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Changes in brain functional connectivity patterns are driven by an individual lesion in MS: a resting-state fMRI study


Diffuse inflammation in multiple sclerosis (MS) extends beyond focal lesion sites, affecting interconnected regions; however, little is known about the impact of an individual lesion affecting major white matter (WM) pathways on brain functional connectivity (FC). Here, we longitudinally assessed the effects of acute and chronic lesions on FC in relapsing-remitting MS (RRMS) patients using resting-state fMRI. 45 MRI data sets from 9 RRMS patients were recorded using 3T MR scanner over 5 time points at 8 week intervals. Patients were divided into two groups based on the presence (n = 5; MS+) and absence (n = 4; MS-) of a lesion at a predilection site for MS. While FC levels were found not to fluctuate significantly in the overall patient group, the MS+ patient group showed increased FC in the contralateral cuneus and precuneus and in the ipsilateral precuneus (p < 0.01, corrected). This can be interpreted as the recruitment of intact cortical regions to compensate for tissue damage. During the study, one patient developed an acute WM lesion in the left posterior periventricular space. A marked increase in FC in the right pre-, post-central gyrus, right superior frontal gyrus, the left cuneus, the vermis and the posterior and anterior lobes of the cerebellum was noted following the clinical relapse, which gradually decreased in subsequent follow-ups, suggesting short-term functional reorganization during the acute phase. This strongly suggests that the lesion-related network changes observed in patients with chronic lesions occur as a result of reorganization processes following the initial appearance of an acute lesion.

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  1. Basile, B., Castelli, M., Monteleone, F., Nocentini, U., Caltagirone, C., Centonze, D., Cercignani, M., & Bozzali, M. (2013). Functional connectivity changes within specific networks parallel the clinical evolution of multiple sclerosis. Multiple Sclerosis, 20, 1050–1057.

  2. Bremel, R. A., & Naismith, R. T. (2015). Using MRI to make informed clinical decisions in multiple sclerosis care. Current Opinion in Neurology, 28, 244–249.

  3. Calabrese, M., Magliozzi, R., Ciccarelli, O., Geurts, J. J. G., Reynolds, R., & Martin, R. (2015). Exploring the origins of grey matter damage in multiple sclerosis. Nature Reviews Neuroscience, 16, 147–158.

  4. Catani, M., & Mesulam, M. (2008). The arcuate fasciculus and the disconnection theme in language and aphasia: history and current state. Cortex, 44, 953–961.

  5. Ceccarelli, A., Rocca, M. A., Pagani, E., Colombo, B., Martinelli, V., Comi, G., & Filippi, M. (2008). A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. NeuroImage, 42, 315–322.

  6. Chard, D. T., & Miller, D. H. (2009). What you see depends on how you look: Gray matter lesions in multiple sclerosis. Neurology, 73, 918–919.

  7. De Stefano, N., Narayanan, S., Francis, S. J., Smith, S., Mortilla, M., Tartaglia, M. C., Bartolozzi, M. L., Guidi, L., Federico, A., & Arnold, D. L. (2002). Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Archives of Neurology, 59, 1565–1571.

  8. Dogonowski, A. M., Siebner, H. R., Solberg- Sorenson, P., Wu, X., Biswal, B., Paulson, O. B., Dyrby, T. B., Skimminge, A., Blinkenberg, M., & Madsen, K. H. (2012). Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis. Multiple Sclerosis, 19, 559–566.

  9. Dogonowski, A.-M., Siebner, H. R., Soelberg Sørensen, P., Paulson, O. B., Dyrby, T. B., Blinkenberg, M., & Madsen, K. H. (2013). Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis. Acta Neurologica Scandinavica, 128, 328–335.

  10. Droby, A., Fleischer, V., Carnini, M., Zimmermann, H., Siffrin, V., Gawehn, J., Hildebrandt, A., Baier, B., & Zipp, F. (2015). The impact of isolated lesions on white matter fiber tracts in multiple sclerosis patients. NeuroImage:Clinical, 8, 110–116.

  11. Faivre, A., Rico, A., Zaaraoui, W., Crespy, L., Reuter, F., Wybrecht, D., Soulier, E., Malikova, I., Confort-Gouny, S., Cozzone, P. J., Pelletier, J., Ranjeva, J. P., & Audoin, B. (2012). Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis. Multiple Sclerosis, 18, 1251–1258.

  12. Filippi, M., & Rocca, M. A. (2010). MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. American Journal of Neuroradiology, 31, 1171–1177.

  13. Filippi, M., Riccitelli, G., Mattioli, F., Capra, R., Stampatori, C., Pagani, E., Valsasina, P., Copetti, M., Falini, A., Comi, G., & Rocca, M. A. (2012). Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures—an explorative study. Radiology, 262, 932–940.

  14. Fox, M. D., & Raichle, M. E. (2007). Spontanous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews Neuroscience, 8, 700–711.

  15. Gamboa, O. L., Tagliazucchi, E., von Wegner, F., Jurcoane, A., Wahl, M., Laufs, H., & Ziemann, U. (2014). Working memory performance of early MS patients correlates inversely with modularity increases in resting state functional connectivity networks. NeuroImage, 94, 385–395.

  16. Jones, D. T., Mateen, F. J., Lucchinetti, C. F., Jack, C. R., & Welker, K. M. (2011). Default mode network disruption secondary to a lesion in the anterior thalamus. Archives of Neurology, 68, 242–247.

  17. Louapre, C., Perlbarg, V., Garcia-Lorenzo, D., Urbanski, M., Benali, H., Assouad, R., Galanaud, D., Freeman, L., Bodini, B., Papeix, C., Tourbah, A., Lubetzki, C., Lehericy, S., & Stankoff, B. (2014). Brain network disconnection in early multiple sclerosis deficits: an anatomofunctional study. Human Brain Mapping, 35, 4706–4717.

  18. Pantano, P., Iannetti, G. D., Caramia, F., Mainero, C., Di Legge, S., Bozzao, L., Pozzilli, C., & Lenzi, G. L. (2002). Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain, 125, 1607–1615.

  19. Polman, C. H., Reingold, S. C., Banwell, B., Clanet, M., Cohen, J. A., Filippi, M., Fujihara, K., Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F. D., Montalban, X., O’Connor, P., Sandberg-Wollheim, M., Thompson, A. J., Waubant, E., Weinshenker, B., & Wolinsky, J. S. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology, 69, 292–302.

  20. Pujol, J., Bello, J., Deus, J., Cardoner, N., Marti-Vilata, J. L., & Capdevila, A. (2000). Beck Depression Inventory factors related to demyelinating lesions of the left arcuate fasciculus regions. Psychiatry Research, 99, 151–159.

  21. Reddy, H., Narayanan, S., Woolrich, M., Mitsumori, T., Lapierre, Y., Arnold, D. L., & Matthews, P. M. (2002). Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain, 125, 2646–2657.

  22. Richiardi, J., Gschwind, M., Simioni, S., Annoni, J.-M., Greco, B., Hagmann, P., Schluep, M., Vuilleumier, P., & Van De Ville, D. (2012). Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity. NeuroImage, 62, 2021–2033.

  23. Rocca, M. A., Valsasina, P., Absinta, M., Riccitelli, G., Rodegher, M. E., Misci, P., Rossi, P., Falini, A., Comi, G., & Filippi, M. (2010). Default-mode network dysfunction and cognitive impairment in progressive MS. Neurology, 74, 1252–1259.

  24. Rocca, M. A., Valsasina, P., Martinelli, V., Misci, P., Falini, A., Comi, G., & Filippi, M. (2012). Large-scale neuronal network dysfunction in relapsing-remitting multiple sclerosis. Neurology, 79, 1449–1457.

  25. Rorden, C., Karnath, H.-O., & Bonilha, L. (2007). Improving lesion-symptom mapping. Journal of Cognitive Neuroscience, 19, 1081–1088.

  26. Rovaris, M., Bozzali, M., Rodegher, M., Tortorella, C., Comi, G., & Filippi, M. (1999). Brain MRI correlates of magnetization transfer imaging metrics in patients with multiple sclerosis. Journal of Neurological Sciences, 166, 58–63.

  27. Rovira, A., Auger, C., & Alonso, J. (2013). Magnetic resonance monitoring of lesion evolution in multiple sclerosis. Therapeutic Advances in Neurological Disorders, 6, 298–310.

  28. Schmidt, P., Gasser, C., Arsic, M., Buck, D., Förschler, A., Berthele, A., Hoshi, M., Ilg, R., Schmid, V. J., Zimmer, C., Hemmer, B., & Mühlau, M. (2012). An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis. NeuroImage, 59, 3774–3783.

  29. Schoonheim, M. M., Geurt, J. J. G., Landi, D., Douw, L., van der Meer, M. L., Vrenken, H., Polman, C. H., Barkhof, F., & Stam, C. J. (2013). Functional connectivity changes in multiple sclerosis patients: a graph analytical study of MEG resting state data. Human Brain Mapping, 34, 52–61.

  30. Siffrin, V., Vogt, J., Radbruch, H., Nitsch, R., & Zipp, F. (2010). Multiple sclerosis—candidate mechanisms underlying CNS atrophy. Trends in Neurosciences, 33, 202–210.

  31. Wojtowicz, M. A., Ishigami, Y., Mazerolle, E. L., & Fisk, J. D. (2014). Stability of intraindividual variability as a marker of neurologic dysfunction in relapsing remitting multiple sclerosis. Journal of Clinical and Experimental Neuropsychology, 36, 455–463.

  32. Zhou, F., Zhuang, Y., Gong, H., Wang, B., Chen, Q., Wu, L., & Wan, H. (2014). Altered inter-subregion connectivity of the default mode network in relapsing remitting multiple sclerosis: a functional and structural connectivity study. PloS One, 9, e101198.

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Author information

Correspondence to Sergiu Groppa.

Ethics declarations

This study was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.


This work has been supported by grants from the German Research Foundation (DFG; CRC-TR 128/B5 to Drs. Deichmann and Zipp).

Conflict of interest

None of the authors declare any relevant conflicts of interest.

Additional information

Frauke Zipp and Sergiu Groppa contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

T1-weighted MPRAGE images time series demonstrating the newly detected WM lesion in the reported single-case patient. The new lesion was detected on the first MRI-follow-up session (red circle) and was still visible throughout the follow-up period. (GIF 50 kb)

Supplementary Table 1

(DOCX 15 kb)

High resolution image

(TIF 6526 kb)

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Droby, A., Yuen, K.S.L., Muthuraman, M. et al. Changes in brain functional connectivity patterns are driven by an individual lesion in MS: a resting-state fMRI study. Brain Imaging and Behavior 10, 1117–1126 (2016).

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  • Compensation
  • Functional connectivity
  • Neuroplasticity
  • rs-fMRI