The severity of microstrokes depends on local vascular topology and baseline perfusion

Schmid, Franca; Conti, Giulia; Jenny, Patrick; Weber, Bruno

doi:10.7554/elife.60208

Cited by 24 publications

(25 citation statements)

References 63 publications

(219 reference statements)

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“…DTPT offers a distinct advantage over the conventional green light-induced photothrombosis by using infrared light that penetrates deeper into the parenchyma. Hence, DTPT should be an effective means to evaluate the theoretical prediction of microstroke outcomes in various microcirculation configurations 20 . Future applications of the DTPT include occlusion of subcortical regions such as the hippocampus, where two-photon or three-photon imaging from the cortical surface is possible 9,[21][22][23] .…”

Section: Discussionmentioning

confidence: 99%

Depth-targeted intracortical microstroke by two-photon photothrombosis in rodent brain

Fukuda

Suda

Matsumura

et al. 2021

Preprint

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SignificancePhotothrombosis is a widely used model of ischemic stroke in rodent experiments. In the photothromboris model, the photosensitizer Rose Bengal is systemically introduced to the blood stream and activated by green light to induce aggregation of platelets that eventually cause vessel occlusion. Since the activation of Rose Bengal is a one-photon phenomenon and the molecules in the illuminated area (light path) are subject to excitation, targeting of thrombosis is unspecific especially in the depth dimension. We have developed a photothrombosis protocol that can target a single vessel in the cortical parenchyma by two-photon excitation.AimWe aim to induce a thrombotic stroke in the cortical parenchyma by two-photon activation of Rose Bengal so that we confine photothrombosis within a vessel of a target depth.ApproachFITC-dextran is injected into the blood stream to visualize the cerebral blood flow in anesthetized adult mice with a cranial window. After a target vessel is chosen by two-photon imaging (950 nm), Rose Bengal is injected into the blood stream. The scanning wavelength is changed to 720 nm and photothrombosis was induced by scanning the target vessel.ResultsTwo-photon depth-targeted single vessel photothrombosis was achieved with a success rate of 84.9±1.7% within 80 s. Attempts without Rose Bengal (i.e., only with FITC) did not result in photothrombosis at the excitation wavelength of 720 nm.ConclusionsWe described a protocol that achieves depth-targeted single vessel photothrombosis by two-photon excitation. Simultaneous imaging of blood flow in the targeted vessel using FITC dextran enabled the confirmation of vessel occlusion and prevention of excess irradiation that possibly induces unintended photodamage.

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Section: Discussionmentioning

confidence: 99%

Depth-targeted intracortical microstroke by two-photon photothrombosis in rodent brain

Fukuda

Suda

Matsumura

et al. 2021

Preprint

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“…These micro-infarcts occur at a scale where in-vivo detection is challenging and therefore computer simulation is important in assessing these effects. It has previously been shown in-silico that the severity of micro-strokes in mice is strongly linked to vascular topology (Schmid et al, 2021 ) and therefore this simulation quantifies increased vulnerability to micro-stroke introduced through the natural ageing process.…”

Section: Methodsmentioning

confidence: 99%

The Ageing Brain: Investigating the Role of Age in Changes to the Human Cerebral Microvasculature With an in silico Model

Graff

Payne

El-Bouri

2021

Front. Aging Neurosci.

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Ageing causes extensive structural changes to the human cerebral microvasculature, which have a significant effect on capillary bed perfusion and oxygen transport. Current models of brain capillary networks in the literature focus on healthy adult brains and do not capture the effects of ageing, which is critical when studying neurodegenerative diseases. This study builds upon a statistically accurate model of the human cerebral microvasculature based on ex-vivo morphological data. This model is adapted for “healthy” ageing using in-vivo measurements from mice at three distinct age groups—young, middle-aged, and old. From this new model, blood and molecular exchange parameters are calculated such as permeability and surface-area-to-volume ratio, and compared across the three age groups. The ability to alter the model vessel-by-vessel is used to create a continuous gradient of ageing. It was found that surface-area-to-volume ratio reduced in old age by 6% and permeability by 24% from middle-age to old age, and variability within the networks also increased with age. The ageing gradient indicated a threshold in the ageing process around 75 years old, after which small changes have an amplified effect on blood flow properties. This gradient enables comparison of studies measuring cerebral properties at discrete points in time. The response of middle aged and old aged capillary beds to micro-emboli showed a lower robustness of the old age capillary bed to vessel occlusion. As the brain ages, there is thus increased vulnerability of the microvasculature—with a “tipping point” beyond which further remodeling of the microvasculature has exaggerated effects on the brain. When developing in-silico models of the brain, age is a very important consideration to accurately assess risk factors for cognitive decline and isolate early biomarkers of microvascular health.

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“…To this end, numerical models have recently been developed to aid in understanding the structure of cerebral microvasculature [26][27][28][29][30][31][32][33][34][35], and the effects of micro-occlusions on blood flow [35][36][37][38] and oxygen transport [39,40]. In our previous work, we simulated the oxygen transport in cerebral capillary cubes using the Green's function method [32] and quantified the tissue hypoxia responding to different level of micro-occlusions [40].…”

Section: Introductionmentioning

confidence: 99%

Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees

et al. 2022

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The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 μm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green’s function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli.

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The severity of microstrokes depends on local vascular topology and baseline perfusion

Cited by 24 publications

References 63 publications

Depth-targeted intracortical microstroke by two-photon photothrombosis in rodent brain

Depth-targeted intracortical microstroke by two-photon photothrombosis in rodent brain

The Ageing Brain: Investigating the Role of Age in Changes to the Human Cerebral Microvasculature With an in silico Model

Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees

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