Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

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Abstract

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.

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Most cited references 42

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Functional ultrasound imaging of the brain.

Gabriel Montaldo, Michel Baulac, Mathias Fink … (2011)

We present functional ultrasound (fUS), a method for imaging transient changes in blood volume in the whole brain at better spatiotemporal resolution than with other functional brain imaging modalities. fUS uses plane-wave illumination at high frame rate and can measure blood volumes in smaller vessels than previous ultrasound methods. fUS identifies regions of brain activation and was used to image whisker-evoked cortical and thalamic responses and the propagation of epileptiform seizures in the rat brain.

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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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A method for dynamic, high-resolution cerebral blood flow (CBF) imaging is presented in this article. By illuminating the cortex with laser light and imaging the resulting speckle pattern, relative CBF images with tens of microns spatial and millisecond temporal resolution are obtained. The regional CBF changes measured with the speckle technique are validated through direct comparison with conventional laser-Doppler measurements. Using this method, dynamic images of the relative CBF changes during focal cerebral ischemia and cortical spreading depression were obtained along with electrophysiologic recordings. Upon middle cerebral artery (MCA) occlusion, the speckle technique yielded high-resolution images of the residual CBF gradient encompassing the ischemic core, penumbra, oligemic, and normally perfused tissues over a 6 x 4 mm cortical area. Successive speckle images demonstrated a further decrease in residual CBF indicating an expansion of the ischemic zone with finely delineated borders. Dynamic CBF images during cortical spreading depression revealed a 2 to 3 mm area of increased CBF (160% to 250%) that propagated with a velocity of 2 to 3 mm/min. This technique is easy to implement and can be used to monitor the spatial and temporal evolution of CBF changes with high resolution in studies of cerebral pathophysiology.

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Author and article information

Contributors

Irene Georgakoudi: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 7 August 2013

Volume: 8

Issue: 8

Electronic Location Identifier: e71478

Affiliations

[1 ]Biomedical Engineering Department, University of California Davis, Davis, California, United States of America

[2 ]Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America

[3 ]Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America

[4 ]Division of Drug Discovery Research, Korea Research Institute of Chemical technology, Yuseonggu, Daejeon, Korea

[5 ]Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America

[6 ]Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America

Tufts University, United States of America

Author notes

* E-mail: vjsriniv@ 123456ucdavis.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: VJS ETM EHL SS KEH CA. Performed the experiments: VJS ETM MC AD HR KEH. Analyzed the data: VJS AC FB MC AD JHL EY HR. Contributed reagents/materials/analysis tools: VJS ETM AC FB MC AD JHL EY EHL KEH CA. Wrote the paper: VJS HR EHL SS KEH CA.

Article

Publisher ID: PONE-D-13-06087

DOI: 10.1371/journal.pone.0071478

PMC ID: 3737090

PubMed ID: 23940761

SO-VID: 3a26978e-7797-4e46-ba88-9c3116c2f412

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 February 2013

Date accepted : 28 June 2013

Page count

Pages: 14

Funding

The authors acknowledge support from the National Institutes of Health (R00NS067050, NS055104, EB001954 R01), the American Heart Association (IRG5440002, SDG7600037, SDG2610275), and the Glaucoma Research Foundation Catalyst for a Cure 2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

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Abstract

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Most cited references 42

Functional ultrasound imaging of the brain.

Viability thresholds and the penumbra of focal ischemia.

Dynamic imaging of cerebral blood flow using laser speckle.

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