Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice

Author:

Wu Limin1,Chan Suk-Tak2,Edmiston William J1,Jin Gina1,Levy Emily S1,Kwong Kenneth K2,Mannix Rebekah3,Meehan William P34,Chifamba Fortunate F5,Lipton Jonathan O56,Whalen Michael J1,Chen Yin-Ching I2

Affiliation:

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

2. Department of Radiology, A. Martino's Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

3. Department of Emergency Medicine, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

4. Department of Orthopedics, Division of Sports Medicine, Boston, MA, USA

5. Department of Neurology, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

6. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

Abstract

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO2 challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity, and an impaired respiratory rate response to CO2 challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO2 brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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