Quantitative estimates of stimulation-induced perfusion response using two-photon fluorescence microscopy of cortical microvascular networks

Chinta, Lakshminarayan V.; Lindvere, Liis; Dorr, Adrienne; Sahota, Bhupinder; Sled, John G.; Stefanović, Bojana

doi:10.1016/j.neuroimage.2012.04.009

Cited by 15 publications

(14 citation statements)

References 39 publications

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“…Our estimations of MTT during resting state were 0.81 AE 0.27 s, much faster than 1.6 AE 0.3 to 2.8 AE 0.2 s, as shown previously. [16][17][18]30 This distinction might result from potential differences between species, as most of the previous measurements were performed in rats. 31 However, we need to note that previous data showed no difference in capillary hemodynamics between species.…”

Section: Discussionmentioning

confidence: 99%

“…15 Bolus tracking techniques have previously been used to estimate MTT in the microvasculature, based on high spatial resolution two-photon microscopy (TPM) data acquired during the passage of a fluorescent dye. [16][17][18] In those studies, MTT was estimated from the time difference between the arterial CTC and the venous CTC (referred to as the venous output function (VOF)) during hypercapnia 16 and functional activation. 17 As an alternative approach, time to peak (TTP) was determined across the vasculature by fitting vessel's CTC to a second-order-plus-dead-time model (SOPDT).…”

Section: Introductionmentioning

confidence: 99%

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Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH)

Gutiérrez‐Jiménez

Cai

Mikkelsen

et al. 2016

J Cereb Blood Flow Metab

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Functional hyperemia reduces oxygen extraction efficacy unless counteracted by a reduction of capillary transit-time heterogeneity of blood. We adapted a bolus tracking approach to capillary transit-time heterogeneity estimation for two-photon microscopy and then quantified changes in plasma mean transit time and capillary transit-time heterogeneity during forepaw stimulation in anesthetized mice (C57BL/6NTac). In addition, we analyzed transit time coefficient of variance = capillary transit-time heterogeneity/mean transit time, which we expect to remain constant in passive, compliant microvascular networks. Electrical forepaw stimulation reduced, both mean transit time (11.3% ± 1.3%) and capillary transit-time heterogeneity (24.1% ± 3.3%), consistent with earlier literature and model predictions. We observed a coefficient of variance reduction (14.3% ± 3.5%) during functional activation, especially for the arteriolar-to-venular passage. Such coefficient of variance reduction during functional activation suggests homogenization of capillary flows beyond that expected as a passive response to increased blood flow by other stimuli. This finding is consistent with an active neurocapillary coupling mechanism, for example via pericyte dilation. Mean transit time and capillary transit-time heterogeneity reductions were consistent with the relative change inferred from capillary hemodynamics (cell velocity and flux). Our findings support the important role of capillary transit-time heterogeneity in flow-metabolism coupling during functional activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH)

Gutiérrez‐Jiménez

Cai

Mikkelsen

et al. 2016

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…The signal peaked first in the artery, then in capillaries, and lastly in the veins (Figure 3 lateral FOV and limited light penetration depth relative to the extent of mouse cortical cerebrovascular network, it is frequently not possible to ascertain whether a given pair of vessels are closely connected, precluding assessment of the effects of the vessel's branching order on the transit time. 86 Flow was estimated by inverse slope of Deming regression to hypercapnic versus normocapnic TTP data across all vessels (since no vesseltype effects were found), as shown in Figure 4. (Deming regression 87 minimizes the sum of distances in both the x and y, appropriate presently in light of errors on TTP estimates both during air breathing and during hypercapnia.)…”

Section: Attenuation Of Blood Flow Response To Hypercapnia After Volumentioning

confidence: 99%

Effects of voluntary exercise on structure and function of cortical microvasculature

Dorr

Thomason

Koletar

et al. 2016

J Cereb Blood Flow Metab

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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% FiCO 2 ) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO 2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p ¼ 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p ¼ 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 CO 2 elevation.

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“…mean) (Chinta et al, 2012;Lindvere et al, 2013, Yang, 2013Handfield et al, 2015). mean) (Chinta et al, 2012;Lindvere et al, 2013, Yang, 2013Handfield et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…The application of more detailed statistical models to quantitative immunofluorescence data may provide more powerful and accurate characterisation of the effects of interventions compared to the more commonly used analysis of point estimates of central tendency (e.g. mean) (Chinta et al, 2012;Lindvere et al, 2013, Yang, 2013Handfield et al, 2015). An underutilised feature of immunofluorescence microscopy data is that the experimental designs used naturally generate hierarchical data that can be leveraged to improve statistical analysis (Park et al, 2013;Vallmitjana et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Biostatistical analysis of quantitative immunofluorescence microscopy images

Giles

Albrecht

Lam

et al. 2016

Journal of Microscopy

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Semiquantitative immunofluorescence microscopy has become a key methodology in biomedical research. Typical statistical workflows are considered in the context of avoiding pseudo-replication and marginalising experimental error. However, immunofluorescence microscopy naturally generates hierarchically structured data that can be leveraged to improve statistical power and enrich biological interpretation. Herein, we describe a robust distribution fitting procedure and compare several statistical tests, outlining their potential advantages/disadvantages in the context of biological interpretation. Further, we describe tractable procedures for power analysis that incorporates the underlying distribution, sample size and number of images captured per sample. The procedures outlined have significant potential for increasing understanding of biological processes and decreasing both ethical and financial burden through experimental optimization.

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Quantitative estimates of stimulation-induced perfusion response using two-photon fluorescence microscopy of cortical microvascular networks

Cited by 15 publications

References 39 publications

Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH)

Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH)

Effects of voluntary exercise on structure and function of cortical microvasculature

Biostatistical analysis of quantitative immunofluorescence microscopy images

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