Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes

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Abstract

Ministrokes induce long-lasting neurovascular dissociations.

Abstract

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we use a multimodal neural platform in a mouse model of stroke and realize long-term, spatially resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions. We observe a pronounced neurovascular dissociation that occurs immediately after small-scale strokes, becomes the most severe a few days after, lasts into chronic periods, and varies with the level of ischemia. Neuronal deficits extend spatiotemporally, whereas restoration of cerebral blood flow occurs sooner and reaches a higher relative value. Our findings reveal the neurovascular impact of ministrokes and inform the limitation of neuroimaging techniques that infer neural activity from hemodynamic responses.

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Most cited references 47

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Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

Hélène Girouard, Costantino Iadecola (2006)

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.

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Induction of reproducible brain infarction by photochemically initiated thrombosis.

B D Watson, W Dietrich, R Busto … (1985)

We have used a photochemical reaction in vivo to induce reproducible thrombosis leading to cerebral infarction in rats. After the intravenous injection of rose bengal, a potent photosensitizing dye, an ischemic lesion was formed by irradiating the left parietal convexity of the exposed skull for 20 minutes with green light (560 nm) from a filtered xenon arc lamp. Animals were allowed to survive from 30 minutes to 15 days after irradiation. Early microscopic alterations within the irradiated zone included the formation of thrombotic plugs and adjacent red blood cell stasis within pial and parenchymal vessels. Scanning electron microscopy revealed frequent platelet aggregates adhering to the vascular endothelium, often resulting in vascular occlusion. Carbon-black brain perfusion demonstrated that occlusion of vascular channels progressed after irradiation and was complete within 4 hours. Histopathological examination at 1, 5, and 15 days revealed that the associated infarct evolved reproducibly through several characteristic stages, including a phase of massive macrophage infiltration. Although cerebral infarction in this model is initiated by thrombosis of small blood vessels, the fact that the main pathological features of stroke are consistently reproduced should permit its use in assessing treatment regimens. Further, the capability of producing infarction in preselected cortical regions may facilitate the study of behavioral, functional, and structural consequences of acute and chronic stroke.

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Viability thresholds and the penumbra of focal ischemia.

K Hossmann (1994)

The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought to suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolarization (< 0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: May 2020

Publication date (Electronic): 22 May 2020

Volume: 6

Issue: 21

Electronic Location Identifier: eaba1933

Affiliations

[1 ]Department of Electrical and Computer Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

[2 ]Neuroengineering Initiative, Rice University, 6500 Main Street, Houston, TX 77005, USA.

[3 ]Department of Biomedical Engineering, The University of Texas at Austin, 107 E. Dean Keeton Street, 1 University Station, C0800, Austin, TX 78712, USA.

[4 ]Institute for Neuroscience, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712, USA.

[5 ]Department of Psychology, The University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, SEA 6.106, Austin, TX 78712, USA.

[6 ]Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

Author notes

[* ]Corresponding author. Email: lan.luan@ 123456rice.edu

Author information

Fei He http://orcid.org/0000-0002-6009-8957

Colin T. Sullender http://orcid.org/0000-0003-4329-7708

Michael R. Williamson http://orcid.org/0000-0002-8049-4463

Theresa A. Jones http://orcid.org/0000-0003-2854-8003

Chong Xie http://orcid.org/0000-0002-5544-2864

Lan Luan http://orcid.org/0000-0002-5327-2240

Article

Publisher ID: aba1933

DOI: 10.1126/sciadv.aba1933

PMC ID: 7244270

PubMed ID: 32494746

SO-VID: 7bc13bd1-3888-4b61-a11a-e33c5f1f7f47

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 12 November 2019

Date accepted : 10 March 2020

Funding

Funded by: doi http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: K25HL140153

Funded by: doi http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R01NS109361

Funded by: doi http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R01NS102917

Funded by: doi http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R37NS056839

Funded by: doi http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R01NS082518

Funded by: doi http://dx.doi.org/10.13039/100000928, Welch Foundation;

Award ID: F-1941-2017035

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Copyeditor Karla Peñamante

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Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes

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Most cited references 47

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

Induction of reproducible brain infarction by photochemically initiated thrombosis.

Viability thresholds and the penumbra of focal ischemia.

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