Different Brain Connectivity between Responders and Nonresponders to Dual-Mode Noninvasive Brain Stimulation over Bilateral Primary Motor Cortices in Stroke Patients

Jungsoo Lee, Ahee Lee, Heegoo Kim, Mina Shin, Sang Moon Yun, Youngjin Jung, Won Hyuk Chang, Yun-Hee Kim, Jungsoo Lee, Ahee Lee, Heegoo Kim, Mina Shin, Sang Moon Yun, Youngjin Jung, Won Hyuk Chang, Yun-Hee Kim

Abstract

Noninvasive brain stimulation (NBS), such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), has been used in stroke patients with motor impairment. NBS can help recovery from brain damage by modulating cortical excitability. However, the efficacy of NBS varies among individuals. To obtain insights of responsiveness to the efficacy of NBS, we investigated characteristic changes of the motor network in responders and nonresponders of NBS over the primary motor cortex (M1). A total of 21 patients with subacute stroke (13 males, mean age 59.6 ± 11.5 years) received NBS in the same manner: 1 Hz rTMS on the contralesional M1 and anodal tDCS on the ipsilesional M1. Participants were classified into responders and nonresponders based on the functional improvement of the affected upper extremity after applying NBS. Twelve age-matched healthy controls (8 males, mean age 56.1 ± 14.3 years) were also recruited. Motor networks were constructed using resting-state functional magnetic resonance imaging. M1 intrahemispheric connectivity, interhemispheric connectivity, and network efficiency were measured to investigate differences in network characteristics between groups. The motor network characteristics were found to differ between both groups. Specifically, M1 intrahemispheric connectivity in responders showed a noticeable imbalance between affected and unaffected hemispheres, which was markedly restored after NBS. The responders also showed greater interhemispheric connectivity and higher efficiency of the motor network than the nonresponders. These results may provide insight on patient-specific NBS treatment based on the brain network characteristics in neurorehabilitation of patients with stroke. This trial is registered with trial registration number NCT03390192.

Figures

Figure 1
Figure 1
Lesion maps. Left lesions are flipped to the right hemisphere, and all lesions are overlaid on the right hemisphere. The colored bars indicate the number of patients.
Figure 2
Figure 2
Changes in M1 intrahemispheric connectivity ((a) ipsilesional, (b) contralesional, (c) laterality index). The laterality index of the M1 intrahemispheric connectivity was significantly lower in the responder group than in the healthy control group. The laterality index in the responder group significantly increased after stimulation (∗p < 0.05).
Figure 3
Figure 3
Changes in interhemispheric connectivity ((a) homotopic and (b) overall) and global network efficiency (c) of the motor network. Interhemispheric connectivity was significantly lower in the responder and nonresponder groups than in the healthy control group. Network efficiency was significantly lower in the nonresponder group than in the healthy control group (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001, respectively).
Figure 4
Figure 4
The significant difference of homotopic connectivity between hemispheres before and after stimulation. White connectivity indicates that the strength of contralesional connectivity is significantly greater than that of ipsilesional connectivity. Black connectivity indicates that the strength of ipsilesional connectivity is significantly greater than that of contralesional connectivity. Gray connectivity indicates that there is no difference in the strength of homotopic connectivity between hemispheres. The more white connectivity the adjacency matrix has, the more contralesional dominance the motor network is. The motor network in the responders before stimulation showed contralesional dominance. After stimulation in the responders, the motor network became symmetric by changing from white connectivity to gray connectivity, whereas the motor network in the nonresponders before stimulation showed relatively symmetric. After stimulation in the nonresponders, there was no change in the degree of symmetry of the motor network.

References

    1. Corti M., Patten C., Triggs W. Repetitive transcranial magnetic stimulation of motor cortex after stroke: a focused review. American Journal of Physical Medicine & Rehabilitation. 2012;91(3):254–270. doi: 10.1097/PHM.0b013e318228bf0c.
    1. Gomez Palacio Schjetnan A., Faraji J., Metz G. A., Tatsuno M., Luczak A. Transcranial direct current stimulation in stroke rehabilitation: a review of recent advancements. Stroke Research and Treatment. 2013;2013:14. doi: 10.1155/2013/170256.170256
    1. Hsu W.-Y., Cheng C.-H., Liao K.-K., Lee I.-H., Lin Y.-Y. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke a meta-analysis. Stroke. 2012;43(7):1849–1857. doi: 10.1161/STROKEAHA.111.649756.
    1. Carter A. R., Astafiev S. V., Lang C. E., et al. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Annals of Neurology. 2010;67(3):365–375. doi: 10.1002/ana.21905.
    1. Rehme A. K., Grefkes C. Cerebral network disorders after stroke: evidence from imaging-based connectivity analyses of active and resting brain states in humans. The Journal of Physiology. 2013;591(1):17–31. doi: 10.1113/jphysiol.2012.243469.
    1. Lee J., Lee A., Kim H., Chang W. H., Kim Y. H. Differences in motor network dynamics during recovery between supra- and infra-tentorial ischemic strokes. Human Brain Mapping. 2018;39(12):4976–4986. doi: 10.1002/hbm.24338.
    1. Lee J., Park E., Lee A., Chang W. H., Kim D. S., Kim Y. H. Alteration and role of interhemispheric and intrahemispheric connectivity in motor network after stroke. Brain Topography. 2018;31(4):708–719. doi: 10.1007/s10548-018-0644-9.
    1. Hummel F., Celnik P., Giraux P., et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005;128(3):490–499. doi: 10.1093/brain/awh369.
    1. Zimerman M., Heise K. F., Hoppe J., Cohen L. G., Gerloff C., Hummel F. C. Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke. 2012;43(8):2185–2191. doi: 10.1161/STROKEAHA.111.645382.
    1. Kim Y.-H., You S. H., Ko M.-H., et al. Repetitive transcranial magnetic stimulation–induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke. 2006;37(6):1471–1476. doi: 10.1161/01.STR.0000221233.55497.51.
    1. Takeuchi N., Tada T., Toshima M., Chuma T., Matsuo Y., Ikoma K. Inhibition of the unaffected motor cortex by 1 Hz repetitive transcranical magnetic stimulation enhances motor performance and training effect of the paretic hand in patients with chronic stroke. Journal of Rehabilitation Medicine. 2008;40(4):298–303. doi: 10.2340/16501977-0181.
    1. Lindenberg R., Renga V., Zhu L. L., Nair D., Schlaug G. Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology. 2010;75(24):2176–2184. doi: 10.1212/WNL.0b013e318202013a.
    1. Takeuchi N., Tada T., Toshima M., Matsuo Y., Ikoma K. Repetitive transcranial magnetic stimulation over bilateral hemispheres enhances motor function and training effect of paretic hand in patients after stroke. Journal of Rehabilitation Medicine. 2009;41(13):1049–1054. doi: 10.2340/16501977-0454.
    1. Cho J. Y., Lee A., Kim M. S., et al. Dual-mode noninvasive brain stimulation over the bilateral primary motor cortices in stroke patients. Restorative Neurology and Neuroscience. 2017;35(1):105–114. doi: 10.3233/RNN-160669.
    1. The Cochrane Collaboration, Elsner B., Kugler J., Pohl M., Mehrholz J. Transcranial direct current stimulation (tDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database of Systematic Reviews. 2013;(11, article CD009645) doi: 10.1002/14651858.CD009645.pub2.
    1. López-Alonso V., Cheeran B., Río-Rodríguez D., Fernández-del-Olmo M. Inter-individual variability in response to non-invasive brain stimulation paradigms. Brain Stimulation. 2014;7(3):372–380. doi: 10.1016/j.brs.2014.02.004.
    1. Kubis N. Non-invasive brain stimulation to enhance post-stroke recovery. Frontiers in Neural Circuits. 2016;10(56) doi: 10.3389/fncir.2016.00056.
    1. Butler A. J., Shuster M., O'hara E., Hurley K., Middlebrooks D., Guilkey K. A meta-analysis of the efficacy of anodal transcranial direct current stimulation for upper limb motor recovery in stroke survivors. Journal of Hand Therapy. 2013;26(2):162–171. doi: 10.1016/j.jht.2012.07.002.
    1. Chang W. H., Kim Y. H., Bang O. Y., Kim S. T., Park Y. H., Lee P. K. Long-term effects of rTMS on motor recovery in patients after subacute stroke. Journal of Rehabilitation Medicine. 2010;42(8):758–764. doi: 10.2340/16501977-0590.
    1. Nettekoven C., Volz L. J., Leimbach M., et al. Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS. NeuroImage. 2015;118(209-218):209–218. doi: 10.1016/j.neuroimage.2015.06.004.
    1. Diekhoff-Krebs S., Pool E.-M., Sarfeld A.-S., et al. Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients. NeuroImage: Clinical. 2017;15(559-571):559–571. doi: 10.1016/j.nicl.2017.06.006.
    1. Kunze T., Hunold A., Haueisen J., Jirsa V., Spiegler A. Transcranial direct current stimulation changes resting state functional connectivity: a large-scale brain network modeling study. Neuroimage. 2016;140:174–187. doi: 10.1016/j.neuroimage.2016.02.015.
    1. Fox M. D., Halko M. A., Eldaief M. C., Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS) NeuroImage. 2012;62(4):2232–2243. doi: 10.1016/j.neuroimage.2012.03.035.
    1. Lee J., Park E., Lee A., et al. Modulating brain connectivity by simultaneous dual-mode stimulation over bilateral primary motor cortices in subacute stroke patients. Neural Plasticity. 2018;2018:9. doi: 10.1155/2018/1458061.1458061
    1. Fuggetta G., Pavone E. F., Fiaschi A., Manganotti P. Acute modulation of cortical oscillatory activities during short trains of high-frequency repetitive transcranial magnetic stimulation of the human motor cortex: a combined EEG and TMS study. Human Brain Mapping. 2008;29(1):1–13. doi: 10.1002/hbm.20371.
    1. Oliviero A., Strens L. H. A., di Lazzaro V., Tonali P. A., Brown P. Persistent effects of high frequency repetitive TMS on the coupling between motor areas in the human. Experimental Brain Research. 2003;149(1):107–113. doi: 10.1007/s00221-002-1344-x.
    1. Zanto T. P., Rubens M. T., Thangavel A., Gazzaley A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory. Nature Neuroscience. 2011;14(5):656–661. doi: 10.1038/nn.2773.
    1. Pal P. K., Hanajima R., Gunraj C. A., et al. Effect of low-frequency repetitive transcranial magnetic stimulation on interhemispheric inhibition. Journal of Neurophysiology. 2005;94(3):1668–1675. doi: 10.1152/jn.01306.2004.
    1. Vercammen A., Knegtering H., Liemburg E. J., Boer J. A. ., Aleman A. Functional connectivity of the temporo-parietal region in schizophrenia: effects of rTMS treatment of auditory hallucinations. Journal of Psychiatric Research. 2010;44(11):725–731. doi: 10.1016/j.jpsychires.2009.12.011.
    1. Fugl-Meyer A. R., Jääskö L., Leyman I., Olsson S., Steglind S. The post-stroke hemiplegic patient. 1. A method for evaluation of physical performance. Scandinavian Journal of Rehabilitation Medicine. 1975;7(1):13–31.
    1. Cheeran B., Talelli P., Mori F., et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. The Journal of Physiology. 2008;586(23):5717–5725. doi: 10.1113/jphysiol.2008.159905.
    1. Shelton F. d. N. A. P., Volpe B. T., Reding M. Motor impairment as a predictor of functional recovery and guide to rehabilitation treatment after stroke. Neurorehabilitation and Neural Repair. 2016;15(3):229–237. doi: 10.1177/154596830101500311.
    1. Nitsche M. A., Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001;57(10):1899–1901. doi: 10.1212/WNL.57.10.1899.
    1. Nitsche M. A., Roth A., Kuo M. F., et al. Timing-dependent modulation of associative plasticity by general network excitability in the human motor cortex. The Journal of Neuroscience. 2007;27(14):3807–3812. doi: 10.1523/JNEUROSCI.5348-06.2007.
    1. Rehme A. K., Eickhoff S. B., Rottschy C., Fink G. R., Grefkes C. Activation likelihood estimation meta-analysis of motor-related neural activity after stroke. NeuroImage. 2012;59(3):2771–2782. doi: 10.1016/j.neuroimage.2011.10.023.
    1. Lee J., Park E., Lee A., Chang W. H., Kim D. S., Kim Y. H. Recovery-related indicators of motor network plasticity according to impairment severity after stroke. European Journal of Neurology. 2017;24(10):1290–1299. doi: 10.1111/ene.13377.
    1. Achard S., Bullmore E. Efficiency and cost of economical brain functional networks. PLoS Computational Biology. 2007;3(2, article e17) doi: 10.1371/journal.pcbi.0030017.
    1. Latora V., Marchiori M. Efficient behavior of small-world networks. Physical Review Letters. 2001;87(19, article 198701) doi: 10.1103/PhysRevLett.87.198701.
    1. Sporns O., Zwi J. D. The small world of the cerebral cortex. Neuroinformatics. 2004;2(2):145–162. doi: 10.1385/NI:2:2:145.
    1. Watts D. J., Strogatz S. H. Collective dynamics of ‘small-world’ networks. Nature. 1998;393(6684):440–442. doi: 10.1038/30918.
    1. Li L. M., Uehara K., Hanakawa T. The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies. Frontiers in Cellular Neuroscience. 2015;9(181) doi: 10.3389/fncel.2015.00181.
    1. Opitz A., Paulus W., Will S., Antunes A., Thielscher A. Determinants of the electric field during transcranial direct current stimulation. NeuroImage. 2015;109:140–150. doi: 10.1016/j.neuroimage.2015.01.033.
    1. Uehara K., Coxon J. P., Byblow W. D. Transcranial direct current stimulation improves ipsilateral selective muscle activation in a frequency dependent manner. PloS One. 2015;10(3, article e0122434) doi: 10.1371/journal.pone.0122434.
    1. Nitsche M. A., Müller-Dahlhaus F., Paulus W., Ziemann U. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs. The Journal of Physiology. 2012;590(19):4641–4662. doi: 10.1113/jphysiol.2012.232975.
    1. Baker J. M., Rorden C., Fridriksson J. Using transcranial direct-current stimulation to treat stroke patients with aphasia. Stroke. 2010;41(6):1229–1236. doi: 10.1161/STROKEAHA.109.576785.
    1. Bütefisch C. M., Weβling M., Netz J., Seitz R. J., Hömberg V. Relationship between interhemispheric inhibition and motor cortex excitability in subacute stroke patients. Neurorehabilitation and Neural Repair. 2007;22(1):4–21. doi: 10.1177/1545968307301769.
    1. Murase N., Duque J., Mazzocchio R., Cohen L. G. Influence of interhemispheric interactions on motor function in chronic stroke. Annals of Neurology. 2004;55(3):400–409. doi: 10.1002/ana.10848.
    1. Shimizu T., Hosaki A., Hino T., et al. Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke. Brain. 2002;125(8):1896–1907. doi: 10.1093/brain/awf183.
    1. Grefkes C., Nowak D. A., Wang L. E., Dafotakis M., Eickhoff S. B., Fink G. R. Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling. NeuroImage. 2010;50(1):233–242. doi: 10.1016/j.neuroimage.2009.12.029.
    1. Khedr E. M., Shawky O. A., El-Hammady D. H., et al. Effect of anodal versus cathodal transcranial direct current stimulation on stroke rehabilitation. Neurorehabilitation and Neural Repair. 2013;27(7):592–601. doi: 10.1177/1545968313484808.
    1. van den Heuvel M. P., Stam C. J., Kahn R. S., Hulshoff Pol H. E. Efficiency of functional brain networks and intellectual performance. The Journal of Neuroscience. 2009;29(23):7619–7624. doi: 10.1523/JNEUROSCI.1443-09.2009.
    1. Langer N., Pedroni A., Gianotti L. R. R., Hänggi J., Knoch D., Jäncke L. Functional brain network efficiency predicts intelligence. Human Brain Mapping. 2012;33(6):1393–1406. doi: 10.1002/hbm.21297.
    1. Langer N., von Bastian C. C., Wirz H., Oberauer K., Jäncke L. The effects of working memory training on functional brain network efficiency. Cortex. 2013;49(9):2424–2438. doi: 10.1016/j.cortex.2013.01.008.
    1. Carter A. R., Patel K. R., Astafiev S. V., et al. Upstream dysfunction of somatomotor functional connectivity after corticospinal damage in stroke. Neurorehabilitation and Neural Repair. 2012;26(1):7–19. doi: 10.1177/1545968311411054.
    1. Liu J., Qin W., Zhang J., Zhang X., Yu C. Enhanced interhemispheric functional connectivity compensates for anatomical connection damages in subcortical stroke. Stroke. 2015;46(4):1045–1051. doi: 10.1161/STROKEAHA.114.007044.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe