Purpose of review
This article highlights recent progress in research on treatment and neurorehabilitation of cognitive impairment in multiple sclerosis (MS) including pharmacological interventions, physical exercise, and neuropsychological rehabilitation, both in conventional and technology-assisted settings.
The most consistent evidence in terms of improvement or preservation of circumscribed cognitive scores in MS patients comes from moderately sampled randomized clinical trials on multimodal approaches that combine conventional or computerized neuropsychological training with psychoeducation or cognitive behavioral therapy. Disease-modifying treatments also appear to have beneficial effects in preventing or attenuating cognitive decline, whereas there is little evidence for agents such as donepezil or stimulants. Finally, physical exercise may yield some cognitive improvement in MS patients.
Despite substantial and often promising research efforts, there is a lack of validated and widely accepted clinical procedures for cognitive neurorehabilitation in MS. Development of such approaches will require collaborative efforts towards the design of interventions that are fundamentally inspired by cognitive neuroscience, potentially guided by neuroimaging, and composed of conventional neuropsychological training and cognitive behavioral therapy as well as physical exercise and therapeutic video games. Subsequently, large-scale validation will be needed with meaningful outcome measures reflecting transfer to everyday cognitive function and maintenance of training effects.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Wingerchuk DM, Weinshenker BG. Disease modifying therapies for relapsing multiple sclerosis. BMJ. 2016;354:i3518.
Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–20.
Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7:1139–51.
• Ruano L, Portaccio E, Goretti B, Niccolai C, Severo M, Patti F, et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. 2017;23:1258–67 This work analyzes the effect of age and disease progression on cognition in multiple sclerosis.
Jones DK, Knosche TR, Turner R. White matter integrity, fiber count, and other fallacies: the do’s and don’ts of diffusion MRI. NeuroImage. 2013;73:239–54.
Dineen RA, Vilisaar J, Hlinka J, Bradshaw CM, Morgan PS, Constantinescu CS, et al. Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis. Brain. 2009;132:239–49.
Bonnier G, Roche A, Romascano D, Simioni S, Meskaldji D, Rotzinger D, et al. Advanced MRI unravels the nature of tissue alterations in early multiple sclerosis. Ann Clin Transl Neurol. 2014;1:423–32.
Rocca MA, Amato MP, de Stefano N, Enzinger C, Geurts JJ, Penner IK, et al. Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis. Lancet Neurol. 2015;14:302–17.
Simioni S, Amarù F, Bonnier G, Kober T, Rotzinger D, du Pasquier R, et al. MP2RAGE provides new clinically-compatible correlates of mild cognitive deficits in relapsing-remitting multiple sclerosis. J Neurol. 2014;261:1606–13.
Jacobsen C, Hagemeier J, Myhr KM, Nyland H, Lode K, Bergsland N, et al. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry. 2014;85:1109–15.
Zakzanis KK. Distinct neurocognitive profiles in multiple sclerosis subtypes. Arch Clin Neuropsychol. 2000;15:115–36.
Morrow SA, Weinstock-Guttman B, Munschauer FE, Hojnacki D, Benedict RH. Subjective fatigue is not associated with cognitive impairment in multiple sclerosis: cross-sectional and longitudinal analysis. Mult Scler. 2009;15:998–1005.
Carter A, Daley A, Humphreys L, Snowdon N, Woodroofe N, Petty J, 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. 2014;20:1112–22.
Velikonja O, Curic K, Ozura A, Jazbec SS. Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis. Clin Neurol Neurosurg. 2010;112:597–601.
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. 2014;35:519–27.
Mattioli F, Stampatori C, Bellomi F, Danni M, Compagnucci L, Uccelli A, et al. A RCT comparing specific intensive cognitive training to aspecific psychological intervention in RRMS: the SMICT study. Front Neurol. 2014;5:278.
Shatil E, Metzer A, Horvitz O, Miller A. Home-based personalized cognitive training in MS patients: a study of adherence and cognitive performance. NeuroRehabilitation. 2010;26:143–53.
Smith A. Symbol digit modalities test. Los Angeles: Western Psychological Services; 1982.
• Sumowski JF, Benedict R, Enzinger C, Filippi M, Geurts JJ, Hamalainen P, et al. Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology. 2018;90:278–88 Informative article on cognitive assessment and rehabilitation in multiple sclerosis.
Benedict RH, DeLuca J, Phillips G, LaRocca N, Hudson LD, Rudick R, et al. Validity of the symbol digit modalities test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23:721–33.
Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills. 1977;44:367–73.
Buschke H. Selective reminding for analysis of memory and learning. J Verbal Learn Verbal Behav. 1973;12:543–50.
Delis DC, Kramer JH, Kaplan E, Ober BA. California verbal learning test–II, second edition. San Antonio: The Psychological Corporation; 2000.
Benedict RHB. Brief visuospatial memory test - revised: Professional manual. Lutz: Psychological Assessment Resources, Inc.; 1997.
Rao SM. A manual for the brief repeatable battery of neuropsychological tests in multiple sclerosis. New York: National Multiple Sclerosis Society; 1990.
Niccolai C, Portaccio E, Goretti B, Hakiki B, Giannini M, Pastò L, et al. A comparison of the brief international cognitive assessment for multiple sclerosis and the brief repeatable battery in multiple sclerosis patients. BMC Neurol. 2015;15:204.
Delis DC, Kaplan E, Kramer JH. Delis-Kaplan Executive Function System (D-KEFS). San Antonio: The Psychological Corporation; 2001.
Benedict RH, et al. Brief international cognitive assessment for MS (BICAMS): international standards for validation. BMC Neurol. 2012;12:55.
•• Langdon DW, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, et al. Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. 2012;18:891–8 Study establishing the rationale, benefits, and roadmap to using the BICAMS as a rapid, feasible in-clinic screen for cognitive impairment in people with MS.
Penner IK, Stemper B, Calabrese P, Freedman MS, Polman CH, Edan G, et al. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler. 2012;18:1466–71.
Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8:987–97.
Edan G, Kappos L, Montalban X, Polman CH, Freedman MS, Hartung HP, et al. Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry. 2014;85:1183–9.
Kappos L, Edan G, Freedman MS, Montalbán X, Hartung HP, Hemmer B, et al. The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology. 2016;87:978–87.
Patti F, et al. Subcutaneous interferon beta-1a may protect against cognitive impairment in patients with relapsing-remitting multiple sclerosis: 5-year follow-up of the COGIMUS study. PLoS One. 2013;8:e74111.
Patti F, Amato MP, Bastianello S, Caniatti L, di Monte E, Ferrazza P, et al. Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis. Mult Scler. 2010;16:68–77.
Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23.
Weinstock-Guttman B, Galetta SL, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, et al. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. J Neurol. 2012;259:898–905.
Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.
Iaffaldano P, et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS One. 2012;7:e35843.
Wilken J, Kane RL, Sullivan CL, Gudesblatt M, Lucas S, Fallis R, et al. Changes in fatigue and cognition in patients with relapsing forms of multiple sclerosis treated with Natalizumab: the ENER-G study. Int J MS Care. 2013;15:120–8.
Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.
Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.
Kappos L, Radue EW, Chin P, Ritter S, Tomic D, Lublin F. Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis. J Neurol. 2016;263:354–60.
Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011;76:1500–7.
Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RHB, DeLuca J. L-amphetamine improves memory in MS patients with objective memory impairment. Mult Scler. 2011;17:1141–5.
Ford-Johnson L, DeLuca J, Zhang J, Elovic E, Lengenfelder J, Chiaravalloti ND. Cognitive effects of modafinil in patients with multiple sclerosis: a clinical trial. Rehabil Psychol. 2016;61:82–91.
Broicher SD, Filli L, Geisseler O, Germann N, Zörner B, Brugger P, et al. Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years. J Neurol. 2018;265:1016–25.
Pavsic K, Pelicon K, Ledinek AH, Sega S. Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients. Clin Neurol Neurosurg. 2015;139:35–40.
•• Chiaravalloti N, Moore NB, Nikelshpur OM, DeLuca J. An RCT to treat learning impairment in multiple sclerosis: the MEMREHAB trial. Neurology. 2013;81:2066–72 First study to convincingly show an effect of cognitive remediation on improvement in verbal learning in people with MS.
Chiaravalloti ND, Wylie G, Leavitt V, DeLuca J. Increased cerebral activation after behavioral treatment for memory deficits in MS. J Neurol. 2012;259:1337–46.
Ernst A, et al. Autobiographical memory in multiple sclerosis patients: assessment and cognitive facilitation. Neuropsychol Rehabil. 2012
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. 2015;33:621–38.
Fink F, Rischkau E, Butt M, Klein J, Eling P, Hildebrandt H. Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudo-randomized trial. Mult Scler. 2010;16:1148–51.
Rilo O, Peña J, Ojeda N, Rodríguez-Antigüedad A, Mendibe-Bilbao M, Gómez-Gastiasoro A, et al. Integrative group-based cognitive rehabilitation efficacy in multiple sclerosis: a randomized clinical trial. Disabil Rehabil. 2018;40:208–16.
Mani A, Chohedri E, Ravanfar P, Mowla A, Nikseresht A. Efficacy of group cognitive rehabilitation therapy in multiple sclerosis. Acta Neurol Scand. 2018;137:589–97.
Hanssen KT, Beiske AG, Landro NI, Hofoss D, Hessen E. Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial. Acta Neurol Scand. 2016;133:30–40.
Shevil E, Finlayson M. Pilot study of a cognitive intervention program for persons with multiple sclerosis. Health Educ Res. 2010;25:41–53.
Pottgen 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. 2015;17:130–7.
Amato MP, Goretti B, Viterbo RG, Portaccio E, Niccolai C, Hakiki B, et al. Computer-assisted rehabilitation of attention in patients with multiple sclerosis: results of a randomized, double-blind trial. Mult Scler. 2014;20:91–8.
• Bonavita S, Sacco R, Della Corte M, Esposito S, Sparaco M, d'Ambrosio A, 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. 2015;262:91–100 Study reporting improvement in processing speed, attention and memory after twice weekly computerized training at home during 8 weeks. The improvements were paralleled by increased resting-state functional MRI connectivity between the posterior cingulate and bilateral inferior parietal cortex.
Brissart H, Leroy M, Morele E, Baumann C, Spitz E, Debouverie M. Cognitive rehabilitation in multiple sclerosis. Neurocase. 2013;19:553–65.
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;2016:4292585.
Cerasa A, Gioia MC, Valentino P, Nisticò R, Chiriaco C, Pirritano D, et al. Computer-assisted cognitive rehabilitation of attention deficits for multiple sclerosis: a randomized trial with fMRI correlates. Neurorehabil Neural Repair. 2013;27:284–95.
Charvet LE, Yang J, Shaw MT, Sherman K, Haider L, Xu J, et al. Cognitive function in multiple sclerosis improves with telerehabilitation: results from a randomized controlled trial. PLoS One. 2017;12:e0177177.
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. 2015;29:453–61.
Hancock LM, Bruce JM, Bruce AS, Lynch SG. Processing speed and working memory training in multiple sclerosis: a double-blind randomized controlled pilot study. J Clin Exp Neuropsychol. 2015;37:113–27.
Janssen A, Boster A, Lee H, Patterson B, Prakash RS. The effects of video-game training on broad cognitive transfer in multiple sclerosis: a pilot randomized controlled trial. J Clin Exp Neuropsychol. 2015;37:285–302.
Mantynen A, et al. Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-Centre trial. Mult Scler. 2014;20:99–107.
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. 2010;288:101–5.
Perez-Martin MY, Gonzalez-Platas M, Eguia-Del Rio P, Croissier-Elias C, Jimenez Sosa A. Efficacy of a short cognitive training program in patients with multiple sclerosis. Neuropsychiatr Dis Treat. 2017;13:245–52.
Stuifbergen AK, Becker H, Perez F, Morison J, Kullberg V, Todd A. A randomized controlled trial of a cognitive rehabilitation intervention for persons with multiple sclerosis. Clin Rehabil. 2012;26:882–93.
Leeuwis AE, et al. Design of the ExCersion-VCI study: the effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment. Alzheimers Dement. 2017;3:157–65.
Lauenroth A, Ioannidis AE, Teichmann B. Influence of combined physical and cognitive training on cognition: a systematic review. BMC Geriatr. 2016;16:141.
Briken S, Gold SM, Patra S, Vettorazzi E, Harbs D, Tallner A, et al. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial. Mult Scler. 2014;20:382–90.
Hoang P, Schoene D, Gandevia S, Smith S, Lord SR. 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. 2016;22:94–103.
Sandroff BM, Balto JM, Klaren RE, Sommer SK, DeLuca J, Motl RW. Systematically developed pilot randomized controlled trial of exercise and cognition in persons with multiple sclerosis. Neurocase. 2016;22:443–50.
Sangelaji B, Estebsari F, Nabavi SM, Jamshidi E, Morsali D, Dastoorpoor M, et al. The effect of exercise therapy on cognitive functions in multiple sclerosis patients: a pilot study. Med J Islam Repub Iran. 2015;29:205.
Sumowski JF, Chiaravalloti N, DeLuca J. Retrieval practice improves memory in multiple sclerosis: clinical application of the testing effect. Neuropsychology. 2010;24:267–72.
Foroughi CK, Monfort SS, Paczynski M, PE MK, Greenwood PM. Placebo effects in cognitive training. Proc Natl Acad Sci U S A. 2016;113:7470–4.
Mishra J, Anguera JA, Gazzaley A. Video games for neuro-cognitive optimization. Neuron. 2016;90:214–8.
Green CS, Bavelier D. Exercising your brain: a review of human brain plasticity and training-induced learning. Psychol Aging. 2008;23:692–701.
•• Anguera JA, Boccanfuso J, Rintoul JL, Al-Hashimi O, Faraji F, Janowich J, et al. Video game training enhances cognitive control in older adults. Nature. 2013;501:97–101 A series of experiments demonstrates that adapative video games can improve cognitive control even in older individuals, and establishes a novel approach to cognitive remediation through videogames.
Mishra J, de Villers-Sidani E, Merzenich M, Gazzaley A. Adaptive training diminishes distractibility in aging across species. Neuron. 2014;84:1091–103.
deBettencourt MT, Cohen JD, Lee RF, Norman KA, Turk-Browne NB. Closed-loop training of attention with real-time brain imaging. Nat Neurosci. 2015;18:470–5.
Gao Y, Mandryk R. The acute cognitive benefits of casual exergame play. Proceedings of the 2012 ACM annual conference on Human Factors in Computing Systems. 2012;12:1863.
Maillot P, Perrot A, Hartley A. Effects of interactive physical-activity video-game training on physical and cognitive function in older adults. Psychol Aging. 2012;27:589–600.
Desjardins-Crepeau L, Berryman N, Fraser S, Vu TTM, Kergoat MJ, Li K, et al. Effects of combined physical and cognitive training on fitness and neuropsychological outcomes in healthy older adults. Clin Interv Aging. 2016;11:1287–99.
Filippi M, Rocca MA, Benedict RHB, DeLuca J, Geurts JJG, Rombouts SARB, et al. The contribution of MRI in assessing cognitive impairment in multiple sclerosis. Neurology. 2010;75:2121–8.
Rocca MA, Battaglini M, Benedict RHB, de Stefano N, Geurts JJG, Henry RG, et al. Brain MRI atrophy quantification in MS: from methods to clinical application. Neurology. 2017;88:403–13.
Weiskopf N, Suckling J, Williams G, Correia MM, Inkster B, Tait R, et al. Quantitative multi-parameter mapping of R1, PD(*), MT, and R2(*) at 3T: a multi-center validation. Front Neurosci. 2013;7:95.
Sokolov AA, et al. Linking structural and effective brain connectivity: structurally informed parametric empirical Bayes (si-PEB). submitted.
Enzinger C, Pinter D, Rocca MA, de Luca J, Sastre-Garriga J, Audoin B, et al. Longitudinal fMRI studies: exploring brain plasticity and repair in MS. Mult Scler. 2016;22:269–78.
Hubacher M, et al. Case-based fMRI analysis after cognitive rehabilitation in MS: a novel approach. Front Neurol. 2015;6:78.
Sokolov AA, Miall RC, Ivry RB. The cerebellum: adaptive prediction for movement and cognition. Trends Cogn Sci. 2017;21:313–32.
Romascano D, Meskaldji DE, Bonnier G, Simioni S, Rotzinger D, Lin YC, et al. Multicontrast connectometry: a new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis. Hum Brain Mapp. 2015;36:1609–19.
Grimaldi G, Argyropoulos GP, Boehringer A, Celnik P, Edwards MJ, Ferrucci R, et al. Non-invasive cerebellar stimulation--a consensus paper. Cerebellum. 2014;13:121–38.
Xia Z, et al. Modeling disease severity in multiple sclerosis using electronic health records. PLoS One. 2013;8:e78927.
Bove R, et al. Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course. PLoS One. 2013;8:e59707.
Bove R, et al. Evaluating more naturalistic outcome measures: a 1-year smartphone study in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e162.
Thaut MH, Peterson DA, McIntosh GC, Hoemberg V. Music mnemonics aid verbal memory and induce learning - related brain plasticity in multiple sclerosis. Front Hum Neurosci. 2014;8:395.
This work was supported by fellowships from the Leenaards Foundation and the Baasch-Medicus Foundation, a Clinical Medicine Plus scholarship from the Dr. Max Cloëtta Foundation and the Uniscientia Foundation Vaduz, and a grant from the Helmut Horten Foundation to A.A.S.
Conflict of interest
Riley Bove reports grants from Akili Interactive, personal fees from Roche Genentech, personal fees from Genzyme Sanofi, personal fees from Novartis, outside the submitted work. Arseny A. Sokolov reports fellowships from the Leenaards Foundation, from the Dr. Max Cloëtta Foundation and the Uniscientia Foundation Vaduz, from the Baasch-Medicus Foundation, and a grant from the Helmut Horten Foundation during the conduct of the study. Petr Grivaz declares no potential conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders
About this article
Cite this article
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). https://doi.org/10.1007/s11940-018-0538-x
- Multiple sclerosis
- Magnetic resonance imaging
- Video games