Remodeling Brain Activity by Repetitive Cervicothoracic Transspinal Stimulation after Human Spinal Cord Injury

Lynda M Murray, Maria Knikou, Lynda M Murray, Maria Knikou

Abstract

Interventions that can produce targeted brain plasticity after human spinal cord injury (SCI) are needed for restoration of impaired movement in these patients. In this study, we tested the effects of repetitive cervicothoracic transspinal stimulation in one person with cervical motor incomplete SCI on cortical and corticospinal excitability, which were assessed via transcranial magnetic stimulation with paired and single pulses, respectively. We found that repetitive cervicothoracic transspinal stimulation potentiated intracortical facilitation in flexor and extensor wrist muscles, recovered intracortical inhibition in the more impaired wrist flexor muscle, increased corticospinal excitability bilaterally, and improved voluntary muscle strength. These effects may have been mediated by improvements in cortical integration of ascending sensory inputs and strengthening of corticospinal connections. Our novel therapeutic intervention opens new avenues for targeted brain neuromodulation protocols in individuals with cervical motor incomplete SCI.

Keywords: cortical plasticity; corticospinal plasticity; primary motor cortex; repetitive transspinal stimulation; spinal cord injury.

Figures

Figure 1
Figure 1
Protocol of transspinal stimulation for neurorecovery. (A) Repetitive cervicothoracic transspinal stimulation protocol. (B) Illustration of single-pulse transspinal stimulation delivered during the intervention, along with the intensities of daily transspinal stimulation normalized to the baseline transspinal-evoked potential motor threshold. (C) Illustration of single and paired transcranial magnetic stimulation (TMS) pulses for recording motor-evoked potentials (MEPs). Single-pulse TMS at different stimulation intensities was delivered for assembling the MEP recruitment input–output curves. Paired-pulse TMS was used to condition MEPs at different interstimulus intervals (ISIs) of 1, 2, 3, 10, 15, 20, 25, and 30 ms.
Figure 2
Figure 2
Conditioned motor evoked potentials (MEPs) of the right arm. MEPs tested in the resting extensor carpi radialis (ECR) muscle upon single- and paired-pulse transcranial magnetic stimulation (TMS) before (A) and after (B) repetitive cervicothoracic transspinal stimulation. Traces show the averages of 24 test MEPs (green traces) and 12 conditioned MEPs (blue traces) for short- and medium-latency interstimulus intervals.
Figure 3
Figure 3
Cortical excitability measures before and after repetitive cervicothoracic transspinal stimulation. Overall amplitude of extensor carpi radialis (ECR) (A) and flexor carpi radialis (FCR) (B). Motor-evoked potentials (MEPs) from the right arm upon paired-pulse transcranial magnetic stimulation (TMS). Conditioned MEPs are presented as a percentage of the mean size of the homonymous test MEP. Error bars indicate SE. *p < 0.05 for before–after comparisons, #p < 0.05 from homonymous test MEP values.
Figure 4
Figure 4
Corticospinal excitability measures before and after repetitive cervicothoracic transspinal stimulation. Motor-evoked potentials (MEPs) recorded from the right extensor carpi radialis (ECR) (A), right flexor carpi radialis (FCR) (B), and left ECR (C) muscles before and after repetitive transspinal stimulation are depicted as the area under the curve (auc) and are plotted against the percentage of the maximum stimulator output. Before and after repetitive transspinal stimulation, MEP recruitment input–output curves were assembled with single-pulse transcranial magnetic stimulation (TMS) at exactly the same stimulation intensities. A sigmoid fit to the data is also shown. Note the significant increases in MEP sizes after repetitive transspinal stimulation regardless of the stimulation intensity.

References

    1. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain (1994) 117(4):847–58.
    1. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology (1997) 48(5):1398–403.
    1. Rosenzweig ES, Courtine G, Jindrich DL, Brock JH, Ferguson AR, Strand SC, et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci (2010) 13(12):1505–10.10.1038/nn.2691
    1. Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med (2008) 14(1):69–74.10.1038/nm1682
    1. Ellaway PH, Catley M, Davey NJ, Kuppuswamy A, Strutton P, Frankel HL, et al. Review of physiological motor outcome measures in spinal cord injury using transcranial magnetic stimulation and spinal reflexes. J Rehabil Res Dev (2007) 44(1):69–76.10.1682/JRRD.2005.08.0140
    1. Buss A, Brook GA, Kakulas B, Martin D, Franzen R, Schoenen J, et al. Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain (2004) 127(1):34–44.10.1093/brain/awh001
    1. Rosenzweig ES, Brock JH, Culbertson MD, Lu P, Moseanko R, Edgerton VR, et al. Extensive spinal decussation and bilateral termination of cervical corticospinal projections in rhesus monkeys. J Comp Neurol (2009) 513(2):151–63.10.1002/cne.21940
    1. Fehlings MG, Tator CH, Linden RD. The effect of direct-current field on recovery from experimental spinal cord injury. J Neurosurg (1988) 68(5):781–92.10.3171/jns.1988.68.5.0781
    1. Schlaier JR, Eichhammer P, Langguth B, Doenitz C, Binder H, Hajak G, et al. Effects of spinal cord stimulation on cortical excitability in patients with chronic neuropathic pain: a pilot study. Eur J Pain (2007) 11(8):863–8.10.1016/j.ejpain.2007.01.004
    1. Einhorn J, Li A, Hazan R, Knikou M. Cervicothoracic multisegmental transpinal evoked potentials in humans. PLoS One (2013) 8(10):e76940.10.1371/journal.pone.0076940
    1. Knikou M. Neurophysiological characterization of transpinal evoked potentials in human leg muscles. Bioelectromagnetics (2013) 34(8):630–40.10.1002/bem.21808
    1. Knikou M. Neurophysiological characteristics of human leg muscle action potentials evoked by transcutaneous magnetic stimulation of the spine. Bioelectromagnetics (2013) 34(3):200–10.10.1002/bem.21768
    1. Knikou M. Transpinal and transcortical stimulation alter corticospinal excitability and increase spinal output. PLoS One (2014) 9(7):e102313.10.1371/journal.pone.0102313
    1. Dixon L, Ibrahim MM, Santora D, Knikou M. Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits. J Neurophysiol (2016) 116(2):904–16.10.1152/jn.00259.2016
    1. Knikou M, Dixon L, Santora D, Ibrahim MM. Transspinal constant-current long-lasting stimulation: a new method to induce cortical and corticospinal plasticity. J Neurophysiol (2015) 114(3):1486–99.10.1152/jn.00449.2015
    1. Minassian K, Hofstoetter US, Danner SM, Mayr W, Bruce JA, McKay WB, et al. Spinal rhythm generation by step-induced feedback and transcutaneous posterior root stimulation in complete spinal cord-injured individuals. Neurorehabil Neural Repair (2016) 30(3):233–43.10.1177/1545968315591706
    1. Gad P, Choe J, Shah P, Garcia-Alias G, Rath M, Gerasimenko Y, et al. Sub-threshold spinal cord stimulation facilitates spontaneous motor activity in spinal rats. J Neuroeng Rehabil (2013) 24(10):108.10.1186/1743-0003-10-108
    1. Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, et al. Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits. Exp Brain Res (1998) 119(2):265–8.
    1. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol (1993) 471:501–19.10.1113/jphysiol.1993.sp019912
    1. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol (1997) 498(3):817–23.10.1113/jphysiol.1997.sp021905
    1. Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol (1996) 496(3):873–81.10.1113/jphysiol.1996.sp021734
    1. Kothari M, Svensson P, Nielsen JF, Baad-Hansen L. Influence of position and stimulation parameters on intracortical inhibition and facilitation in human tongue motor cortex. Brain Res (2014) 1557:83–9.10.1016/j.brainres.2014.02.017
    1. Ellaway PH. Cumulative sum technique and its application to the analysis of peristimulus time histograms. Electroencephalogr Clin Neurophysiol (1978) 45(2):302–4.
    1. Costa P, Deletis V. Cortical activity after stimulation of the corticospinal tract in the spinal cord. Clin Neurophysiol (2016) 127(2):1726–33.10.1016/j.clinph.2015.11.004
    1. Shimizu T, Hino T, Komori T, Hirai S. Loss of the muscle silent period evoked by transcranial magnetic stimulation of the motor cortex in patients with cervical cord lesions. Neurosci Lett (2000) 286(3):199–202.10.1016/S0304-3940(00)01125-3
    1. Nardone R, Golaszewski S, Bergmann J, Venturi A, Prünster I, Bratti A, et al. Motor cortex excitability changes following a lesion in the posterior columns of the cervical spinal cord. Neurosci Lett (2008) 434(1):119–23.10.1016/j.neulet.2008.01.038
    1. Chang CW, Lien IN. Estimate of motor conduction in human spinal cord: slowed conduction in spinal cord injury. Muscle Nerve (1991) 14(10):990–6.10.1002/mus.880141010
    1. Xerri C. Plasticity of cortical maps: multiple triggers for adaptive reorganization following brain damage and spinal cord injury. Neuroscientist (2012) 18(2):133–48.10.1177/1073858410397894
    1. Streletz LJ, Belevich JK, Jones SM, Bhushan A, Shah SH, Herbison GJ. Transcranial magnetic stimulation: cortical motor maps in acute spinal cord injury. Brain Topogr (1995) 7(3):245–50.
    1. Ziemann U, Hallett M, Cohen LG. Mechanisms of deafferentation-induced plasticity in human motor cortex. J Neurosci (1998) 18(17):7000–7.
    1. Krassioukov AV, Karlsson AK, Wecht JM, Wuermser LA, Mathias CJ, Marino RJ, et al. Assessment of autonomic dysfunction following spinal cord injury: rationale for additions to international standards for neurological assessment. J Rehabil Res Dev (2007) 44(1):103–12.10.1682/JRRD.2005.10.0159
    1. Reitz A, Schmid DM, Curt A, Knapp PA, Schurch B. Sympathetic sudomotor skin activity in human after complete spinal cord injury. Auton Neurosci (2002) 102(1–2):78–84.10.1016/S1566-0702(02)00207-2
    1. Linderoth B, Fedorcsak I, Meyerson BA. Peripheral vasodilatation after spinal cord stimulation: animal studies of putative effector mechanisms. Neurosurgery (1991) 28(2):187–95.
    1. Linderoth B, Gunasekera L, Meyerson BA. Effects of sympathectomy on skin and muscle microcirculation during dorsal column stimulation: animal studies. Neurosurgery (1991) 29(6):874–9.
    1. Linderoth B, Herregodts P, Meyerson BA. Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neurosurgery (1994) 35(4):711–9.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться