Emerging data suggest that pediatric traumatic brain injury (TBI) is associated with impaired developmental plasticity and poorer neuropsychological outcomes than adults with similar head injuries. Unlike adult mild TBI (mTBI), the effects of mTBI on white matter (WM) microstructure and vascular supply are not well understood in the pediatric population. The cerebral vasculature plays an important role providing necessary nutrients and removing waste. To address this critical element, we examined the microstructure of the corpus callosum (CC) following pediatric mTBI using diffusion tensor magnetic resonance imaging (DTI), and investigated myelin, oligodendrocytes, and vasculature of WM with immunohistochemistry (IHC). We hypothesized that pediatric mTBI leads to abnormal WM microstructure and impacts the vasculature within the CC, and that these alterations to WM vasculature contribute to the long-term altered microstructure. We induced in mice a closed-head injury (CHI) mTBI at post-natal day (P) 14; then at 4, 14, and 60 days post-injury (DPI) mice were sacrificed for analysis. We observed persistent changes in apparent diffusion coefficient (ADC) within the ipsilateral CC following mTBI, indicating microstructural changes, but surprisingly changes in myelin and oligodendrocyte densities were minimal. However, vascular features of the ipsilateral CC such as vessel density, length, and number of junctions were persistently altered following mTBI. Correlative analysis showed a strong inverse relationship between ADC and vessel density at 60 DPI, suggesting increased vessel density following mTBI may restrict WM diffusion characteristics. Our findings suggest that WM vasculature contributes to the long-term microstructural changes within the ipsilateral CC following mTBI.
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References
1.
FaulM., WaldM.M., XuL., and CoronadoV.G. (2010). Traumatic brain injury in the United States; emergency department visits, hospitalizations, and deaths, 2002–2006. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Injury Prevention and Control: Atlanta, GA.
2.
National Center for Injury Prevention and Control. (2003). Report to Congress on mild traumatic brain injury in the United States: steps to prevent a serious public health problem. Centers for Disease Control and Prevention: Atlanta, GA.
3.
MannixR., O'BrienM.J., and MeehanW.P.3rd. (2013). The epidemiology of outpatient visits for minor head injury: 2005 to 2009. Neurosurgery, 73, 129–134; discussion 134.
4.
Centers for Disease Control and Prevention (2016). Report from the Pediatric Mild Traumatic Brain Injury Guideline Workgroup: Systematic Review and Clinical Recommendations for Healthcare Providers on the Diagnosis and Management of Mild Traumatic Brain Injury Among Children. Atlanta, GA.
5.
HessenE., NestvoldK., and AndersonV. (2007). Neuropsychological function 23 years after mild traumatic brain injury: a comparison of outcome after paediatric and adult head injuries. Brain Inj. 21, 963–979.
6.
GizaC.C., and PrinsM.L. (2006). Is being plastic fantastic? Mechanisms of altered plasticity after developmental traumatic brain injury. Dev. Neurosci., 28, 364–379.
7.
GizaC.C., MinkR.B., and MadikiansA. (2007). Pediatric traumatic brain injury: not just little adults. Curr. Opin. Crit. Care, 13, 143–152.
8.
GencS., AndersonV., RyanN.P., MalpasC.B., CatroppaC., BeauchampM.H., and SilkT.J. (2017). Recovery of white matter following pediatric traumatic brain injury depends on injury severity. J. Neurotrauma, 34, 798–806.
9.
UdomphornY., ArmsteadW.M., and VavilalaM.S. (2008). Cerebral blood flow and autoregulation after pediatric traumatic brain injury. Pediatr. Neurol., 38, 225–234.
10.
StammJ.M., KoerteI.K., MuehlmannM., PasternakO., BourlasA.P., BaughC.M., GiwercM.Y., ZhuA., ColemanM.J., BouixS., FrittsN.G., MartinB.M., ChaissonC., McCleanM.D., LinA.P., CantuR.C., TripodisY., SternR.A., and ShentonM.E. (2015). Age at first exposure to football is associated with altered corpus callosum white matter microstructure in former professional football players. J. Neurotrauma, 32, 1768–1776.
11.
KonigsM., PouwelsP.J., Ernest van HeurnL.W., BakxR., Jeroen VermeulenR., Carel GoslingsJ., Poll-TheB.T., van der WeesM., Catsman-BerrevoetsC.E., and OosterlaanJ. (2017). Relevance of neuroimaging for neurocognitive and behavioral outcome after pediatric traumatic brain injury. Brain Imaging Behav. 12, 29–43.
12.
AjaoD.O., PopV., KamperJ.E., AdamiA., RudobeckE., HuangL., VlkolinskyR., HartmanR.E., AshwalS., ObenausA., and BadautJ. (2012). Traumatic brain injury in young rats leads to progressive behavioral deficits coincident with altered tissue properties in adulthood. J. Neurotrauma, 29, 2060–2074.
13.
DennisE.L., EllisM.U., MarionS.D., JinY., MoranL., OlsenA., KernanC., BabikianT., MinkR., BabbittC., JohnsonJ., GizaC.C., ThompsonP.M., and AsarnowR.F. (2015). Callosal function in pediatric traumatic brain injury linked to disrupted white matter integrity. J. Neurosci., 35, 10202–10211.
14.
ReevesT.M., PhillipsL.L., and PovlishockJ.T. (2005). Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury. Exp. Neurol., 196, 126–137.
15.
ArmstrongR.C., MierzwaA.J., MarionC.M., and SullivanG.M. (2016). White matter involvement after TBI: clues to axon and myelin repair capacity. Exp. Neurol., 275, Pt. 3:328–333.
16.
MillerD.J., DukaT., StimpsonC.D., SchapiroS.J., BazeW.B., McArthurM.J., FobbsA.J., SousaA.M., SestanN., WildmanD.E., LipovichL., KuzawaC.W., HofP.R., and SherwoodC.C. (2012). Prolonged myelination in human neocortical evolution. Proc. Natl. Acad. Sci. U S A, 109, 16480–16485.
17.
PujolJ., VendrellP., JunqueC., Marti-VilaltaJ.L., and CapdevilaA. (1993). When does human brain development end? Evidence of corpus callosum growth up to adulthood. Ann. Neurol., 34, 71–75.
18.
SempleB.D., BlomgrenK., GimlinK., FerrieroD.M., and Noble-HaeussleinL.J. (2013). Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog. Neurobiol., 106, 1–16.
19.
IchkovaA., Rodriguez-GrandeB., BarC., VillegaF., KonsmanJ.P., and BadautJ. (2017). Vascular impairment as a pathological mechanism underlying long-lasting cognitive dysfunction after pediatric traumatic brain injury. Neurochem. Int., 111, 93–102.
20.
VavilalaM.S., LeeL.A., BodduK., ViscoE., NewellD.W., ZimmermanJ.J., and LamA.M. (2004). Cerebral autoregulation in pediatric traumatic brain injury. Pediatr. Crit. Care Med., 5, 257–263.
21.
PopV., and BadautJ. (2011). A neurovascular perspective for long-term changes after brain trauma. Transl. Stroke Res., 2, 533–545.
22.
MuramatsuK., FukudaA., TogariH., WadaY., and NishinoH. (1997). Vulnerability to cerebral hypoxic-ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood-brain barrier. Stroke, 28, 2281–2288; discussion 2288–2289.
23.
AffeldtB.M., ObenausA., ChanJ., and PardoA.C. (2017). Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury. Int. J. Dev. Neurosci., 61, 1–11.
24.
KimE.J., LeungC.T., ReedR.R., and JohnsonJ.E. (2007). In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J. Neurosci., 27, 12764–12774.
25.
JiangH., van ZijlP.C., KimJ., PearlsonG.D., and MoriS. (2006). DtiStudio: resource program for diffusion tensor computation and fiber bundle tracking. Comput. Methods Programs Biomed., 81, 106–116.
26.
SongS.K., SunS.W., JuW.K., LinS.J., CrossA.H., and NeufeldA.H. (2003). Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage, 20, 1714–1722.
27.
ObenausA., and JacobsR.E. (2007). Magnetic resonance imaging of functional anatomy: use for small animal epilepsy models. Epilepsia, 48, Suppl. 4, 11–17.
28.
SalehiA., JullienneA., BaghchechiM., HamerM., WalsworthM., DonovanV., TangJ., ZhangJ.H., PearceW.J., and ObenausA. (2017). Up-regulation of Wnt/beta-catenin expression is accompanied with vascular repair after traumatic brain injury. J. Cereb. Blood Flow Metab., 38, 274–289.
29.
ObenausA., NgM., OrantesA.M., Kinney-LangE., RashidF., HamerM., DeFazioR.A., TangJ., ZhangJ.H., and PearceW.J. (2017). Traumatic brain injury results in acute rarefication of the vascular network. Sci. Rep., 7, 239.
30.
SchneiderC.A., RasbandW.S., and EliceiriK.W. (2012). NIH Image to ImageJ: 25 years of image analysis. Nat. Methods, 9, 671–675.
31.
ZudaireE., GambardellaL., KurczC., and VermerenS. (2011). A computational tool for quantitative analysis of vascular networks. PLoS One, 6, e27385.
32.
BernklauI., LucasL., JekleM., and BeckerT. (2016). Protein network analysis—a new approach for quantifying wheat dough microstructure. Food Res. Int., 89, 812–819.
33.
GambardellaL., ZudaireE., and VermerenS. (2012). Quantitative analysis of angiogenesis in the allantois explant model, in: The Textbook of Angiogenesis and Lymphangiogenesis: Methods and Applications. Springer, pps. 189–204.
34.
WessaP. (2017). Bagplot (v1.0.3) in Free Statistics Software (v1.2.1). Office for Research Development and Education. Available at: https://www.wessa.net/rwasp_bagplot.wasp/. Accessed June28, 2017.
35.
KreisT., and ValeR. (eds). (1999). Guidebook to the Extracellular Matrix, Anchor, and Adhesion Proteins. Sambrook and Tooze Publishing Partnership; Oxford University Press: New York.
KimuraM., SatoM., AkatsukaA., Nozawa-KimuraS., TakahashiR., YokoyamaM., NomuraT., and KatsukiM. (1989). Restoration of myelin formation by a single type of myelin basic protein in transgenic shiverer mice. Proc. Natl. Acad. Sci., 86, 5661–5665.
38.
BockhorstK.H., NarayanaP.A., LiuR., Ahobila-VijjulaP., RamuJ., KamelM., WosikJ., BockhorstT., HahnK., HasanK.M., and Perez-PoloJ.R. (2008). Early postnatal development of rat brain: in vivo diffusion tensor imaging. J. Neurosci. Res., 86, 1520–1528.
39.
LiN., YangY., GloverD.P., ZhangJ., SaraswatiM., RobertsonC., and PelledG. (2014). Evidence for impaired plasticity after traumatic brain injury in the developing brain. J. Neurotrauma, 31, 395–403.
40.
LongJ.A., WattsL.T., ChemelloJ., HuangS., ShenQ., and DuongT.Q. (2015). Multiparametric and longitudinal MRI characterization of mild traumatic brain injury in rats. J. Neurotrauma, 32, 598–607.
41.
AkiyamaK., IchinoseS., OmoriA., SakuraiY., and AsouH. (2002). Study of expression of myelin basic proteins (MBPs) in developing rat brain using a novel antibody reacting with four major isoforms of MBP. J. Neurosci. Res., 68, 19–28.
42.
SempleB.D., CarlsonJ., and Noble-haeussleinL.J. (2016). Chapter 18; Pediatric rodent models of traumatic brain injury, in: Injury Models of the Central Nervous System. KobeissyF.H., DixonC.E., HayesR>L., and MondelloS. (eds). Humana Press, pps. 325–344.
43.
Ewing-CobbsL., PrasadM.R., SwankP., KramerL., CoxC.S.Jr., FletcherJ.M., BarnesM., ZhangX., and HasanK.M. (2008). Arrested development and disrupted callosal microstructure following pediatric traumatic brain injury: relation to neurobehavioral outcomes. Neuroimage, 42, 1305–1315.
44.
RosenbluthJ. (1966). Redundant myelin sheaths and other ultrastructural features of the toad cerebellum. J. Cell Biol., 28, 73–93.
45.
ArmstrongR.C., MierzwaA.J., SullivanG.M., and SanchezM.A. (2016). Myelin and oligodendrocyte lineage cells in white matter pathology and plasticity after traumatic brain injury. Neuropharmacology, 110, 654–659.
46.
MierzwaA.J., MarionC.M., SullivanG.M., McDanielD.P., and ArmstrongR.C. (2015). Components of myelin damage and repair in the progression of white matter pathology after mild traumatic brain injury. J. Neuropathol. Exp. Neurol., 74, 218–232.
47.
FavraisG., van de LooijY., FleissB., RamanantsoaN., BonninP., Stoltenburg-DidingerG., LacaudA., SalibaE., DammannO., GallegoJ., SizonenkoS., HagbergH., LelievreV., and GressensP. (2011). Systemic inflammation disrupts the developmental program of white matter. Ann. Neurol., 70, 550–565.
48.
PotenteM., GerhardtH., and CarmelietP. (2011). Basic and therapeutic aspects of angiogenesis. Cell, 146, 873–887.
49.
WalchliT., MateosJ.M., WeinmanO., BabicD., RegliL., HoerstrupS.P., GerhardtH., SchwabM.E., and VogelJ. (2015). Quantitative assessment of angiogenesis, perfused blood vessels and endothelial tip cells in the postnatal mouse brain. Nat. Protoc., 10, 53–74.
50.
FruttigerM. (2007). Development of the retinal vasculature. Angiogenesis, 10, 77–88.
51.
KornC., and AugustinH.G. (2015). Mechanisms of vessel pruning and regression. Dev. Cell, 34, 5–17.
52.
GiacominiA., AckermannM., BelleriM., ColtriniD., NicoB., RibattiD., KonerdingM.A., PrestaM., and RighiM. (2015). Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease. Angiogenesis, 18, 499–510.
53.
LumbrosoB., RispoliM., and SavastanoM.C. (2015). Longitudinal optical coherence tomography—angiography study of type 2 naive choroidal neovascularization early response after treatment. Retina, 35, 2242–2251.
54.
Bartnik-OlsonB.L., HolshouserB., WangH., GrubeM., TongK., WongV., and AshwalS. (2014). Impaired neurovascular unit function contributes to persistent symptoms after concussion: a pilot study. J. Neurotrauma, 31, 1497–1506.
55.
SadeghiN., D'HaeneN., DecaesteckerC., LevivierM., MetensT., MarisC., WiklerD., BaleriauxD., SalmonI., and GoldmanS. (2008). Apparent diffusion coefficient and cerebral blood volume in brain gliomas: relation to tumor cell density and tumor microvessel density based on stereotactic biopsies. AJNR Am. J. Neuroradiol., 29, 476–482.
56.
FischerI., GagnerJ.P., LawM., NewcombE.W., and ZagzagD. (2005). Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol. 15, 297–310.
57.
SongS.K., YoshinoJ., LeT.Q., LinS.J., SunS.W., CrossA.H., and ArmstrongR.C. (2005). Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage, 26, 132–140.
58.
SunS.W., LiangH.F., TrinkausK., CrossA.H., ArmstrongR.C., and SongS.K. (2006). Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magn. Reson. Med., 55, 302–308.
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