Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Treatment and management of cognitive dysfunction in patients with multiple sclerosis

Nature Reviews Neurology volume 16, pages 319–332 (2020)Cite this article

Subjects

Abstract

Cognitive impairment is a common and devastating manifestation of multiple sclerosis (MS). Although disease-modifying therapies have been efficacious for reducing relapse rates in MS, such treatments are ineffective for treating cognitive dysfunction. Alternative treatment approaches for mitigating cognitive problems are greatly needed in this population. To date, cognitive rehabilitation and exercise training have been identified as possible candidates for treating MS-related cognitive impairment; however, cognitive dysfunction is still often considered to be poorly managed in patients with MS. This Review provides a comprehensive overview of recent developments in the treatment and management of cognitive impairment in people with MS. We describe the theoretical rationales, current states of the science, field-wide challenges and recent advances in cognitive rehabilitation and exercise training for treating MS-related cognitive impairment. We also discuss future directions for research into the treatment of cognitive impairment in MS that should set the stage for the inclusion of cognitive rehabilitation and exercise training into clinical practice within the next decade.

Key points

  • Cognitive deficits are common in people with multiple sclerosis (MS) and have a substantial impact on daily life functioning; effective treatment of such deficits is essential.

  • Studies examining the efficacy of cognitive rehabilitation in MS have become more frequent in recent years and a few effective cognitive rehabilitation programmes for individuals with MS have been identified.

  • Research on exercise training as a promising approach for improving cognition in MS has been growing, but more research is necessary.

  • Insufficient evidence is currently available to support pharmacological approaches for treating cognitive impairment in patients with MS.

  • Research is needed on factors such as the treatment timing, dosage and duration, and the impact of treatment on everyday life in patients with MS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Literature on cognitive rehabilitation and exercise training in multiple sclerosis.
Fig. 2: Cognitive rehabilitation in multiple sclerosis.

Similar content being viewed by others

References

  1. Benedict, R. H. et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J. Int. Neuropsychol. Soc. 12, 549–558 (2006).

    Article  PubMed  Google Scholar 

  2. Chiaravalloti, N. D. & DeLuca, J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 7, 1139–1151 (2008).

    Article  PubMed  Google Scholar 

  3. Benedict, R. H. B. et al. Neuropsychology of multiple sclerosis: looking back and moving forward. J. Int. Neuropsychol. Soc. 23, 832–842 (2017).

    Article  PubMed  Google Scholar 

  4. Kalb, R. et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult. Scler. 24, 1665–1680 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. DeLuca, J., Chelune, G. J., Tulsky, D. S., Lengenfelder, J. & Chiaravalloti, N. D. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J. Clin. Exp. Neuropsychol. 26, 550–562 (2004).

    Article  PubMed  Google Scholar 

  6. Bergendal, G., Fredrikson, S. & Almkvist, O. Selective decline in information processing in subgroups of multiple sclerosis: an 8-year longitudinal study. Eur. Neurol. 57, 193–202 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Beatty, W. W. et al. Memory disturbance in multiple sclerosis: reconsideration of patterns of performance on the selective reminding test. J. Clin. Exp. Neuropsychol. 18, 56–62 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Lazeron, R. H., Rombouts, S. A., Scheltens, P., Polman, C. H. & Barkhof, F. An fMRI study of planning-related brain activity in patients with moderately advanced multiple sclerosis. Mult. Scler. 10, 549–555 (2004).

    Article  PubMed  Google Scholar 

  9. Denney, D. R., Sworowski, L. A. & Lynch, S. G. Cognitive impairment in three subtypes of multiple sclerosis. Arch. Clin. Neuropsychol. 20, 967–981 (2005).

    Article  PubMed  Google Scholar 

  10. Audoin, B. et al. Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis. Hum. Brain Mapp. 24, 216–228 (2005).

    Article  PubMed  Google Scholar 

  11. Rao, S. M. et al. Memory dysfunction in multiple sclerosis: its relation to working memory, semantic encoding and implicit learning. Neuropsychology 7, 364–374 (1993).

    Article  Google Scholar 

  12. Di Filippo, M., Portaccio, E., Mancini, A. & Calabresi, P. Multiple sclerosis and cognition: synaptic failure and network dysfunction. Nat. Rev. Neurosci. 19, 599–609 (2018).

    Article  PubMed  CAS  Google Scholar 

  13. Cotter, J. et al. Social cognition in multiple sclerosis: a systematic review and meta-analysis. Neurology 87, 1727–1736 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ruano, L. et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult. Scler. 23, 1258–1267 (2017).

    Article  PubMed  Google Scholar 

  15. Branco, M. et al. Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Neurol. Sci. 40, 1651–1657 (2019).

    Article  PubMed  Google Scholar 

  16. Benedict, R. H. et al. Brief International Cognitive Assessment for MS (BICAMS): international standards for validation. BMC Neurol. 12, 55 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gromisch, E. S. et al. Assessing the criterion validity of four highly abbreviated measures from the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS). Clin. Neuropsychol. 30, 1032–1049 (2016).

    Article  PubMed  Google Scholar 

  18. Foley, F. W., Benedict, R. H. B., Gromisch, E. S. & DeLuca, J. The need for screening, assessment, and treatment for cognitive dysfunction in multiple sclerosis: results of a multidisciplinary CMSC consensus conference, September 24, 2010. Int. J. MS Care 14, 58–64 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. O’Brien, A. et al. Relationship of the multiple sclerosis neuropsychological questionnaire (MSNQ) to functional, emotional, and neuropsychological outcomes. Arch. Clin. Neuropsychol. 22, 933–948 (2007).

    Article  PubMed  Google Scholar 

  20. Romero, K., Shammi, P. & Feinstein, A. Neurologists’ accuracy in predicting cognitive impairment in multiple sclerosis. Mult. Scler. Relat. Disord. 4, 291–295 (2015).

    Article  PubMed  Google Scholar 

  21. National Institute for Health and Care Excellence. Multiple sclerosis in adults: management (NICE, 2019).

  22. Amato, M. P. et al. Cognitive assessment in multiple sclerosis — an Italian consensus. Neurol. Sci. 39, 1317–1324 (2018).

    Article  PubMed  Google Scholar 

  23. Rocca, M. A. et al. Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis. Lancet Neurol. 14, 302–317 (2015).

    Article  PubMed  Google Scholar 

  24. Rao, S. M., Leo, G. J., Haughton, V. M., St Aubin-Faubert, P. & Bernardin, L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology 39, 161–166 (1989).

    Article  CAS  PubMed  Google Scholar 

  25. Calabrese, M., Favaretto, A., Martini, V. & Gallo, P. Grey matter lesions in MS: from histology to clinical implications. Prion 7, 20–27 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Amato, M. P. et al. Relevance of cognitive deterioration in early relapsing–remitting MS: a 3-year follow-up study. Mult. Scler. 16, 1474–1482 (2010).

    Article  PubMed  Google Scholar 

  27. Sanfilipo, M. P., Benedict, R. H. B., Weinstock-Guttman, B. & Bakshi, R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology 66, 685–692 (2006).

    Article  PubMed  Google Scholar 

  28. Rocca, M. A. et al. The hippocampus in multiple sclerosis. Lancet Neurol. 17, 918–926 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Bergsland, N., Zivadinov, R., Dwyer, M. G., Weinstock-Guttman, B. & Benedict, R. H. B. Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients. Mult. Scler. 22, 1327–1336 (2016).

    Article  PubMed  Google Scholar 

  30. Benedict, R. H. B., Ramasamy, D., Munschauer, F., Weinstock-Guttman, B. & Zivadinov, R. Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy. J. Neurol. Neurosurg. Psychiat. 80, 201–206 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Mandolesi, G. et al. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat. Rev. Neurol. 11, 711–724 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Loitfelder, M. et al. Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis — insights from a longitudinal fMRI study. PLoS One 9, e93715 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Chiaravalloti, N. D. et al. Cerebral activation patterns during working memory performance in multiple sclerosis using fMRI. J. Clin. Exp. Neuropsychol. 27, 33–54 (2005).

    Article  PubMed  Google Scholar 

  34. Hillary, F. G. et al. An investigation of working memory rehearsal in multiple sclerosis using fMRI. J. Clin. Exp. Neuropsychol. 25, 965–978 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Hulst, H. E. et al. Memory impairment in multiple sclerosis: relevance of hippocampal activation and hippocampal connectivity. Mult. Scler. 21, 1705–1712 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Schoonheim, M. M. et al. Thalamus structure and function determine severity of cognitive impairment in multiple sclerosis. Neurology 84, 776–783 (2015).

    Article  PubMed  Google Scholar 

  37. Bonavita, S. et al. Distributed changes in default-mode resting-state connectivity in multiple sclerosis. Mult. Scler. 17, 411–422 (2011).

    Article  PubMed  Google Scholar 

  38. Louapre, C. et al. Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study. Hum. Brain Mapp. 35, 4706–4717 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tona, F. et al. Multiple sclerosis: altered thalamic resting-state functional connectivity and its effect on cognitive function. Radiology 271, 814–821 (2014).

    Article  PubMed  Google Scholar 

  40. Dobryakova, E. et al. Abnormalities of the executive control network in multiple sclerosis phenotypes: an fMRI effective connectivity study. Hum. Brain Mapp. 37, 2293–2304 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chiaravalloti, N. D., Genova, H. M. & DeLuca, J. Cognitive rehabilitation in multiple sclerosis: the role of plasticity. Front. Neurol. 6, 67 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Sandroff, B. M., Schwartz, C. E. & DeLuca, J. Measurement and maintenance of reserve in multiple sclerosis. J. Neurol. 263, 2158–2169 (2016).

    Article  PubMed  Google Scholar 

  43. Fuchs, T. A. et al. Preserved network functional connectivity underlies cognitive reserve in multiple sclerosis. Hum. Brain Mapp. 40, 5231–5241 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rao, S. M. et al. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 41, 692–696 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Strober, L., Chiaravalloti, N., Moore, N. & DeLuca, J. Unemployment in multiple sclerosis (MS): utility of the MS functional composite and cognitive testing. Mult. Scler. 20, 112–115 (2014).

    Article  PubMed  Google Scholar 

  46. Strober, L. B., Chiaravalloti, N. & DeLuca, J. Should I stay or should I go? A prospective investigation examining individual factors impacting employment status among individuals with multiple sclerosis (MS). Work 59, 39–47 (2018).

    Article  PubMed  Google Scholar 

  47. Morrow, S. A. et al. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin. Neuropsychol. 24, 1131–1145 (2010).

    Article  PubMed  Google Scholar 

  48. Campbell, J., Rashid, W., Cercignani, M. & Langdon, D. Cognitive impairment among patients with multiple sclerosis: associations with employment and quality of life. Postgrad. Med. J. 93, 143–147 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Clemens, L. & Langdon, D. How does cognition relate to employment in multiple sclerosis? A systematic review. Mult. Scler. Relat. Disord. 26, 183–191 (2018).

    Article  PubMed  Google Scholar 

  50. D’hooghe, M. B. et al. Perceived neuropsychological impairment inversely related to self-reported health and employment in multiple sclerosis. Eur. J. Neurol. 26, 1447–1454 (2019).

    Article  PubMed  Google Scholar 

  51. Kavaliunas, A. et al. Cognitive function is a major determinant of income among multiple sclerosis patients in Sweden acting independently from physical disability. Mult. Scler. 25, 104–112 (2019).

    Article  PubMed  Google Scholar 

  52. Schultheis, M. T., Garay, E., Millis, S. R. & DeLuca, J. Motor vehicle crashes and violations among drivers with multiple sclerosis. Arch. Phys. Med. Rehabil. 83, 1175–1178 (2002).

    Article  PubMed  Google Scholar 

  53. Schultheis, M. T., Garay, E. & DeLuca, J. The influence of cognitive impairment on driving performance in multiple sclerosis. Neurology 56, 1089–1094 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Goverover, Y., Genova, H. M., DeLuca, J. & Chiaravalloti, N. D. in Changes in the Brain: Impact on Daily Life (eds Chiaravalloti, N.D. & Goverover, Y.) 145–165 (Springer, 2016).

  55. Kalmar, J. H., Gaudino, E. A., Moore, N. B., Halper, J. & DeLuca, J. The relationship between cognitive deficits and everyday functional activities in multiple sclerosis. Neuropsychology 22, 442–449 (2008).

    Article  PubMed  Google Scholar 

  56. Goverover, Y., O’Brien, A. R., Moore, N. B. & DeLuca, J. Actual reality: a new approach to functional assessment in persons with multiple sclerosis. Arch. Phys. Med. Rehabil. 91, 252–260 (2010).

    Article  PubMed  Google Scholar 

  57. Amato, M. P. et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J. Neurol. 260, 1452–1468 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Miller, E., Morel, A., Redlicka, J., Miller, I. & Saluk, J. Pharmacological and non-pharmacological therapies of cognitive impairment in multiple sclerosis. Curr. Neuropharmacol. 16, 475–483 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Satchidanand, N. et al. Dalfampridine benefits ambulation but not cognition in multiple sclerosis. Mult. Scler. 26, 91–98 (2020).

    Article  PubMed  Google Scholar 

  60. Goodman, A. D. et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann. Neurol. 68, 494–502 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. De Giglio, L. et al. Effect of dalfampridine on information processing speed impairment in multiple sclerosis. Neurology 93, e733–e746 (2019).

    Article  PubMed  Google Scholar 

  62. Rebok, G. W. et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J. Am. Geriatr. Soc. 62, 16–24 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ball, K., Edwards, J. D., Ross, L. A. & McGwin, G. Cognitive training decreases motor vehicle collision involvement of older drivers. J. Am. Geriatr. Soc. 58, 2107–2113 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Solari, A. et al. Computer-aided retraining of memory and attention in people with multiple sclerosis: a randomized, double-blind controlled trial. J. Neurol. Sci. 222, 99–104 (2004).

    Article  PubMed  Google Scholar 

  65. Cerasa, A. et al. Computer-assisted cognitive rehabilitation of attention deficits for multiple sclerosis: a randomized trial with fMRI correlates. Neurorehabil. Neural Repair. 27, 284–295 (2013).

    Article  PubMed  Google Scholar 

  66. Mattioli, F. et al. A RCT comparing specific intensive cognitive training to aspecific psychological intervention in RRMS: the SMICT study. Front. Neurol. 5, 278 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Plohmann, A. M. et al. Computer assisted retraining of attentional impairments in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 64, 455–462 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Foley, F. W. et al. Psychoremediation of communication skills for cognitively impaired persons with multiple sclerosis. J. Neurol. Rehabil. 8, 165–176 (1994).

    Google Scholar 

  69. Ernst, A. et al. Autobiographical memory in multiple sclerosis patients: assessment and cognitive facilitation. Neuropsychol. Rehabil. 23, 161–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Chiaravalloti, N. D., Moore, N. B., Nikelshpur, O. M. & DeLuca, J. An RCT to treat learning impairment in multiple sclerosis: the MEMREHAB trial. Neurology 81, 2066–2072 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Simone, M., Viterbo, R. G., Margari, L. & Iaffaldano, P. Computer-assisted rehabilitation of attention in pediatric multiple sclerosis and ADHD patients: a pilot trial. BMC Neurol. 18, 82 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Amato, M. P. et al. Computer-assisted rehabilitation of attention in patients with MS: results of randomized, double blind trial. Mult. Scler. 20, 91–98 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Grasso, M. G. et al. Evaluation of the impact of cognitive training on quality of life in patients with multiple sclerosis. Eur. Neurol. 78, 111–117 (2017).

    Article  PubMed  Google Scholar 

  74. Campbell, J., Langdon, D., Cercignani, M. & Rashid, W. A randomised controlled trial of efficacy of cognitive rehabilitation in multiple sclerosis: a cognitive, behavioural, and MRI study. Neural Plast. 2016, 4292585 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Parisi, L. et al. Cognitive rehabilitation correlates with the functional connectivity of the anterior cingulate cortex in patients with multiple sclerosis. Brain Imaging Behav. 8, 387–393 (2014).

    Article  PubMed  Google Scholar 

  76. Jønsson, A., Korfitzen, E. M., Heltberg, A., Ravnborg, M. H. & Byskov-Ottosen, E. Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurol. Scand. 88, 394–400 (1993).

    Article  PubMed  Google Scholar 

  77. Mendoza, R. J., Pittenger, D. J. & Weinstein, C. S. Unit management of depression of patients with multiple sclerosis using cognitive remediation strategies: a preliminary study. Neurorehabil. Neural Repair. 15, 9–14 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Brenk, A., Laun, K. & Haase, C. G. Short-term cognitive training improves mental efficiency and mood in patients with multiple sclerosis. Eur. Neurol. 60, 304–309 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Lincoln, N. B., Dent, A. & Harding, J. Treatment of cognitive problems for people with multiple sclerosis. Br. J. Ther. Rehabil. 10, 13495 (2013).

    Google Scholar 

  80. Klein, O. A., Drummond, A., Mhizha-Murira, J. R., Mansford, L. & dasNair, R. Effectiveness of cognitive rehabilitation for people with multiple sclerosis: a meta-synthesis of patient perspectives. Neuropsychol. Rehabil. 29, 491–512 (2017).

    Article  PubMed  Google Scholar 

  81. Ruff, R. M. et al. Neuropsychological rehabilitation: an experimental study with head-injured patients. J. Head Trauma Rehabil. 4, 20–36 (1989).

    Article  Google Scholar 

  82. Sohlberg, M. M. & Mateer, C. A. Effectiveness of an attention-training program. J. Clin. Exp. Neuropsychol. 9, 117–130 (1987).

    Article  CAS  PubMed  Google Scholar 

  83. Sohlberg, M. M., McLaughlin, K. A., Pavese, A., Heidrich, A. & Posner, M. I. Evaluation of attention process training and brain injury education in persons with acquired brain injury. J. Clin. Exp. Neuropsychol. 22, 656–676 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Sohlberg, M. & Mateer C. Attention Process Training (APT) (Center for Cognitive Rehabilitation, 1986).

  85. Sohlberg, M. M., Johnson, L., Paule, L., Raskin, S. A. & Mateer, C. A. Attention Process Training APT-2 for Persons with Mild Cognitive Dysfunction 2nd edn (Lash & Associates, 2001).

  86. Sohlberg, M. M. & Mateer C. Attention Process Training APT-3: A Direct Attention Training Program for Persons with Acquired Brain Injury (Lash & Associates, 2011).

  87. Pusswald, G., Mildner, C., Zebenholzer, K., Auff, E. & Lehrner, J. A neuropsychological rehabilitation program for patients with multiple sclerosis based on the model of the ICF. NeuroRehabilitation 35, 519–527 (2014).

    Article  PubMed  Google Scholar 

  88. Flachenecker, P., Meissner, H., Frey, R. & Guldin, W. Neuropsychological training of attention improves MS-related fatigue: results of a randomized, placebo-controlled, double-blind pilot study. Eur. Neurol. 78, 312–317 (2017).

    Article  PubMed  Google Scholar 

  89. Charvet, L. E., Shaw, M. T., Haider, L., Melville, P. & Krupp, L. B. Remotely-delivered cognitive remediation in multiple sclerosis (MS): protocol and results from a pilot study. Mult. Scler. J. Exp. Transl. Clin. 1, 2055217315609629 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Charvet, L. E. et al. Cognitive function in multiple sclerosis improves with telerehabilitation: results from a randomized controlled trial. PLoS One 12, e0177177 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Pedullà, L. et al. Adaptive vs. non-adaptive cognitive training by means of a personalized app: a randomized trial in people with multiple sclerosis. J. Neuroeng. Rehabil. 13, 88 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bonzano, L. et al. Brain activity pattern changes after adaptive working memory training in multiple sclerosis. Brain Imaging Behav. 14, 142–154 (2018).

    Article  PubMed Central  Google Scholar 

  93. Bove, R. M. et al. A videogame-based digital therapeutic to improve processing speed in people with multiple sclerosis: a feasibility study. Neurol. Ther. 8, 135–145 (2019).

    Article  PubMed  Google Scholar 

  94. Hubacher, M. et al. Case-based fMRI analysis after cognitive rehabilitation in MS: a novel approach. Front. Neurol. 6, 78 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Vogt, A. et al. Working memory training in patients with multiple sclerosis — comparison of two different training schedules. Restor. Neurol. Neurosci. 27, 225–235 (2009).

    PubMed  Google Scholar 

  96. Covey, T. J., Shucard, J. L., Benedict, R. H., Weinstock-Guttman, B. & Shucard, D. W. Improved cognitive performance and event-related potential changes following working memory training in patients with multiple sclerosis. Mult. Scler. J. Exp. Transl. Clin. 4, 2055217317747626 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. Mousavi, S., Zare, H., Etemadifar, M. & Taher Neshatdoost, H. Memory rehabilitation for the working memory of patients with multiple sclerosis (MS). J. Clin. Exp. Neuropsychol. 40, 405–410 (2018).

    Article  PubMed  Google Scholar 

  98. Hubacher, M. et al. Cognitive rehabilitation of working memory in juvenile multiple sclerosis — effects on cognitive functioning, functional MRI and network related connectivity. Restor. Neurol. Neurosci. 33, 713–725 (2015).

    PubMed  Google Scholar 

  99. Fink, F. et al. Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudo-randomized trial. Mult. Scler. 16, 1148–1151 (2010).

    Article  PubMed  Google Scholar 

  100. Hanssen, K. T., Beiske, A. G., Landrø, N. I., Hofoss, D. & Hessen, E. Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial. Acta Neurol. Scand. 133, 30–40 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Kiresuk, T. J. & Sherman, R. E. Goal attainment scaling: a general method for evaluating comprehensive community mental health programs. Community Ment. Health J. 4, 443–453 (1968).

    Article  CAS  PubMed  Google Scholar 

  102. Hanssen, K. T., Šaltyte Benth, J., Beiske, A. G., Landrø, N. I. & Hessen, E. Goal attainment in cognitive rehabilitation in MS patients. Neuropsychol. Rehabil. 25, 137–154 (2015).

    Article  PubMed  Google Scholar 

  103. Goverover, Y., Chiaravalloti, N. D., O’Brien, A. R. & DeLuca, J. Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016. Arch. Phys. Med. Rehabil. 99, 390–407 (2018).

    Article  PubMed  Google Scholar 

  104. Chiaravalloti, N. D., DeLuca, J., Moore, N. & Ricker, J. H. Treating learning impairments improves memory performance in multiple sclerosis: a randomized clinical trial. Mult. Scler. 11, 58–68 (2005).

    Article  PubMed  Google Scholar 

  105. Chiaravalloti, N. D., Moore, N. B. & DeLuca, J. The efficacy of the modified Story Memory Technique in progressive MS. Mult. Scler. 26, 354–362 (2019).

    Article  PubMed  Google Scholar 

  106. Chiaravalloti, N. D., Wylie, G., Leavitt, V. & Deluca, J. Increased cerebral activation after behavioral treatment for memory deficits in MS. J. Neurol. 259, 1337–1346 (2012).

    Article  PubMed  Google Scholar 

  107. Dobryakova, E., Wylie, G. R., DeLuca, J. & Chiaravalloti, N. D. A pilot study examining functional brain activity 6 months after memory retraining in MS: the MEMREHAB trial. Brain Imaging Behav. 8, 403–406 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ernst, A., Blanc, F., De Seze, J. & Manning, L. Using mental visual imagery to improve autobiographical memory and episodic future thinking in relapsing–remitting multiple sclerosis patients: a randomised-controlled trial study. Restor. Neurol. Neurosci. 33, 621–638 (2015).

    PubMed  Google Scholar 

  109. Ernst, A. et al. Benefits from an autobiographical memory facilitation programme in relapsing–remitting multiple sclerosis patients: a clinical and neuroimaging study. Neuropsychol. Rehabil. 28, 1110–1130 (2018).

    Article  PubMed  Google Scholar 

  110. Basso, M., Ghormley, C., Lowery, N., Combs, D. & Bornstein, R. A. Self-generated learning in people with multiple sclerosis: an extension of Chiaravalloti and DeLuca (2002). J. Clin. Exp. Neuropsychol. 30, 63–69 (2008).

    Article  PubMed  Google Scholar 

  111. Goverover, Y., Chiaravalloti, N. & DeLuca, J. Self-generation to improve learning and memory of functional activities in persons with multiple sclerosis: meal preparation and managing finances. Arch. Phys. Med. Rehabil. 89, 1514–1521 (2008).

    Article  PubMed  Google Scholar 

  112. Voelbel, G. T. et al. The relationship between neurocognitive behavior of executive functions and the EFPT in individuals with multiple sclerosis. OTJR 31, S30–S37 (2011).

    PubMed  Google Scholar 

  113. Goverover, Y., Hillary, F. G., Chiaravalloti, N., Arango-Lasprilla, J. C. & Deluca, J. A functional application of the spacing effect to improve learning and memory in persons with multiple sclerosis. J. Clin. Exp. Neuropsychol. 31, 513–522 (2009).

    Article  PubMed  Google Scholar 

  114. Goverover, Y., Basso, M., Wood, H., Chiaravalloti, N. & Deluca, J. Examining the benefits of combining two learning strategies on recall of functional information in persons with multiple sclerosis. Mult. Scler. 17, 1488–1497 (2011).

    Article  PubMed  Google Scholar 

  115. Sumowski, J. F. et al. Retrieval practice: a simple strategy for improving memory after traumatic brain injury. J. Int. Neuropsychol. Soc. 16, 1147–1150 (2010).

    Article  PubMed  Google Scholar 

  116. Chiaravalloti, N. D., Moore, N. B., Weber, E. & DeLuca, J. The application of Strategy-based Training to Enhance Memory (STEM) in multiple sclerosis: a pilot RCT. Neuropsychol. Rehabil. https://doi.org/10.1080/09602011.2019.1685550 (2019).

    Article  PubMed  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03983681 (2020).

  118. Mantynen, A. et al. Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with MS. Mult. Scler. 20, 99–107 (2014).

    Article  PubMed  Google Scholar 

  119. Janssen, A., Boster, A., Lee, H., Patterson, B. & Prakash, R. S. The effects of video-game training on broad cognitive transfer in multiple sclerosis: a pilot randomized controlled trial. J. Clin. Exp. Neuropsychol. 37, 285–302 (2015).

    Article  PubMed  Google Scholar 

  120. De Giglio, L. et al. A low-cost cognitive rehabilitation with a commercial video game improves sustained attention and executive functions in multiple sclerosis: a pilot study. Neurorehabil. Neural Repair. 29, 453–461 (2015).

    Article  PubMed  Google Scholar 

  121. Gich, J. et al. A randomized, controlled, single-blind 6-month pilot study to evaluate the efficacy of MS-Line!: a cognitive rehabilitation programme for patients with multiple sclerosis. Mult. Scler. J. 21, 1332–1343 (2015).

    Article  Google Scholar 

  122. Mattioli, F., Stampatori, C., Zanotti, D., Parrinello, G. & Capra, R. Efficacy and specificity of intensive cognitive rehabilitation of attention and executive functions in multiple sclerosis. J. Neurol. Sci. 288, 101–105 (2010).

    Article  PubMed  Google Scholar 

  123. Messinis, L. et al. Efficacy of a computer-assisted cognitive rehabilitation intervention in relapsing–remitting multiple sclerosis patients: a multicenter randomized controlled trial. Behav. Neurol. 2017, 5919841 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Mattioli, F., Stampatori, C., Scarpazza, C., Parrinello, G. & Capra, R. Persistence of the effects of attention and executive functions intensive rehabilitation in relapsing remitting multiple sclerosis. Mult. Scler. Relat. Disord. 1, 168–173 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Mattioli, F. et al. Two years follow up of domain specific cognitive training in relapsing remitting multiple sclerosis: a randomized clinical trial. Front. Behav. Neurosci. 10, 28 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Parisi, L. et al. Changes of brain resting state functional connectivity predict the persistence of cognitive rehabilitation effects in patients with multiple sclerosis. Mult. Scler. 20, 686–694 (2014).

    Article  PubMed  Google Scholar 

  127. Bonavita, S. et al. Computer-aided cognitive rehabilitation improves cognitive performances and induces brain functional connectivity changes in relapsing remitting multiple sclerosis patients: an exploratory study. J. Neurol. 262, 91–100 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Filippi, M. et al. Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures — an explorative study. Radiology 262, 932–940 (2012).

    Article  PubMed  Google Scholar 

  129. Stuifbergen, A. K. et al. Computer-assisted cognitive rehabilitation in persons with multiple sclerosis: results of a multi-site randomized controlled trial with six month follow-up. Disabil. Health J. 11, 427–434 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lincoln, N. B. et al. Cognitive Rehabilitation for Attention and Memory in people with Multiple Sclerosis: study protocol for a randomised controlled trial (CRAMMS). Trials 16, 556 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Hynes, S. M. & Forwell, S. A Cognitive Occupation-based Programme for people with Multiple Sclerosis: a new occupational therapy cognitive rehabilitation intervention. Hong Kong J. Occup. Ther. 32, 41–52 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Nauta, I. M. et al. Cognitive Rehabilitation and Mindfulness in Multiple Sclerosis (REMIND-MS): a study protocol for a randomised controlled trial. BMC Neurol. 17, 201 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Nouchi, R. et al. Brain training game boosts executive functions, working memory and processing speed in the young adults: a randomized controlled trial. PLoS One 8, e55518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rilo, O. et al. Integrative group-based cognitive rehabilitation efficacy in multiple sclerosis: a randomized clinical trial. Disabil. Rehabil. 40, 208–216 (2018).

    Article  PubMed  Google Scholar 

  135. das Nair, R. & Lincoln, N. B. Evaluation of Rehabilitation of Memory in Neurological Disabilities (ReMiND): a randomized controlled trial. Clin. Rehabil. 26, 894–903 (2015).

    Article  Google Scholar 

  136. Carr, S. E., das Nair, R., Schwartz, A. F. & Lincoln, N. B. Group memory rehabilitation for people with multiple sclerosis: a feasibility randomized controlled trial. Clin. Rehabil. 28, 552–561 (2014).

    Article  PubMed  Google Scholar 

  137. Chouliara, N. & Lincoln, N. B. Qualitative exploration of the benefits of group-based memory rehabilitation for people with neurological disabilities: implications for rehabilitation delivery and evaluation. BMJ Open 6, e011225 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Mani, A., Chohedri, E., Ravanfar, P., Mowla, A. & Nikseresht, A. Efficacy of group cognitive rehabilitation therapy in multiple sclerosis. Acta Neurol. Scand. 137, 589–597 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Shevil, E. & Finlayson, M. Pilot study of a cognitive intervention program for persons with multiple sclerosis. Health Educ. Res. 25, 41–53 (2010).

    Article  PubMed  Google Scholar 

  140. Thaut, M. H. et al. Music mnemonics aid verbal memory and induce learning-related brain plasticity in multiple sclerosis. Front. Hum. Neurosci. 8, 395 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Gentry, T. PDAs as cognitive aids for people with multiple sclerosis. Am. J. Occup. Ther. 62, 18–27 (2008).

    Article  PubMed  Google Scholar 

  142. Pöttgen, J., Lau, S., Penner, I., Heesen, C. & Moritz, S. Managing neuropsychological impairment in multiple sclerosis pilot study on a standardized metacognitive intervention. Int. J. MS Care 17, 130–137 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Martinez-Gonzalez, A. & Piqueras, J. A. Long-term effectiveness of combined cognitive–behavioral and neuropsychological intervention in a case of multiple sclerosis. Neurocase 21, 584–591 (2015).

    Article  PubMed  Google Scholar 

  144. Mattioli, F., Bellomi, F., Stampatori, C., Capra, R. & Miniussi, C. Neuroenhancement through cognitive training and anodal tDCS in MS. Mult. Scler. 22, 222–230 (2016).

    Article  PubMed  Google Scholar 

  145. Jimenez-Morales, R. M. et al. Cognitive training combined with aerobic exercises in multiple sclerosis patients: a pilot study [Spanish]. Rev. Neurol. 64, 489–495 (2017).

    CAS  PubMed  Google Scholar 

  146. Barbarulo, A. M. et al. Integrated cognitive and neuromotor rehabilitation in multiple sclerosis: a pragmatic study. Front. Behav. Neurosci. 12, 196 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Costello, F., Stüve, O., Weber, M. S., Zamvil, S. S. & Frohman, E. Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice. Curr. Opin. Neurol. 20, 281–285 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Khan, F. & Amatya, B. Rehabilitation in multiple sclerosis: a systematic review of systematic reviews. Arch. Phys. Med. Rehabil. 98, 353–367 (2017).

    Article  PubMed  Google Scholar 

  149. das Nair, R. Evaluating cognitive rehabilitation in multiple sclerosis: on the bumpy road to establishing evidence. Neurodegener. Dis. Manag. 5, 473–478 (2015).

    Article  PubMed  Google Scholar 

  150. George, S. & Rampling, S. People with multiple sclerosis report cognitive rehabilitation is effective in increasing strategy use and quality of life but they recommend more caregiver involvement and personal feedback to enhance outcomes. Aust. Occup. Ther. J. 65, 161–162 (2018).

    Article  PubMed  Google Scholar 

  151. Sokolov, A. A., Grivaz, P. & Bove, R. Cognitive deficits in multiple sclerosis: recent advances in treatment and neurorehabilitation. Curr. Treat. Options Neurol. 20, 53 (2018).

    Article  PubMed  Google Scholar 

  152. Prosperini, L., Piattella, M. C., Giannì, C. & Pantano, P. Functional and structural brain plasticity enhanced by motor and cognitive rehabilitation in multiple sclerosis. Neural Plast. 2015, 481574 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Dardiotis, E. et al. Efficacy of computer-based cognitive training in neuropsychological performance of patients with multiple sclerosis: a systematic review and meta-analysis. Mult. Scler. Relat. Disord. 20, 58–66 (2018).

    Article  PubMed  Google Scholar 

  154. Chiaravalloti, N. D., Goverover, Y., Costa, S. L. & DeLuca, J. A pilot study examining speed of processing training (SPT) to improve processing speed in persons with multiple sclerosis. Front. Neurol. 9, 685 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Arsoy, E., Tüzün, E. & Türkoğlu, R. Effects of computer-assisted cognitive rehabilitation in benign multiple sclerosis. Turk. J. Med. Sci. 48, 999–1005 (2018).

    Article  PubMed  Google Scholar 

  156. Maggio, M. G. et al. Virtual reality in multiple sclerosis rehabilitation: a review on cognitive and motor outcomes. J. Clin. Neurosci. 65, 106–111 (2019).

    Article  PubMed  Google Scholar 

  157. Lampit, A. et al. Computerized cognitive training in multiple sclerosis: a systematic review and meta-analysis. Neurorehabil. Neural Repair. 33, 695–706 (2019).

    Article  PubMed  Google Scholar 

  158. Voss, M. W., Nagamatsu, L. S., Liu-Ambrose, T. & Kramer, A. F. Exercise, brain, and cognition across the life span. J. Appl. Physiol. 111, 1505–1513 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Motl, R. W., Sandroff, B. M. & Benedict, R. H. B. Cognitive dysfunction and multiple sclerosis: developing a rationale for considering the efficacy of exercise training. Mult. Scler. 17, 1034–1040 (2011).

    Article  PubMed  Google Scholar 

  160. Benedict, R. H. et al. Upper and lower extremity motor function and cognitive impairment in multiple sclerosis. J. Int. Neuropsychol. Soc. 17, 643–653 (2011).

    Article  PubMed  Google Scholar 

  161. Sandroff, B. M. et al. Integrative CNS plasticity with exercise in MS: the PRIMERS (PRocessing, Integration of Multisensory Exercise-Related Stimuli) conceptual framework. Neurorehabil. Neural Repair. 32, 847–862 (2018).

    Article  PubMed  Google Scholar 

  162. Motl, R. W., Sandroff, B. M. & DeLuca, J. Exercise training and cognitive rehabilitation: a symbiotic approach for rehabilitating walking and cognitive functions in multiple sclerosis? Neurorehabil. Neural Repair. 30, 499–511 (2016).

    Article  PubMed  Google Scholar 

  163. Sandroff, B. M., Motl, R. W., Scudder, M. R. & DeLuca, J. Systematic, evidence-based review of exercise, physical activity, and physical fitness effects on cognition in persons with multiple sclerosis. Neuropsychol. Rev. 26, 271–294 (2016).

    Article  PubMed  Google Scholar 

  164. Oken, B. S. et al. Randomized controlled trial of yoga and exercise in multiple sclerosis. Neurology 62, 2058–2064 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Romberg, A., Virtanen, A. & Ruutiainen, R. Long-term exercise improves functional impairment but not quality of life in multiple sclerosis. J. Neurol. 252, 839–845 (2005).

    Article  PubMed  Google Scholar 

  166. Velikonja, O., Čurić, K., Ožura, A. & Jazbec, S. Š. Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis. Clin. Neurol. Neurosurg. 112, 597–601 (2010).

    Article  PubMed  Google Scholar 

  167. Pilutti, L. A. et al. Effects of 12 weeks of supported treadmill training on functional ability and quality of life in progressive multiple sclerosis: a pilot study. Arch. Phys. Med. Rehabil. 92, 31–36 (2011).

    Article  PubMed  Google Scholar 

  168. Carter, A. et al. Pragmatic intervention for increasing self-directed exercise behaviour and improving important health outcomes in people with multiple sclerosis: a randomised controlled trial. Mult. Scler. 20, 1112–1122 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Briken, S. et al. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial. Mult. Scler. 20, 382–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Leavitt, V. M. et al. Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings. Neurocase 20, 695–697 (2013).

    Article  PubMed  Google Scholar 

  171. Hoang, P., Schoene, D., Gandevia, S., Smith, S. & Lord, S. R. Effects of a home-based step training programme on balance, stepping, cognition and functional performance in people with multiple sclerosis — a randomized controlled trial. Mult. Scler. 22, 94–103 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Sangelaji, B. et al. The effect of exercise therapy on cognitive functions in multiple sclerosis patients: a pilot study. Med. J. Islam. Repub. Iran. 29, 205 (2015).

    PubMed  PubMed Central  Google Scholar 

  173. Küçük, F., Kara, B., Poyraz, E. Ç. & İdiman, E. Improvements in cognition, quality of life, and physical performance with clinical pilates in multiple sclerosis: a randomized controlled trial. J. Phys. Ther. Sci. 28, 761–768 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Kierkegaard, M. et al. High-intensity resistance training in multiple sclerosis — an exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition. J. Neurol. Sci. 362, 251–257 (2016).

    Article  PubMed  Google Scholar 

  175. Felippe, L. A., Salgado, P. R., De Souza Silvestre, D., Smaili, S. M. & Christofoletti, G. A controlled clinical trial on the effects of exercise on cognition and mobility in adults with multiple sclerosis. Am. J. Phys. Med. Rehabil. 98, 97–102 (2019).

    Article  PubMed  Google Scholar 

  176. Coghe, G. et al. Fatigue, as measured using the Modified Fatigue Impact Scale, is a predictor of processing speed improvement induced by exercise in patients with multiple sclerosis: data from a randomized controlled trial. J. Neurol. 265, 1328–1333 (2018).

    Article  PubMed  Google Scholar 

  177. Barry, A. et al. Impact of short-term cycle ergometer training on quality of life, cognition and depressive symptomatology in multiple sclerosis patients: a pilot study. Neurol. Sci. 39, 461–469 (2018).

    Article  PubMed  Google Scholar 

  178. Baquet, L. et al. Short-term interval aerobic exercise training does not improve memory functioning in relapsing–remitting multiple sclerosis — a randomized controlled trial. PeerJ 6, e6037 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Huiskamp, M. et al. A pilot study of the effects of running training on visuospatial memory in MS: a stronger functional embedding of the hippocampus in the default-mode network? Mult. Scler. https://doi.org/10.1177/1352458519863644 (2019).

    Article  PubMed  Google Scholar 

  180. Ng, A. et al. Ballroom dance for persons with multiple sclerosis: a pilot feasibility study. Disabil. Rehabil. 42, 1115–1121 (2019).

    Article  PubMed  Google Scholar 

  181. Coote, S. et al. Effect of exercising at minimum recommendations of the multiple sclerosis exercise guideline combined with structured education or attention control education — secondary results of the step it up randomised controlled trial. BMC Neurol. 17, 119 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Kara, B., Küçük, F., Poyraz, E. C., Tomruk, M. S. & Idiman, E. Different types of exercise in multiple sclerosis: aerobic exercise or pilates, a single-blind clinical study. J. Back Musculoskelet. Rehabil. 30, 565–573 (2017).

    Article  PubMed  Google Scholar 

  183. Kjølhede, T. et al. Can resistance training impact MRI outcomes in relapsing–remitting multiple sclerosis? Mult. Scler. 24, 1356–1365 (2018).

    Article  PubMed  Google Scholar 

  184. Abasıyanık, Z., Ertekin, Ö., Kahraman, T., Yigit, P. & Özakbaş, S. The effects of clinical pilates training on walking, balance, fall risk, respiratory, and cognitive functions in persons with multiple sclerosis: a randomized controlled trial. Explore 16, 12–20 (2020).

    Article  PubMed  Google Scholar 

  185. Sandroff, B. M. et al. Systematically developed pilot randomized controlled trial of exercise and cognition in persons with multiple sclerosis. Neurocase 22, 443–450 (2016).

    Article  PubMed  Google Scholar 

  186. Orban, A. et al. Effect of high-intensity exercise on multiple sclerosis function and phosphorous magnetic resonance spectroscopy outcomes. Med. Sci. Sports Exerc. 51, 1380–1386 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Feys, P. et al. Effects of an individual 12-week community-located “start-to-run” program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis. Mult. Scler. 25, 92–103 (2019).

    Article  PubMed  Google Scholar 

  188. Gonzales, B. et al. Effects of a training program involving body cooling on physical and cognitive capacities and quality of life in multiple sclerosis patients: a pilot study. Eur. Neurol. 78, 71–77 (2017).

    Article  PubMed  Google Scholar 

  189. Sandroff, B. M., Johnson, C. L. & Motl, R. W. Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography. Neuroradiology 59, 61–67 (2017).

    Article  PubMed  Google Scholar 

  190. Sandroff, B. M. et al. Multimodal exercise training in multiple sclerosis: a randomized controlled trial in persons with substantial mobility disability. Contemp. Clin. Trials 61, 39–47 (2017).

    Article  PubMed  Google Scholar 

  191. Zimmer, P. et al. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: a randomized controlled trial. Mult. Scler. J. 24, 1635–1644 (2018).

    Article  CAS  Google Scholar 

  192. Sandroff, B. M. et al. Treadmill walking exercise training and brain function in multiple sclerosis: preliminary evidence setting the stage for a network-based approach to rehabilitation. Mult. Scler. J. Exp. Transl. Clin. 4, 2055217318760641 (2018).

    PubMed  PubMed Central  Google Scholar 

  193. Sebastião, E. et al. Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study. Contemp. Clin. Trials 73, 136–144 (2018).

    Article  PubMed  Google Scholar 

  194. Sandroff, B. M. & DeLuca, J. Will behavioral treatments for cognitive impairment in multiple sclerosis become standards-of-care? Int. J. Psychophysiol. https://doi.org/10.1016/j.ijpsycho.2019.02.010 (2019).

    Article  PubMed  Google Scholar 

  195. Sandroff, B. M. et al. Rationale and design of a single-blind, randomised controlled trial of exercise training for managing learning and memory impairment in persons with multiple sclerosis. BMJ Open 8, e023231 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Sandroff, B. M. et al. Protocol for a systematically-developed, phase I/II, single-blind randomized controlled trial of treadmill walking exercise training effects on cognition and brain function in persons with multiple sclerosis. Contemp. Clin. Trials 87, 105878 (2019).

    Article  PubMed  Google Scholar 

  197. Motl, R. W. et al. Exercise in patients with multiple sclerosis. Lancet Neurol. 16, 848–856 (2017).

    Article  PubMed  Google Scholar 

  198. Motl, R. W. & Sandroff, B. M. Exercise as a countermeasure to declining central nervous system function in multiple sclerosis. Clin. Ther. 40, 16–25 (2018).

    Article  PubMed  Google Scholar 

  199. Spirduso, W. W. Physical fitness, aging, and psychomotor speed: a review. J. Gerontol. 35, 850–865 (1980).

    Article  CAS  PubMed  Google Scholar 

  200. Dustman, R. E. et al. Aerobic exercise training and improved neuropsychological function of older individuals. Neurobiol. Aging 5, 35–42 (1984).

    Article  CAS  PubMed  Google Scholar 

  201. Bherer, L., Erickson, K. I. & Liu-Ambrose, T. A review of the effects of physical activity and exercise on cognitive and brain functions in older adults. J. Aging Res. 2013, 657508 (2013).

    PubMed  PubMed Central  Google Scholar 

  202. Heyn, P., Abreu, B. C. & Ottenbacher, K. J. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch. Phys. Med. Rehabil. 85, 1694–1704 (2004).

    Article  PubMed  Google Scholar 

  203. American College of Sports Medicine. ACSM’s Resource Manual for Guidelines for Exercise Testing and Prescription 7th edn (Lippincott Williams & Wilkins, 2013).

  204. Portney, L. G. & Watkins, M. P. Foundations of Clinical Research: Applications to Practice 3rd edn (Pearson/Prentice Hall, 2009).

  205. Brochet, B. & Ruet, A. Cognitive impairment in multiple sclerosis with regards to disease duration and clinical phenotypes. Front. Neurol. 10, 261 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Hart, T. et al. A theory-driven system for the specification of rehabilitation treatments. Arch. Phys. Med. Rehabil. 100, 172–180 (2019).

    Article  PubMed  Google Scholar 

  207. Chiaravalloti, N. D. & DeLuca, J. The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: a sub-analysis of the MEMREHAB trial. Mult. Scler. 21, 1575–1582 (2015).

    Article  CAS  PubMed  Google Scholar 

  208. Baird, J. F. & Motl, R. W. Response heterogeneity with exercise training and physical activity interventions among persons with multiple sclerosis. Neurorehabil. Neural Repair 33, 3–14 (2019).

    Article  PubMed  Google Scholar 

  209. Fuchs, T. A. et al. Response heterogeneity to home-based restorative cognitive rehabilitation in multiple sclerosis: an exploratory study. Mult. Scler. Relat. Disord. 34, 103–111 (2019).

    Article  PubMed  Google Scholar 

  210. Sandroff, B. M., Baird, J. F., Silveira, S. L. & Motl, R. W. Response heterogeneity in fitness, mobility and cognition with exercise-training in MS. Acta Neurol. Scand. 139, 183–191 (2019).

    Article  PubMed  Google Scholar 

  211. Boringa, J. B. et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult. Scler. 7, 263–267 (2001).

    Article  CAS  PubMed  Google Scholar 

  212. Benedict, R. H. B. et al. Minimal neuropsychological assessment of MS patients: a consensus approach. Clin. Neuropsychol. 16, 381–397 (2002).

    Article  PubMed  Google Scholar 

  213. Langdon, D. W. et al. Recommendations for a brief international cognitive assessment for multiple sclerosis (BICAMS). Mult. Scler. 18, 891–898 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The preparation of this paper was supported by the Kessler Foundation and the University of Alabama at Birmingham. The preparation of this paper was not supported by an externally funded grant award.

Author information

Authors and Affiliations

  1. Kessler Foundation, East Hanover, NJ, USA

    John DeLuca & Nancy D. Chiaravalloti

  2. Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA

    Brian M. Sandroff

Authors
  1. John DeLuca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy D. Chiaravalloti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian M. Sandroff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Each author contributed equally to researching data for the article and wrote the sections of the manuscript that fell within their area of expertise (J.D.: cognitive impairment in MS and imaging; N.D.C.: cognitive rehabilitation; B.M.S.: exercise). All authors edited the manuscript in its entirety and provided comments and suggestions prior to submission.

Corresponding author

Correspondence to John DeLuca.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks C. Heesen, E. Portaccio and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Processing speed

The rate at which the brain is able to take in information, process it and give an appropriate response.

Executive functioning

A set of cognitive processes necessary for the cognitive control of behaviour, including monitoring behaviours that facilitate the attainment of chosen goals.

Working memory

A cognitive process that involves storing, focusing attention on and manipulating information for a relatively short period of time (such as a few seconds).

Cognitive rehabilitation

A systematically applied set of medical and therapeutic services designed to improve cognitive functioning and participation in activities that might be affected by difficulties in one or more cognitive domains.

Exercise training

Planned, structured, repetitive physical activity performed to improve or maintain one or more aspects of physical fitness.

Neuroplasticity

The ability of the brain to form and reorganize synaptic connections, especially in response to learning or experience or following injury.

Functional connectivity

The temporal correlation between the time series of different brain regions or the presence of statistical dependence between two sets of neurophysiological data.

Effective connectivity

The influence of one neural system over another, either at a synaptic or a cortical level.

Cognitive reserve

The extent to which the brain can sustain damage, as from Alzheimer disease, stroke, alcohol overuse or head injury, for example, without affecting intellectual capacity.

n-back

A continuous performance task often used to measure working memory capacity. The participant is presented with a sequence of letters and must indicate when the current stimulus matches the one occurring n steps earlier. The load factor n can be adjusted to make the task more or less difficult (for example, 1-back, 2-back, 3-back).

Trait conscientiousness

The degree to which an individual is conscientious as a personality trait. Conscientiousness refers to being careful or diligent, or having a desire to do a task well. Individuals high on persistence are considered ambitious and perfectionistic and demonstrate a determination and tenacity to achieve a goal. Such descriptions are most consistent with the trait of conscientiousness.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

DeLuca, J., Chiaravalloti, N.D. & Sandroff, B.M. Treatment and management of cognitive dysfunction in patients with multiple sclerosis. Nat Rev Neurol 16, 319–332 (2020). https://doi.org/10.1038/s41582-020-0355-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-020-0355-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing