The objective of the study was to investigate degenerative changes of white matter volume (WMV) and gray matter volume (GMV) in individuals after a spinal cord injury (SCI). Published studies of whole-brain voxel-based morphometry (VBM) published between January 1, 2006 and March 1, 2018 comparing SCI patients with controls were collected by searching PubMed, Web of Science, and EMBASE databases. Voxel-wise meta-analyses of GMV and WMV differences between SCI patients and controls were performed separately using seed-based d mapping. Twelve studies with 12 GMV data sets and 9 WMV data sets yielded a total of 466 individuals (190 SCI patients and 276 controls) who were included in this meta-analysis. Compared with controls, SCI patients showed GMV atrophy in sensorimotor system regions including the bilateral sensorimotor cortex (S1 and M1), the supplementary motor area (SMA), paracentral gyrus, thalamus, and basal ganglia, as well as WMV loss in the corticospinal tract.GMV aberrancies were also demonstrated in brain regions responsible for cognition and emotion, such as the orbitofrontal cortex (OFC) and the left insula. Additionally, GMV in both the bilateral S1 and the left SMA was positively correlated with the time span after the injury.
In conclusion, anatomical atrophy in cortical-thalamic-spinal pathways suggested that SCIs may result in degenerative changes of the sensorimotor system. Further, OFC and insula GMV abnormalities may explain symptoms such as neuropathic pain and potential cognitive-emotional impairments in chronic SCI patients. These findings indicate that anatomical brain magnetic resonance imaging (MRI) protocols could be neuroimaging biomarkers for interventional studies and treatments.
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References
1.
AlilainW.J., HornK.P., HuH., DickT.E., and SilverJ. (2011). Functional regeneration of respiratory pathways after spinal cord injury. Nature, 475, 196–200.
2.
CristanteA.F., de Barros FilhoT.E.P., MarconR.M., LetaifO.B., and da RochaI.D. (2012). Therapeutic approaches for spinal cord injury. Clinics, 67, 1219–1224.
3.
BayonaN.A., BitenskyJ., and TeasellR. (2005). Plasticity and reorganization of the uninjured brain. Top. Stroke Rehabil. 12, 1–10.
4.
BisbyM.A. (1981). Axonal transport in the central axon of sensory neurons during regeneration of their peripheral axon. Neurosci. Lett. 21, 7–11.
5.
HainsB.C., BlackJ.A., and WaxmanS.G. (2003). Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J. Comp. Neurol. 462, 328–341.
6.
KimB.G., DaiH.N., McAteeM., ViciniS., and BregmanB.S. (2006). Remodeling of synaptic structures in the motor cortex following spinal cord injury. Exp. Neurol. 198, 401–415.
7.
KaasJ.H., QiH.X., BurishM.J., GharbawieO.A., OniferS.M., and MasseyJ.M. (2008). Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord. Exp. Neurol. 209, 407–416.
8.
KambiN., HalderP., RajanR., AroraV., ChandP., AroraM. and JainN. (2014). Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity. Nat. Commun. 5, 3602.
9.
KambiN., TandonS., MohammedH., LazarL., and JainN. (2011). Reorganization of the primary motor cortex of adult macaque monkeys after sensory loss resulting from partial spinal cord injuries. J. Neurosci. 31, 3696–3707.
10.
DietzV., and FouadK. (2014). Restoration of sensorimotor functions after spinal cord injury. Brain, 137, 654–667.
11.
AshburnerJ., and FristonK.J. (2000). Voxel-based morphometry–the methods. Neuroimage, 11, 805–821.
12.
FreundP., WeiskopfN., AshburnerJ., WolfK., SutterR., AltmannD.R., FristonK., ThompsonA., and CurtA. (2013). MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study. Lancet Neurol. 12, 873–881.
13.
WrigleyP.J., GustinS.M., MaceyP.M., NashP.G., GandeviaS.C., MacefieldV.G., SiddallP.J., and HendersonL.A. (2009). Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury. Cereb. Cortex, 19, 224–232.
14.
FreundP., WeiskopfN., WardN.S., HuttonC., GallA., CiccarelliO., CraggsM., FristonK., and ThompsonA.J. (2011). Disability, atrophy and cortical reorganization following spinal cord injury. Brain, 134, 1610–1622.
15.
YoonE.J., KimY.K., ShinH.I., LeeY., and KimS.E. (2013). Cortical and white matter alterations in patients with neuropathic pain after spinal cord injury. Brain Res. 1540, 64–73.
16.
MoleT.B., MacIverK., SlumingV., RidgwayG.R., and NurmikkoT.J. (2014). Specific brain morphometric changes in spinal cord injury with and without neuropathic pain. Neuroimage Clin. 5, 28–35.
17.
CrawleyA.P., JurkiewiczM.T., YimA., HeynS., VerrierM.C., FehlingsM.G., and MikulisD.J. (2004). Absence of localized grey matter volume changes in the motor cortex following spinal cord injury. Brain Res. 1028, 19–25.
18.
HouJ.M., YanR.B., XiangZ.M., ZhangH., LiuJ., WuY.T., ZhaoM., PanQ.Y., SongL.H., ZhangW., LiH.T., LiuH.L., and SunT.S. (2014). Brain sensorimotor system atrophy during the early stage of spinal cord injury in humans. Neuroscience, 266, 208–215.
19.
ChenX., QinW., WanL., ZhengW.M., ChenN., and LiK.C. (2015). Reorganization of brain structure after chronic spinal cord injury: a magnetic resonance imaging study. Chin. J. Med. Imaging, Tech., 673–677.
20.
MüllerV.I., CieslikE.C., LairdA.R., FoxP.T., RaduaJ., Mataix-ColsD., TenchC.R., YarkoniT., NicholsT.E., TurkeltaubP.E., WagerT.D., and EickhoffS.B. (2018). Ten simple rules for neuroimaging meta-analysis. Neurosci. Biobehav. Rev. 84, 151–161.
21.
RaduaJ., Mataix-ColsD., PhillipsM.L., El-HageW., KronhausD.M., CardonerN., and SurguladzeS. (2012). A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. Eur. Psychiatry, 27, 605–611.
KokotiloK.J., EngJ.J., and CurtA. (2009). Reorganization and preservation of motor control of the brain in spinal cord injury: a systematic review. J. Neurotrauma, 26, 2113–2126.
24.
RaduaJ., and Mataix-ColsD. (2012). Meta-analytic methods for neuroimaging data explained. Biol. Mood Anxiety Disord. 2, 6.
25.
RaduaJ., RubiaK., CanalesE., Pomarol-ClotetE., Fusar-PoliP., and Mataix-ColsD. (2014). Anisotropic kernels for coordinate-based meta-analyses of neuroimaging studies. Front. Psychiatry. 5.
26.
RaduaJ., and Mataix-ColsD. (2009). Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br. J. Psychiatry, 195, 393–402.
27.
GoldsteinR.L., WaliaP., TeylanM., LazzariA.A., TunC.G., HartJ.E., and GarshickE. (2017). Clinical factors associated with C-reactive protein in chronic spinal cord injury. Spinal Cord, 55, 108–1095.
28.
SiegelM., BuschmanT.J., and MillerE.K. (2015). Cortical information flow during flexible sensorimotor decisions. Science, 348, 1352–1355.
29.
HylandB., ChenD.F., MaierV., PalmeriA., and WiesendangerM. (1989). What is the role of the supplementary motor area in movement initiation?. Prog. Brain Res. 80, 431–436; discussion 427–430.
30.
WallerA. (1850). Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Philosoph. Trans. Royal Soc. London, 140, 423–429.
31.
BussA., BrookG.A., KakulasB., MartinD., FranzenR., SchoenenJ., NothJ., and SchmittA.B. (2004). Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain, 127, 34–44.
32.
WrigleyP.J., PressS.R., GustinS.M., MacefieldV.G., GandeviaS.C., CousinsM.J., MiddletonJ.W., HendersonL.A., and SiddallP.J. (2009). Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury.
33.
RaineteauO., and SchwabM.E. (2001). Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273.
34.
DunlopS.A. (2008). Activity-dependent plasticity: implications for recovery after spinal cord injury. Trends Neurosci. 31, 410–418.
35.
TetzlaffW., KobayashiN.R., GiehlK.M., TsuiB.J., CassarS.L., and BedardA.M. (1994). Response of rubrospinal and corticospinal neurons to injury and neurotrophins. Prog. Brain Res. 103, 271–286.
36.
FeringaE.R., GilbertieW.J., and VahlsingH.L. (1984). Histologic evidence for death of cortical neurons after spinal cord transection. Neurology, 34, 1002–1006.
37.
FieldsR.D. (2008). White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 31, 361–370.
38.
GhoshA., HaissF., SydekumE., SchneiderR., GulloM., WyssM.T., MuegglerT., BaltesC., RudinM., WeberB., and SchwabM.E. (2010). Rewiring of hindlimb corticospinal neurons after spinal cord injury. Nat. Neurosci. 13, 97–104.
39.
JonesE.G. (2000). Cortical and subcortical contributions to activity-dependent plasticity in primate somatosensory cortex. Annu. Rev. Neurosci. 23, 1–37.
40.
HendersonL.A., GustinS.M., MaceyP.M., WrigleyP.J., and SiddallP.J. (2011). Functional reorganization of the brain in humans following spinal cord injury: evidence for underlying changes in cortical anatomy. J. Neurosci. 31, 2630–2637.
41.
ZieglerG., GrabherP., ThompsonA., AltmannD., HuppM., AshburnerJ., FristonK., WeiskopfN., CurtA., and FreundP. (2018). Progressive neurodegeneration following spinal cord injury: implications for clinical trials. Neurology, 90, e1257–e1266.
42.
DraganskiB., GaserC., BuschV., SchuiererG., BogdahnU., and MayA. (2004). Neuroplasticity: changes in grey matter induced by training. Nature, 427, 311–312.
43.
WoollettK., and MaguireE.A. (2011). Acquiring “the Knowledge” of London's layout drives structural brain changes. Curr. Biol. 21, 2109–2114.
44.
LangerN., HanggiJ., MullerN.A., SimmenH.P., and JanckeL. (2012). Effects of limb immobilization on brain plasticity. Neurology, 78, 182–188.
45.
CurtA., AlkadhiH., CrelierG.R., BoendermakerS.H., Hepp-ReymondM.-C., and KolliasS.S. (2002). Changes of non-affected upper limb cortical representation in paraplegic patients as assessed by fMRI. Brain, 125(Pt. 11), 2567–2578.
46.
GhoshA., PeduzziS., SnyderM., SchneiderR., StarkeyM., and SchwabM.E. (2012). Heterogeneous spine loss in layer 5 cortical neurons after spinal cord injury. Cereb. Cortex, 22, 1309–1317.
47.
BruehlmeierM., DietzV., LeendersK.L., RoelckeU., MissimerJ., and CurtA. (1998). How does the human brain deal with a spinal cord injury?. Eur. J. Neurosci. 10, 3918–3922.
48.
RouillerE.M., TanneJ., MoretV., and BoussaoudD. (1999). Origin of thalamic inputs to the primary, premotor, and supplementary motor cortical areas and to area 46 in macaque monkeys: a multiple retrograde tracing study. J. Comp. Neurol. 409, 131–152.
49.
OrioliP.J., and StrickP.L. (1989). Cerebellar connections with the motor cortex and the arcuate premotor area: an analysis employing retrograde transneuronal transport of WGA-HRP. J. Comp. Neurol. 288, 612–626.
50.
SeeleyW.W., MenonV., SchatzbergA.F., KellerJ., GloverG.H., KennaH., ReissA.L., and GreiciusM.D. (2007). dissociable intrinsic connectivity networks for salience processing and executive control. J. Neuroscience, 27, 2349–2356.
51.
RollsE.T. (2004). The functions of the orbitofrontal cortex. Brain Cogn. 55, 11–29.
52.
EbmeierK., RoseE., and SteeleD. (2006). Cognitive impairment and fMRI in major depression. Neurotox. Res. 10, 87–92.
53.
GreiciusM.D., FloresB.H., MenonV., GloverG.H., SolvasonH.B., KennaH., ReissA.L., and SchatzbergA.F. (2007). Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol. Psychiatry, 62, 429–437.
54.
MakovacE., MeetenF., WatsonD.R., HermanA., GarfinkelS.N., D. CritchleyH., and OttavianiC. (2016). Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder. Biol. Psychiatry, 80, 786–795.
55.
JutzelerC.R., HuberE., CallaghanM.F., LuechingerR., CurtA., KramerJ.L., and FreundP. (2016). Association of pain and CNS structural changes after spinal cord injury. Sci. Rep. 6, 18534.
56.
FreundP., CurtA., FristonK., and ThompsonA. (2013). Tracking changes following spinal cord injury: insights from neuroimaging. Neuroscientist, 19, 116–128.
57.
ElbertT., FlorH., BirbaumerN., KnechtS., HampsonS., LarbigW., and TaubE. (1994). Extensive reorganization of the somatosensory cortex in adult humans after nervous system injury. Neuroreport, 5, 2593–2597.
58.
JurkiewiczM.T., CrawleyA.P., VerrierM.C., FehlingsM.G., and MikulisD.J. (2006). Somatosensory cortical atrophy after spinal cord injury: a voxel-based morphometry study. Neurology, 66, 762.
59.
LundellH., ChristensenM.S., BarthelemyD., Willerslev-OlsenM., Biering-SorensenF., and NielsenJ.B. (2011). Cerebral activation is correlated to regional atrophy of the spinal cord and functional motor disability in spinal cord injured individuals. Neuroimage, 54, 1254–1261.
60.
JiaoJ., SunT.S., HouJ.M., XiangZ.M., ZhangY., BaoX.G., ZhongJ.F., and GuoL. (2015). Brain cortex structural changes in complete spinal cord injury detected by MRI. Chin. J. Spine Spinal, Cord, 213–217.
61.
VilligerM., GrabherP., Hepp-ReymondM.C., KiperD., CurtA., BolligerM., Hotz-BoendermakerS., KolliasS., EngK., and FreundP. (2015). Relationship between structural brainstem and brain plasticity and lower-limb training in spinal cord injury: a longitudinal pilot study. Front. Hum. Neurosci. 9, 254.
62.
ChenQ., ZhengW., ChenX., WanL., QinW., QiZ., ChenN., and LiK. (2017). Brain gray matter atrophy after spinal cord injury: a voxel-based morphometry study. Front. Hum. Neurosci. 11, 211.
63.
SeifM., CurtA., ThompsonA.J., GrabherP., WeiskopfN., and FreundP. (2018). Quantitative MRI of rostral spinal cord and brain regions is predictive of functional recovery in acute spinal cord injury. Neuroimage Clin. 20, 556–563.
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