Smartphones and Video Cameras: Future Methods for Blood Pressure Measurement.

Regular blood pressure (BP) monitoring enables earlier detection of hypertension and reduces cardiovascular disease. Cuff-based BP measurements require equipment that is inconvenient for some individuals and deters regular home-based monitoring. Since smartphones contain sensors such as video cameras that detect arterial pulsations, they could also be used to assess cardiovascular health. Researchers have developed a variety of image processing and machine learning techniques for predicting BP via smartphone or video camera. This review highlights research behind smartphone and video camera methods for measuring BP. These methods may in future be used at home or in clinics, but must be tested over a larger range of BP and lighting conditions. The review concludes with a discussion of the advantages of the various techniques, their potential clinical applications, and future directions and challenges. Video cameras may potentially measure multiple cardiovascular metrics including and beyond BP, reducing the risk of cardiovascular disease.

Brain microvascular damage linked to a moderate level of strain induced by controlled cortical impact.

Cerebral blood vessels play an important role in brain metabolic activity in general and following traumatic brain injury (TBI) in particular. However, the extent to which TBI alters microvessel structure is not well understood. Specifically, how intracranial mechanical responses produced during impacts relate to vascular damage needs to be better studied. Therefore, the objective of this study was to investigate the biomechanical mechanisms and thresholds of brain microvascular injury. Detailed microvascular damage of mouse brain was quantified using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) and ex vivo Serial Two-Photon Tomography (STPT) in seven mice that had undergone controlled cortical impact. Mechanical strains were investigated through finite element (FE) modeling of the mouse brain. We then compared the post-injury vessel density map with FE-predicted strain and found a moderate correlation between the vessel length density and the predicted peak maximum principal strains (MPS) (R2 = 0.52). High MPS was observed at the impact regions with low vessel length density, supporting the mechanism of strain-triggered microvascular damage. Using logistic regression, the MPS corresponding to a 50% probability of injury was found to be 0.17. Given the literature reporting MPS of over 0.2 in the human brain for mild TBI/concussion cases, it is highly recommended to consider microvascular damage when investigating mild TBI/concussion in the future.

The effects of voluntary running on cerebrovascular morphology and spatial short-term memory in a mouse model of amyloidosis.

Physical activity has been correlated with a reduced risk of cognitive decline, including that associated with vascular dementia, mild cognitive impairment (MCI) and Alzheimer's disease (AD); recent literature suggests this may in part result from benefits to the cerebrovascular network. Using a transgenic (Tg) mouse model of AD, we evaluated the effect of running on cortical and hippocampal vascular morphology, cerebral amyloid angiopathy, amyloid plaque load, and spatial memory. TgCRND8 mice present with progressive amyloid pathology, advancing from the cortex to the hippocampus in a time-dependent manner. We postulated that the characteristic progression of pathology could lead to differential, time-dependent effects of physical activity on vascular morphology in these brain regions at 6 months of age. We used two-photon fluorescent microscopy and 3D vessel tracking to characterize vascular and amyloid pathology in sedentary TgCRND8 mice compared those who have a history of physical activity (unlimited access to a running wheel, from 3 to 6 months of age). In sedentary TgCRND8 mice, capillary density was found to be lower in the cortex and higher in the hippocampus compared to non-transgenic (nonTg) littermates. Capillary length, vessel branching, and non-capillary vessel tortuosity were also higher in the hippocampus of sedentary TgCRND8 compared to nonTg mice. Three months of voluntary running resulted in normalizing cortical and hippocampal microvascular morphology, with no significant difference between TgCRND8 and nonTg mice. The benefits of physical activity on cortical and hippocampal vasculature in 6-month old TgCRND8 mice were not paralleled by significant changes on parenchymal and cerebral amyloid pathology. Short-term spatial memory- as evaluated by performance in the Y-maze- was significantly improved in running compared to sedentary TgCRND8 mice. These results suggest that long-term voluntary running contributes to the maintenance of vascular morphology and spatial memory in TgCRND8 mice, even in the absence of an effect on amyloid pathology.

Non-Invasive Ultrasound Detection of Cerebrovascular Changes in a Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) can induce changes in vascular architecture. Although ultrasound metrics such as pulsatility index (PI) are sensitive to changes in hemodynamic resistance downstream from major arteries, these metrics depend on features unrelated to vessel architecture, such as blood pressure and heart rate. In contrast, input impedance and reflection coefficient that are derived from wave reflection theory seek to minimize the effects of altered cardiac output or heart rate. In this article, we investigate the use of ultrasound to assess changes in vascular impedance and wave reflection in the common carotid arteries of mice exposed to a controlled cortical impact. Focusing on the first harmonics of the reflected waves, the impedance phase was increased ipsilaterally in impacted mice compared with shams, whereas the magnitude of the impedance was unchanged. In contrast, PI was reduced bilaterally. Interestingly, PI and the first harmonic magnitude of input impedance in the carotid artery were correlated on the contralateral but not ipsilateral side. We investigated the use of these metrics to classify mice as sham or TBI, finding an area under the receiver operating characteristic curve ipsilaterally of 0.792 (confidence interval [CI]: 0.648-0.936) for correct classification with first harmonic impedance magnitude and phase as predictors and 0.716 (CI: 0.553-0.879) using carotid artery PI and diameter as predictors. Overall, the findings support the use of wave reflection analysis as a more specific measure of vascular changes following TBI and motivate the translation of this approach for monitoring vascular changes in humans affected by TBI.

Microvascular Alterations in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with continual decline in cognition and ability to perform routine functions such as remembering familiar places or understanding speech. For decades, amyloid beta (Aß) was viewed as the driver of AD, triggering neurodegenerative processes such as inflammation and formation of neurofibrillary tangles (NFTs). This approach has not yielded therapeutics that cure the disease or significant improvements in long-term cognition through removal of plaques and Aß oligomers. Some researchers propose alternate mechanisms that drive AD or act in conjunction with amyloid to promote neurodegeneration. This review summarizes the status of AD research and examines research directions including and beyond Aß, such as tau, inflammation, and protein clearance mechanisms. The effect of aging on microvasculature is highlighted, including its contribution to reduced blood flow that impairs cognition. Microvascular alterations observed in AD are outlined, emphasizing imaging studies of capillary malfunction. The review concludes with a discussion of two therapies to protect tissue without directly targeting Aß for removal: (1) administration of growth factors to promote vascular recovery in AD; (2) inhibiting activity of a calcium-permeable ion channels to reduce microglial activation and restore cerebral vascular function.

Ultrasound Detection of Abnormal Cerebrovascular Morphology in a Mouse Model of Sickle Cell Disease Based on Wave Reflection.

Sickle cell disease (SCD) is associated with a high risk of stroke, and affected individuals often have focal brain lesions termed silent cerebral infarcts. The mechanisms leading to these types of injuries are at present poorly understood. Our group has recently demonstrated a non-invasive measurement of cerebrovascular impedance and wave reflection in mice using high-frequency ultrasound in the common carotid artery. To better understand the pathophysiology in SCD, we used this approach in combination with micro-computed tomography to investigate changes in cerebrovascular morphology in the Townes mouse model of SCD. Relative to controls, the SCD mice demonstrated the following: (i) increased carotid artery diameter, blood flow and vessel wall thickness; (ii) elevated pulse wave velocity; (iii) increased reflection coefficient; and (iv) an increase in the total number of vessel segments in the brain. This study highlights the potential for wave reflection to aid the non-invasive clinical assessment of vascular pathology in SCD.

Acute and chronic stage adaptations of vascular architecture and cerebral blood flow in a mouse model of TBI.

The 3D organization of cerebral blood vessels determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. Imaging methodologies which combine 3D microvascular structural imaging with blood flow quantification can shed light on the relationship between vascular structure and function, in health and disease. This study applies Arterial Spin Labeling (ASL) MRI with a hypercapnic challenge and ex vivo Serial Two-Photon Tomography (STPT) to examine the relationship between blood flow and vascular architecture following traumatic brain injury (TBI) in a mouse. Mice were exposed to a controlled cortical impact TBI and allowed to recover for either 1 day or 4 weeks. At each time point, ASL MRI was performed to quantify cerebral perfusion and the brain vasculature was imaged in 3D with STPT. Registration of ASL to STPT enabled flow changes to be related to the underlying microvascular structure in each ASL voxel. Hypoperfusion under rest and hypercapnia was observed both 1 day and 4 weeks post-TBI. Vessel density and vascular volume were reduced 1 day post-TBI, recovering by 4 weeks; however, the reorganized vasculature at the latter time point possessed an abnormal radial pattern. Our findings demonstrate functionally significant long-term changes in the vascular architecture following injury and illustrate why metrics beyond traditional measures of vessel density are required to understand the impact of vascular structure on function.

Neurogliovascular dysfunction in a model of repeated traumatic brain injury.

Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period. Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence. Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival. Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.

3D morphological analysis of the mouse cerebral vasculature: Comparison of in vivo and ex vivo methods.

Ex vivo 2-photon fluorescence microscopy (2PFM) with optical clearing enables vascular imaging deep into tissue. However, optical clearing may also produce spherical aberrations if the objective lens is not index-matched to the clearing material, while the perfusion, clearing, and fixation procedure may alter vascular morphology. We compared in vivo and ex vivo 2PFM in mice, focusing on apparent differences in microvascular signal and morphology. Following in vivo imaging, the mice (four total) were perfused with a fluorescent gel and their brains fructose-cleared. The brain regions imaged in vivo were imaged ex vivo. Vessels were segmented in both images using an automated tracing algorithm that accounts for the spatially varying PSF in the ex vivo images. This spatial variance is induced by spherical aberrations caused by imaging fructose-cleared tissue with a water-immersion objective. Alignment of the ex vivo image to the in vivo image through a non-linear warping algorithm enabled comparison of apparent vessel diameter, as well as differences in signal. Shrinkage varied as a function of diameter, with capillaries rendered smaller ex vivo by 13%, while penetrating vessels shrunk by 34%. The pial vasculature attenuated in vivo microvascular signal by 40% 300 µm below the tissue surface, but this effect was absent ex vivo. On the whole, ex vivo imaging was found to be valuable for studying deep cortical vasculature.

Effects of voluntary exercise on structure and function of cortical microvasculature.

Aerobic activity has been shown highly beneficial to brain health, yet much uncertainty still surrounds the effects of exercise on the functioning of cerebral microvasculature. This study used two-photon fluorescence microscopy to examine cerebral hemodynamic alterations as well as accompanying geometric changes in the cortical microvascular network following five weeks of voluntary exercise in transgenic mice endogenously expressing tdTomato in vascular endothelial cells to allow visualization of microvessels irrespective of their perfusion levels. We found a diminished microvascular response to a hypercapnic challenge (10% FiCO2) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p = 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p = 0.0085). No changes were seen in resting hemodynamics or in the systemic physiological parameters measured. Although a few unperfused new vessels were observed on visual inspection, running did not produce significant morphological differences in the microvascular morphometric parameters, quantified following semiautomated tracking of the microvascular networks. We propose that voluntary running led to increased cortical microvascular efficiency and desensitization to CO2 elevation.