Restricted accessResearch articleFirst published online 2015-09
Experimental Traumatic Brain Injury Results in Long-Term Recovery of Functional Responsiveness in Sensory Cortex but Persisting Structural Changes and Sensorimotor,Cognitive,and Emotional Deficits
Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits.
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References
1.
ThompsonH.J., LifshitzJ., MarklundN., GradyM.S., GrahamD.I., HovdaD.A., and McIntoshT.K. (2005). Lateral fluid percussion brain injury: a 15-year review and evaluation. J. Neurotrauma, 22, 42–75.
2.
MaselB.E., and DeWittD.S. (2010). Traumatic brain injury: a disease process, not an event. J. Neurotrauma, 27, 1529–1540.
3.
MarklundN., and HilleredL. (2011). Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here?. Br. J. Pharmacol., 164, 1207–1229.
4.
GalvinJ., FroudeE.H., and ImmsC. (2009). Sensory processing abilities of children who have sustained traumatic brain injuries. Am. J. Occup. Ther., 63, 701–709.
5.
LewH.L., GarvertD.W., PogodaT.K., HsuP.T., DevineJ.M., WhiteD.K., MyersP.J., and GoodrichG.L. (2009). Auditory and visual impairments in patients with blast-related traumatic brain injury: effect of dual sensory impairment on functional independence measure. J. Rehabil. Res. Dev., 46, 819–826.
6.
JohnstoneV.P.A., YanE.B., AlwisD.S., and RajanR. (2013). Cortical hypoexcitation defines neuronal responses in the immediate aftermath of traumatic brain injury. PLoS One, 7, e63454.
7.
YanE., JohnstoneV., AlwisD., Morganti-KossmannM.C., and RajanR. (2013). Characterising the effects of impact velocity and animal biometrics on brain and behaviour in a model of diffuse traumatic axonal injury. Neuroscience, 2, 17–29.
8.
AlwisD., YanE.B., Morganti-KossmannM.C., and RajanR. (2012). Sensory cortex underpinnings of traumatic brain injury deficits. PLoS One, 7, e52169.
9.
GrahamD.I., RaghupathiR., SaatmanK.E., MeaneyD., and McIntoshT.K. (2000). Tissue tears in the white matter after lateral fluid percussion brain injury in the rat: relevance to human brain injury. Acta Neuropathol., 99, 117–124.
10.
ShultzS.R., CardamoneL., LiuY.R., HoganR.E., MaccottaL., WrightD.K., ZhengP., KoeA., GregoireM.C., WilliamsJ.P., HicksR.J., JonesN.C., MyersD.E., O'BrienT.J., and BouilleretV. (2013). Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?. Epilepsia, 54, 1240–1250.
11.
JohnstoneV., ShultzS., YanE., O'BrienT.J. and RajanR. (2014). The acute phase of mild traumatic brain injury is characterised by a distance-dependent neuronal hypoactivity. J. Neurotrauma, 31, 1881–1895.
12.
ShultzS.R., BaoF., OmanaV., ChiuC., BrownA., and CainD.P. (2012). Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. J. Neurotrauma, 29, 281–294.
13.
ShultzS.R., BaoF., WeaverL.C., CainD.P., and BrownA. (2013). Treatment with an anti-CD11d integrin antibody reduces neuroinflammation and improves outcome in a rat model of repeated concussion. J. Neuroinflammation, 10, 26.
14.
ShultzS.R., MacFabeD.F., FoleyK.A., TaylorR., and CainD.P. (2011). A single mild fluid percussion injury induces short-term behavioral and neuropathological changes in the Long-Evans rat: support for an animal model of concussion. Behav. Brain Res., 224, 326–335.
15.
ShultzS.R., MacFabeD.F., FoleyK.A., TaylorR., and CainD.P. (2012). Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments. Behav. Brain Res., 229, 145–152.
16.
BaoF., ShultzS.R., HepburnJ.D., OmanaV., WeaverL.C., CainD.P., and BrownA. (2012). A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats. J. Neurotrauma, 29, 2375–2392.
17.
WalfA.A., and FryeC.A. (2007). The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat. Protoc., 2, 322–328.
18.
JonesN.C., CardamoneL., WilliamsJ.P., SalzbergM.R., MyersD., and O'BrienT.J. (2008). Experimental traumatic brain injury induces a pervasive hyperanxious phenotype in rats. J. Neurotrauma, 25, 1367–1374.
19.
HennigJ., NauerthA., and FriedburgH. (1986). RARE imaging: a fast imaging method for clinical MR. Magn. Reson. Med., 3, 823–833.
20.
StejskalE.O., and TannerJ.E. (1965). Spin diffusion measurements: spin echoes in the presence of a time-dependent field gradient. J. Chem. Phys., 42, 288–292.
21.
ShultzS.R., TanX.L., WrightD.K., LiuS.J., SempleB.D., JohnstonL., JonesN.C., CookA.D., HamiltonJ.A., and O'BrienT.J. (2014). Granulocyte-macrophage colony-stimulating factor is neuroprotective in experimental traumatic brain injury. J. Neurotrauma, 31, 976–983.
22.
PaxinosG. and WatsonC. (2007). The rat brain in stereotaxic coordinates. Elsevier, Amsterdam, p.456.
23.
FarquharsonS., TournierJ.D., CalamanteF., FabinyiG., Schneider-KolskyM., JacksonG.D., and ConnellyA. (2013). White matter fiber tractography: why we need to move beyond DTI. J. Neurosurg., 118, 1367–1377.
24.
TournierJ.D., CalamanteF., and ConnellyA. (2013). Determination of the appropriate b value and number of gradient directions for high-angular-resolution diffusion-weighted imaging. NMR Biomed., 26, 1775–1786.
25.
RajanR., BourkeJ., and CassellJ. (2006). A novel stimulus system for applying tactile stimuli to the macrovibrissae in electrophysiological experiments. J. Neurosci. Methods, 157, 103–117.
26.
RajanR., BrowningA.S., and BourkeJ.L. (2007). Heterogeneity in the coding in rat barrel cortex of the velocity of protraction of the macrovibrissae. Eur. J. Neurosci., 25, 2383–2403.
27.
AlwisD.S., and RajanR. (2013). Environmental enrichment causes a global potentiation of neuronal responses across stimulus complexity and lamina of sensory cortex. Front. Cell. Neurosci., 7, 124.
28.
HartmannM.J., JohnsonN.J., TowalR.B., and AssadC. (2003). Mechanical characteristics of rat vibrissae: resonant frequencies and damping in isolated whiskers and in the awake behaving animal. J. Neurosci., 23, 6510–6519.
29.
RittJ.T., AndermannM.L., and MooreC.I. (2008). Embodied information processing: vibrissa mechanics and texture features shape micromotions in actively sensing rats. Neuron, 57, 599–613.
30.
GaoP., BermejoR., and ZeiglerH.P. (2001). Whisker deafferentation and rodent whisking patterns: behavioral evidence for a central pattern generator. J. Neurosci., 21, 5374–5380.
31.
VorheesC.V., and WilliamsM.T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc., 1, 848–858.
32.
ArabzadehE., PanzeriS., and DiamondM.E. (2004). Whisker vibration information carried by rat barrel cortex neurons. J. Neurosci., 24, 6011–6020.
33.
ArabzadehE., PetersenR.S., and DiamondM.E. (2003). Encoding of whisker vibration by rat barrel cortex neurons: implications for texture discrimination. J. Neurosci., 23, 9146–9154.
34.
PintoD.J., BrumbergJ.C., and SimonsD.J. (2000). Circuit dynamics and coding strategies in rodent somatosensory cortex. J. Neurophysiol., 83, 1158–1166.
35.
IwamotoY., YamakiT., MurakamiN., UmedaM., TanakaC., HiguchiT., AokiI., NaruseS., and UedaS. (1997). Investigation of morphological change of lateral and midline fluid percussion injury in rats, using magnetic resonance imaging. Neurosurgery, 40, 163–167.
36.
HylinM.J., OrsiS.A., ZhaoJ., BockhorstK., PerezA., MooreA.N., and DashP.K. (2013). Behavioral and histopathological alterations resulting from mild fluid percussion injury. J. Neurotrauma, 30, 702–715.
37.
HammR.J. (2001). Neurobehavioral assessment of outcome following traumatic brain injury in rats: an evaluation of selected measures. J. Neurotrauma, 18, 1207–1216.
38.
WashingtonP.M., ForcelliP.A., WilkinsT., ZappleD.N., ParsadanianM., and BurnsM.P. (2012). The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J. Neurotrauma, 29, 2283–2296.
39.
SchwarzboldM.L., RialD., De BemT., MachadoD.G., CunhaM.P., dos SantosA.A., dos SantosD.B., FigueiredoC.P., FarinaM., GoldfederE.M., RodriguesA.L., PredigerR.D., and WalzR. (2010). Effects of traumatic brain injury of different severities on emotional, cognitive, and oxidative stress-related parameters in mice. J. Neurotrauma, 27, 1883–1893.
40.
PandeyD.K., YadavS.K., MaheshR., and RajkumarR. (2009). Depression-like and anxiety-like behavioural aftermaths of impact accelerated traumatic brain injury in rats: a model of comorbid depression and anxiety?. Behav. Brain Res., 205, 436–442.
41.
GouldK.R., PonsfordJ.L., JohnstonL., and SchonbergerM. (2011). The nature, frequency and course of psychiatric disorders in the first year after traumatic brain injury: a prospective study. Psychol. Med., 41, 2099–2109.
42.
ArciniegasD.B., HeldK., and WagnerP. (2002). Cognitive impairment following traumatic brain injury. Curr. Treat. Options Neurol., 4, 43–57.
43.
LiuY.R., CardamoneL., HoganR.E., GregoireM.C., WilliamsJ.P., HicksR.J., BinnsD., KoeA., JonesN.C., MyersD.E., O'BrienT.J., and BouilleretV. (2010). Progressive metabolic and structural cerebral perturbations after traumatic brain injury: an in vivo imaging study in the rat. J. Nucl. Med., 51, 1788–1795.
44.
DavisA.S., and DeanR.S. (2010). Assessing sensory-motor deficits in pediatric traumatic brain injury. Appl. Neuropsychol., 17, 104–109.
45.
DebertC.T., HerterT.M., ScottS.H., and DukelowS. (2012). Robotic assessment of sensorimotor deficits after traumatic brain injury. J. Neurol. Phys. Ther., 36, 58–67.
MarkramH., Toledo-RodriguezM., WangY., GuptaA., SilberbergG., and WuC. (2004). Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci., 5, 793–807.
48.
SmithM.L., AuerR.N., and SiesjoB.K. (1984). The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol., 64, 319–332.
49.
YaghmaiA., and PovlishockJ. (1992). Traumatically induced reactive change as visualized through the use of monoclonal antibodies targeted to neurofilament subunits. J. Neuropathol. Exp. Neurol., 51, 158–176.
50.
DingG.L., ChoppM., PoulsenD.J., LiL., QuC., LiQ., Nejad-DavaraniS.P., BudajJ.S., WuH., MahmoodA., and JiangQ. (2013). MRI of neuronal recovery after low-dose methamphetamine treatment of traumatic brain injury in rats. PLoS One, 8, e61241.
51.
BuddeM.D., JanesL., GoldE., TurtzoL.C., and FrankJ.A. (2011). The contribution of gliosis to diffusion tensor anisotropy and tractography following traumatic brain injury: validation in the rat using Fourier analysis of stained tissue sections. Brain, 134, 2248–2260.
52.
DietrichW.D., AlonsoO., BustoR., and GinsbergM.D. (1994). Widespread metabolic depression and reduced somatosensory circuit activation following traumatic brain injury in rats. J. Neurotrauma, 11, 629–640.
53.
HarrisonT.C., SilasiG., BoydJ.D., and MurphyT.H. (2013). Displacement of sensory maps and disorganization of motor cortex after targeted stroke in mice. Stroke, 44, 2300–2306.
54.
CarmichaelS.T., and ChesseletM.F. (2002). Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J. Neurosci., 22, 6062–6070.
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