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Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury

  • Cortical Spreading Depolarization
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Abstract

Background

Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI.

Methods

Adult male C57Bl/6J mice (8–14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests.

Results

CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10−7 CHI without CSD [CSD−] vs. 1.17 ± 0.04 × 10−7 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD− (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1–2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD− mice (n = 11 CHI CSD−).

Conclusions

The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

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Data Availability

The data of this study are available from the corresponding author on request.

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Funding

This work was funded by the National Institutes of Health (R25NS065743, KL2TR002542, and K08NS112601 to DYC; R01GM116177 and R21EB028626 to MAF; R01NS096550 and R01NS121792 to MJW), the American Heart Association and American Stroke Association (18POST34030369 to DYC), the Andrew David Heitman Foundation (DYC), the Aneurysm and AVM Foundation (DYC), and the Brain Aneurysm Foundation’s Timothy P. Susco and Andrew David Heitman Foundation Chairs of Research (DYC).

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Authors and Affiliations

  1. Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Nathaniel Mosley, Joon Y. Chung, Gina Jin & Michael J. Whalen

  2. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Maria A. Franceschini

  3. Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Charlestown, MA, 02129, USA

    David Y. Chung

  4. Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA

    David Y. Chung

Authors
  1. Nathaniel Mosley
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  2. Joon Y. Chung
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  3. Gina Jin
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  4. Maria A. Franceschini
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  5. Michael J. Whalen
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  6. David Y. Chung
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Contributions

NM, MJW, and DYC conceptualized and designed the study. NM, JYC, GJ, MJW, and DYC collected the data. NM, MJW, and DYC performed statistical analysis. NM, MJW, and DYC made the figures. NM prepared the first draft of the manuscript. MAF, MJW, and DYC made substantial revisions to the article. All authors gave approval of the final manuscript.

Corresponding author

Correspondence to David Y. Chung.

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Conflicts of Interest

MAF has a financial interest in 149 Medical, Inc., a company developing DCS technology for assessing and monitoring cerebral blood flow in newborn infants. MAF’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. The remaining authors state no conflict of interests.

Ethical Approval/Informed Consent

Ethical approvals through the Institutional Animal Care and Use Committee (IACUC) for animal studies were obtained as stated in the article.

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Mosley, N., Chung, J.Y., Jin, G. et al. Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury. Neurocrit Care 37 (Suppl 1), 102–111 (2022). https://doi.org/10.1007/s12028-022-01474-7

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  • DOI: https://doi.org/10.1007/s12028-022-01474-7

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