptoms. A change of 10% in the model's adjusted r2 and effect size was considered as a threshold for confounding. RESULTS: Overall subcortical CBF was not associated with self-paced gait. When examining individual ROI, gait velocity was directly related to thalamic CBF (p = 0.026), and across all gait variables the largest effect sizes were observed in relation to thalamic CBF. In the dual-task condition, gait variables were not related to CBF in either the omnibus approach or individual multiple regressions. Furthermore, no significant associations were observed between frontal CBF and gait variables in either the self-paced or dual-task condition. Sensitivity analyses which were restricted to examine the association of velocity and thalamic CBF identified a cofounding effect of depressive symptoms which increased the effect size of the CBF-gait association by 12%. CONCLUSION: Subcortical hypoperfusion, particularly in regions that comprise central input/output tracts to the cortical tissue, may underlie the association between gait deficits and brain aging.

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.

Metabolic and vascular risk factors are associated with reduced cerebral blood flow and poorer midlife memory performance.

Midlife metabolic and vascular risk factors (MVRFs) predict cognitive decline and dementia; however, these risk factors tend to overlap, and the mechanisms underlying their effects on cognitive performance are not well understood. This cross-sectional study investigates the contributions of MVRFs to regional cerebral blood flow (CBF) and verbal learning & memory among middle-aged adults. We used partial least squares (PLS) analysis to create latent risk factor profiles and examine their associations to CBF in 93 regions of interest among 451 participants (age 50.3 ± 3.5 years) of the Coronary Artery Risk Development in Young Adults. This multivariate analysis revealed regional CBF was lower in relation to obesity (higher body mass index and waist circumference), dysregulated glucose homeostasis (higher fasting glucose, oral glucose tolerance, and higher fasting insulin), and adverse fasting lipid profile (lower high-density lipoprotein cholesterol and higher triglycerides). In a sensitivity analysis, we found that significant associations between MVRFs and CBF were prominent in the hypertension-medicated subgroup. In a mediation model, the PLS-based MVRFs profile was associated with memory performance (rey auditory verbal learning test); however, CBF was not a significant mediator of this association. The results describe an adverse midlife metabolic profile that might set the stage for incipient dementia and contribute to widespread changes in CBF.

Cerebrovascular Pulsatility During Rest and Exercise Reflects Hemodynamic Impairment in Stroke and Cerebral Small Vessel Disease.

Although aerobic exercise is recommended as a core component of stroke rehabilitation, knowledge of acute cerebrovascular responses in patients is limited. This study tested the hypothesis that older adults with chronic stroke or cerebral small vessel disease (SVD) exhibit a greater increase in pulsatile hemodynamics during exercise compared with young and age-matched healthy adults. Middle cerebral artery blood flow velocity was acquired during 20 min of moderate intensity cycling in 51 participants from four groups (young, old, SVD and stroke). During rest, only the stroke group had a higher pulsatility index (PI) compared with the young group (1.02 ± 0.17 vs 0.83 ± 0.13; p = 0.038). During exercise, however, the SVD group exhibited a larger increase in PI (68 ± 20% relative to rest) than the young (47 ± 19%), old (45 ± 17%) and stroke (40 ± 25%) groups (p < 0.05, for each). The stress of aerobic exercise may reveal arterial dysfunction associated with latent and overt cerebrovascular disease.

BOLD-based cerebrovascular reactivity vascular transfer function isolates amplitude and timing responses to better characterize cerebral small vessel disease.

Cerebrovascular reactivity (CVR) is a dynamic measure of the cerebral blood vessel response to vasoactive stimulus. Conventional CVR measures amplitude changes in the blood-oxygenation-level-dependent (BOLD) signal per unit change in end-tidal CO2 (PET CO2 ), effectively discarding potential timing information. This study proposes a deconvolution procedure to characterize CVR responses based on a vascular transfer function (VTF) that separates amplitude and timing CVR effects. We implemented the CVR-VTF to primarily evaluate normal-appearing white matter (WM) responses in those with a range of small vessel disease. Comparisons between simulations of PET CO2 input models revealed that boxcar and ramp hypercapnia paradigms had the lowest relative deconvolution error. We used a T2 * BOLD-MRI sequence on a 3 T MRI scanner, with a boxcar delivery model of CO2 , to test the CVR-VTF approach in 18 healthy adults and three white matter hyperintensity (WMH) groups: 20 adults with moderate WMH, 12 adults with severe WMH, and 10 adults with genetic WMH (CADASIL). A subset of participants performed a second CVR session at a one-year follow-up. Conventional CVR, area under the curve of VTF (VTF-AUC), and VTF time-to-peak (VTF-TTP) were assessed in WM and grey matter (GM) at baseline and one-year follow-up. WMH groups had lower WM VTF-AUC compared with the healthy group (p < 0.0001), whereas GM CVR did not differ between groups (p > 0.1). WM VTF-TTP of the healthy group was less than that in the moderate WMH group (p = 0.016). Baseline VTF-AUC was lower than follow-up VTF-AUC in WM (p = 0.013) and GM (p = 0.026). The intraclass correlation for VTF-AUC in WM was 0.39 and coefficient of repeatability was 0.08 [%BOLD/mm Hg]. This study assessed CVR timing and amplitude information without applying model assumptions to the CVR response; this approach may be useful in the development of robust clinical biomarkers of CSVD.

Attention-Related Brain Activation Is Altered in Older Adults With White Matter Hyperintensities Using Multi-Echo fMRI.

Cognitive decline is often undetectable in the early stages of accelerated vascular aging. Attentional processes are particularly affected in older adults with white matter hyperintensities (WMH), although specific neurovascular mechanisms have not been elucidated. We aimed to identify differences in attention-related neurofunctional activation and behavior between adults with and without WMH. Older adults with moderate to severe WMH (n = 18, mean age = 70 years), age-matched adults (n = 28, mean age = 72), and healthy younger adults (n = 19, mean age = 25) performed a modified flanker task during multi-echo blood oxygenation level dependent functional magnetic resonance imaging. Task-related activation was assessed using a weighted-echo approach. Healthy older adults had more widespread response and higher amplitude of activation compared to WMH adults in fronto-temporal and parietal cortices. Activation associated with processing speed was absent in the WMH group, suggesting attention-related activation deficits that may be a consequence of cerebral small vessel disease. WMH adults had greater executive contrast activation in the precuneous and posterior cingulate gyrus compared to HYA, despite no performance benefits, reinforcing the network dysfunction theory in WMH.

Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats.

Androgen loss is an important clinical concern because of its cognitive and behavioral effects. Changes in androgen levels are also suspected to contribute to neurological disease. However, the available data on the effects of androgen deprivation in areas of the brain that are central to cognition, like the hippocampus, are mixed. In this study, morphological analysis of pyramidal cells was used to investigate if structural changes could potentially contribute to the mixed cognitive effects that have been observed after androgen loss in males. Male Sprague-Dawley rats were orchidectomized or sham-operated. Two months later, their brains were Golgi-impregnated for morphological analysis. Morphological endpoints were studied in areas CA3 and CA1, with comparisons to females either intact or 2 months after ovariectomy. CA3 pyramidal neurons of orchidectomized rats exhibited marked increases in apical dendritic arborization. There were increases in mossy fiber afferent density in area CA3, as well as robust enhancements to dendritic structure in area CA3 of orchidectomized males, but not in CA1. Remarkably, apical dendritic length of CA3 pyramidal cells increased, while spine density declined. By contrast, in females overall dendritic structure was minimally affected by ovariectomy, while dendritic spine density was greatly reduced. Sex differences and subfield-specific effects of gonadal hormone deprivation on the hippocampal circuitry may help explain the different behavioral effects reported in males and females after gonadectomy, or other conditions associated with declining gonadal hormone secretion.

Androgen Modulation of Hippocampal Structure and Function.

Androgens have profound effects on hippocampal structure and function, including induction of spines and spine synapses on the dendrites of CA1 pyramidal neurons, as well as alterations in long-term synaptic plasticity (LTP) and hippocampally dependent cognitive behaviors. How these effects occur remains largely unknown. Emerging evidence, however, suggests that one of the key elements in the response mechanism may be modulation of brain-derived neurotrophic factor (BDNF) in the mossy fiber (MF) system. In male rats, orchidectomy increases synaptic transmission and excitability in the MF pathway. Testosterone reverses these effects, suggesting that testosterone exerts tonic suppression on MF BDNF levels. These findings suggest that changes in hippocampal function resulting from declining androgen levels may reflect the outcome of responses mediated through normally balanced, but opposing, mechanisms: loss of androgen effects on the hippocampal circuitry may be compensated, at least in part, by an increase in BDNF-dependent MF plasticity.