In recent years, enormous strides have been made in increasing the range and efficacy of disease-modifying drugs available for the treatment of multiple sclerosis (MS) in its early and remitting stages, and more continue to emerge. Another equally important concept of successful treatment of MS is neurorehabilitation, which must be pursued alongside these medications. Key factors that contribute to the impact of neurorehabilitation include resilience and neuroplasticity. In the former, components such as nutrition, self-belief and physical activity provide a stronger response to the disease and improved responses to treatment. Neuroplasticity is the capacity of the brain to establish new neuronal networks after lesion damage has occurred and distant brain regions assume control of lost functions. In MS, it is vital that each patient is treated by a coordinated multidisciplinary team. This enables all aspects of the disease including problems with mobility, gait, bladder/bowel disturbances, fatigue and depression to be effectively treated. It is also important that the treating team adopts current best practice and provides internationally agreed standards of care. A further vital aspect of MS management is patient engagement, in which individuals are fully involved and are encouraged to strive and put effort into meeting treatment goals. In this approach, healthcare providers become motivators and patients need less intervention and consume fewer resources. Numerous interventions that promote neurorehabilitation are available, though evidence to support their use is limited by a lack of data from large randomised controlled trials. Combining interventions that promote neurorehabilitation with newer, more effective treatments creates a promising potential to substantially improve the outlook for patients at all stages of MS.
Multiple sclerosis, resilience, neurorehabilitation, neuroplasticity
Jürg Kesselring has nothing to disclose in relation to this article. No support was received for the publication of this article.
Medical writing assistance was provided by James Gilbart, Freelance Writer, and was supported by Touch Medical Media.
Compliance with Ethics: This article involves a review of the literature and did not involve any studies with human or animal subjects performed by the author.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
October 27, 2016 Accepted
January 05, 2017
Jürg Kesselring, Head of the Department of Neurology and Neurorehabilitation Rehabilitation Centre Valens, CH-7317 Valens, Switzerland. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Approaches to managing multiple sclerosis (MS) are changing rapidly and are achieving markedly improved efficacy in inhibiting the disease process.1–3 As a result, treatment goals have progressed beyond halting disability progression. The most apparent reason for these achievements is the increasing use of disease-modifying drugs (DMDs) and the emergence of new DMDs that are more effective than those previously available. Despite these advances in DMDs and symptomatic therapies, there remains a need for comprehensive rehabilitation interventions in order to reduce disease symptoms, and to achieve maximal independence and quality of life, particularly in patients with progressive disease.4
When initiating a neurorehabilitation programme, it is important to appreciate the value of maintaining resilience and neuroplasticity in MS patients and to understand the approaches that can encourage these factors and promote neurorehabilitation. Whilst DMDs can limit the occurrence of relapses and inhibit or delay disease progression, those developed so far have limited capacity to ameliorate all the existing disabilities that patients may have, particularly those with progressive disease. It is critical therefore that healthcare providers, who treat patients with MS, are aware of the potential of physical and cognitive therapies, and the benefits that neurorehabilitation can provide for the patient, especially when combined with DMD therapy. This review therefore considers the mechanism of action of neurorehabilitation in MS and interventions that can promote it in particular with respect to resilience and neuroplasticity.
Resilience in multiple sclerosis
In neurological conditions including MS, the concept of resilience is important in terms of impact of the disease and response to treatment. It is difficult to give a concise definition of resilience in the context of MS but it is related to psychological adaptation, social connection, life meaning, planning and physical wellness.5 The concept of resilience comprises physical, mental and emotional components including good nutrition, rest and self-belief (see Figure 1). Without such activity and participation, there is insufficient neuronal stimulation, diminishing or eliminating the prospect of recovery. Patients must be encouraged to develop resilience in order to maximise their potential for regaining some degree of their lost physical abilities.
In a study of MS patients, the effect of occupational therapy on resilience was assessed.6 The findings indicated that resilience has an important role in terms of functional recovery and maintenance. The authors concluded that the use of occupational therapy within multidisciplinary
care has a crucial role and should be considered in the management of MS patients. Furthermore, Black et al. developed a holistic model of resilience, which was tested in people with MS.7 Both direct and indirect pathways were identified to resilience and the findings suggest that psychological interventions to enhance personal resources and assets needed to cope would be effective in MS. These reports suggest that there should be a greater focus on resilience in managing MS patients.
The importance of neuroplasticity in multiple sclerosis
Neuroplasticity is another important concept in MS and is defined as the physical ability of the nervous system to adapt to changes. The recognition of recovery mechanisms in neurological tissue is not new; Constantin von Monakow proposed the idea of diaschisis, now known as neuroplasticity, in 1914.8 This affects the ability of the brain to recover during neurological disease or after injury.9 von Monakow believed that neurons in contact with or surrounding damaged brain areas, suddenly function abnormally or cease to function. This proposal was highly prescient and was confirmed by imaging and electrophysiological studies almost a century later.10–12
Neuroplasticity involves functional adaptations that occur at various different levels in MS.13–17 At the cellular level, changes include axonal sprouting (increased arborisation of neurones), changes of synaptic stability and reorganisation of synapses. At the tissue level, there is resorption of oedema and rearrangement of Na-channels on axons beyond the nodes of Ranvier.18 Re-myelination also occurs, even in adult brains. On the system level, takeover of functions occurs via the contralateral homologous cortex and enlargement of representation zones.
Results from a small cohort study (n=22) found that brain response to an electrical stimulus known as paired associative stimulation (PAS), a measure of neuroplasticity, may predict recovery from a relapse in RRMS.19 Measures of neuroplasticity therefore potentially represent powerful markers that may enable physicians to determine optimal treatment for individuals with MS based on their ability to cope with brain tissue injury.
Not all of the changes in brain activity occurring in MS are adaptive, and thus behaviourally beneficial. Neuroplasticity can also be maladaptive and contribute to or sustain disability.20,21 Furthermore, it is not known whether neuroplasticity is diminished with progressive disease. One study found that brain plasticity (measured as improvements with practice in performing visuomotor tasks) is preserved in MS patients with a high burden of cerebral pathology.21 Another study showed that neuroplasticity in MS can be improved nearly to the same level as healthy controls when individuals are given repeated isometric visuomotor tracking tasks to perform.9,20 With task practice, patients showed decreasing tracking errors and decreased areas of brain oxygenation, as shown by functional magnetic resonance imaging (fMRI). However, other investigations show that patients with primary progressive MS had impaired or absent brain neuroplasticity compared with those with relapsing-remitting MS (RRMS).22
At the behavioural level, neuroplasticity can be induced using novel motor and cognitive strategies, which counter problems of despair and resignation common to many MS patients. These principles were demonstrated in a study of rats given a single neurological lesion using pro-inflammatory cytokines.23 Despite cellular damage and inflammation at the lesion site, function was restored over 28 days post-injury. At cortical sites remote from the lesion, reorganisation of neurones effectively bypassed the damage, suggesting high levels of neuroplasticity in animal brains. The authors of the study proposed that these findings provide a better understanding of endogenous repair capacity in the central nervous system and may help in the development of therapeutic strategies for this repair.
Further work on human brains using fMRI has shown that simple functions such as moving a hand involves more areas of the brain and more energy usage in non-disabled patients with MS than in normal control individuals.24,25 Various other MRI studies in MS have indicated recruitment of related brain regions after damage has occurred at a specific lesion. These changes in brain connectivity affect various functions including motor function, cognition and memory.26–29 In some conditions, such as stroke, there is restoration towards the original physiological network over time, whereas in MS this does not seem to occur and different and more complex patterns of network connections are established.30–35 Studies have also shown that, following an initial increase in brain functional connectivity, it then declines over the following two years, resulting in a decreased ability to compensate for neuronal damage, which leads to disability progression in MS.36
These studies collectively provide evidence of functional change at brain sites remote from the injury or lesions in MS and stress the importance of treatments aimed at maintaining neuroplasticity and brain reserve to inhibit or prevent irreversible disability progression. In order to harness neuroplasticity to achieve neurorehabilitation, we need interventions that combine a strong scientific rationale and a strong biological rationale with monitoring of clinically meaningful functional and structural changes in the brain.17
Neuroplasticity is an important concept, both in terms of functional improvement and in directing future treatment. This was emphasised by the findings of a study that suggested platelet-derived growth factor (PDGF) plays a substantial role in promoting neuroplasticity in progressive MS.37 Enhancing PDGF signalling might therefore be a valuable treatment approach.
1. Derwenskus J, Lublin FD, Future treatment approaches to multiple sclerosis, Handb Clin Neurol, 2014;122:563-77.
2. Fox EJ, Rhoades RW, New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis, Curr Opin Neurol, 2012;25 Suppl:S11–9.
3. Ziemssen T, Derfuss T, de Stefano N, et al., Optimizing treatment success in multiple sclerosis, J Neurol, 2016;263:1053–65.
4. Wiendl H, Meuth SG, Pharmacological Approaches to Delaying Disability Progression in Patients with Multiple Sclerosis, Drugs, 2015;75:947–77.
5. Silverman AM, Verrall AM, Alschuler KN, et al., Bouncing back again, and again: a qualitative study of resilience in people with multiple sclerosis, Disabil Rehabil, 2017;39:14–22.
6. Falk-Kessler J, Kalina JT, Miller P, Influence of occupational therapy on resilience in individuals with multiple sclerosis, Int J MS Care, 2012;14:160–8.
7. Black R, Dorstyn D, A biopsychosocial model of resilience for multiple sclerosis, J Health Psychol, 2015;20:1434–44.
8. Kesselring J, Constantin von Monakow’s formative years in Pfafers, J Neurol, 2000;247:200–5.
9. Tomassini V, Johansen-Berg H, Leonardi L, et al., Preservation of motor skill learning in patients with multiple sclerosis, Mult Scler, 2011;17:103–15.
10. Carrera E, Tononi G, Diaschisis: past, present, future, Brain, 2014;137:2408–22.
11. Fornito A, Zalesky A, Breakspear M, The connectomics of brain disorders, Nat Rev Neurosci, 2015;16:159–72.
12. Heiss WD, Radionuclide imaging in ischemic stroke, J Nucl Med, 2014;55:1831–41.
13. Henze T, Symptomatische Therapie der Multiplen Sklerose [Symptomatic treatment of multiple sclerosis], Stuttgart: Georg Thieme Verlag, 2005.
14. Dobkin BH, Neurobiology of rehabilitation, Ann N Y Acad Sci, 2004;1038:148–70.
15. Flachenecker P, Clinical implications of neuroplasticity - the role of rehabilitation in multiple sclerosis, Front Neurol, 2015;6:36.
16. Kolb B, Muhammad A, Harnessing the power of neuroplasticity for intervention, Front Hum Neurosci, 2014;8:377.
17. Lipp I, Tomassini V, Neuroplasticity and motor rehabilitation in multiple sclerosis, Front Neurol, 2015;6:59.
18. Arancibia-Carcamo IL, Attwell D, The node of Ranvier in CNS pathology, Acta Neuropathol, 2014;128:161–75.
19. Mori F, Kusayanagi H, Nicoletti CG, et al., Cortical plasticity predicts recovery from relapse in multiple sclerosis, Mult Scler, 2014;20:451–7.
20. Tomassini V, Matthews PM, Thompson AJ, et al., Neuroplasticity and functional recovery in multiple sclerosis, Nat Rev Neurol, 2012;8:635–46.
21. Tomassini V, Johansen-Berg H, Jbabdi S, et al., Relating brain damage to brain plasticity in patients with multiple sclerosis, Neurorehabil Neural Repair, 2012;26:581–93.
22. Mori F, Rossi S, Piccinin S, et al., Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis, J Neurosci, 2013;33:19112–9.
23. Kerschensteiner M, Bareyre FM, Buddeberg BS, et al., Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis, J Exp Med, 2004;200:1027–38.
24. Filippi M, Rocca MA, Cortical reorganisation in patients with MS, J Neurol Neurosurg Psychiatry, 2004;75:1087–9.
25. Reddy H, Narayanan S, Woolrich M, et al., Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability, Brain, 2002;125:2646–57.
26. Filippi M, Rocca MA, Present and future of fMRI in multiple sclerosis, Expert Rev Neurother, 2013;13:27–31.
27. Hillary FG, Chiaravalloti ND, Ricker JH, et al., An investigation of working memory rehearsal in multiple sclerosis using fMRI, J Clin Exp Neuropsychol, 2003;25:965–78.
28. Rocca MA, Valsasina P, Hulst HE, et al., Functional correlates of cognitive dysfunction in multiple sclerosis: A multicenter fMRI Study, Hum Brain Mapp, 2014;35:5799–814.
29. Valsasina P, Rocca MA, Absinta M, et al., A multicentre study of motor functional connectivity changes in patients with multiple sclerosis, Eur J Neurosci, 2011;33:1256–63.
30. Calautti C, Baron JC, Functional neuroimaging studies of motor recovery after stroke in adults: a review, Stroke, 2003;34:1553–66.
31. Dobryakova E, Rocca MA, Valsasina P, et al., Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study, Hum Brain Mapp, 2016;37:2293–304.
32. Reddy H, Narayanan S, Arnoutelis R, et al., Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis, Brain, 2000;123(Pt 11):2314–20.
33. Rocca MA, Matthews PM, Caputo D, et al., Evidence for widespread movement-associated functional MRI changes in patients with PPMS, Neurology, 2002;58:866–72.
35. Rocca MA, Valsasina P, Martinelli V, et al., Large-scale neuronal network dysfunction in relapsing-remitting multiple sclerosis, , 2012;79:1449–57.
36. Faivre A, Robinet E, Guye M, et al., Depletion of brain functional connectivity enhancement leads to disability progression in multiple sclerosis: A longitudinal resting-state fMRI study, Mult Scler, 2016;22:1695–708.
37. Cerasa A, Gioia MC, Valentino P, 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.
38. Khan F, Amatya B, Galea MP, et al., Neurorehabilitation: applied neuroplasticity, J Neurol, 2016; doi:10.1007/s00415-016-8307.
39. Kesselring J, Beer S, Symptomatic therapy and neurorehabilitation in multiple sclerosis, Lancet Neurol, 2005;4:643–52.
40. Kesselring J, Comi G, Thompson AJ, Multiple sclerosis - recovery of function and neurorehabilitation, Cambridge: Cambridge University Press, 2010.
41. National Institute for Health and Care Excellence: Clinical Guidelines, Multiple Sclerosis: Management of Multiple Sclerosis in Primary and Secondary Care, London: National Clinical Guideline Centre, 2014.
42. Buzaid A, Dodge MP, Handmacher L, et al., Activities of daily living: evaluation and treatment in persons with multiple sclerosis, Phys Med Rehabil Clin N Am, 2013;24:629–38.
43. DasGupta R, Fowler CJ, Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies, Drugs, 2003;63:153–66.
44. Khan F, Amatya B, Kesselring J, et al., Telerehabilitation for persons with multiple sclerosis. A Cochrane review, Eur J Phys Rehabil Med, 2015;51:311–25.
45. Langdon DW, Cognition in multiple sclerosis, Curr Opin Neurol, 2011;24:244–9.
46. Lo AC, Triche EW, Improving gait in multiple sclerosis using robot-assisted, body weight supported treadmill training, Neurorehabil Neural Repair, 2008;22:661–71.
47. Pepping M, Brunings J, Goldberg M, Cognition, cognitive dysfunction, and cognitive rehabilitation in multiple sclerosis, Phys Med Rehabil Clin N Am, 2013;24:663–72.
48. Renom M, Conrad A, Bascunana H, et al., Content validity of the Comprehensive ICF Core Set for multiple sclerosis from the perspective of speech and language therapists, Int J Lang Commun Disord, 2014;49:672–86.
49. Svestkova O, Angerova Y, Sladkova P, et al., Functioning and disability in multiple sclerosis, Disabil Rehabil, 2010;32(Suppl 1):S59–67.
50. Rieckmann P, Boyko A, Centonze D, et al., Achieving patient engagement in multiple sclerosis: A perspective from the multiple sclerosis in the 21st Century Steering Group, Mult Scler Relat Disord, 2015;4:202–18.
51. Chase D, Patient engagement is the blockbuster drug of the century, 2013. Available at: www.kevinmd.com/blog/2013/10/ patient-engagement-blockbuster-drug-century.htm (accessed 28 July 2016).
52. Rieckmann P, Boyko A, Centonze D, et al., Future MS care: a consensus statement of the MS in the 21st Century Steering Group, J Neurol, 2013;260:462–9.
53. Coulter A, What do patients and the public want from primary care?, BMJ, 2005;331:1199–201.
54. Coulter A, Patient engagement--what works?, J Ambul Care Manage, 2012;35:80–9.
55. Heesen C, Kopke S, Solari A, et al., Patient autonomy in multiple sclerosis--possible goals and assessment strategies, J Neurol Sci, 2013;331:2–9.
56. Jha AK, Orav EJ, Zheng J, et al., Patients’ perception of hospital care in the United States, N Engl J Med, 2008;359:1921–31.
57. Goodworth MC, Stepleman L, Hibbard J, et al., Variables associated with patient activation in persons with multiple sclerosis, J Health Psychol, 2016;21:82–92.
58. Barry A, Cronin O, Ryan AM, et al., Impact of Exercise on Innate Immunity in Multiple Sclerosis Progression and Symptomatology, Front Physiol, 2016;7:194.
59. Beer S, Khan F, Kesselring J, Rehabilitation interventions in multiple sclerosis: an overview, J Neurol, 2012;259:1994–2008.
60. Giesser BS, Exercise in the management of persons with multiple sclerosis, Ther Adv Neurol Disord, 2015;8:123–30.
61. Heine M, van de Port I, Rietberg MB, et al., Exercise therapy for fatigue in multiple sclerosis, Cochrane Database Syst Rev, 2015;CD009956.
62. Motl RW, Benefits, safety, and prescription of exercise in persons with multiple sclerosis, Expert Rev Neurother, 2014;14:1429–36.
63. Pedersen BK, Saltin B, Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases, Scand J Med Sci Sports, 2015;25(Suppl 3):1–72.
64. White LJ, Dressendorfer RH, Exercise and multiple sclerosis, Sports Med, 2004;34:1077–100.
65. Jongen PJ, Ter Horst AT, Brands AM, Cognitive impairment in multiple sclerosis, Minerva Med, 2012;103:73–96.
66. Mostert S, Kesselring J, Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis, Mult Scler, 2002;8:161–8.
67. Schwartz CE, Snook E, Quaranto B, et al., Cognitive reserve and patient-reported outcomes in multiple sclerosis, Mult Scler, 2013;19:87–105.
68. White LJ, Castellano V, Exercise and brain health--implications for multiple sclerosis: Part 1-neuronal growth factors, Sports Med, 2008;38:91–100.
69. Burns JM, Cronk BB, Anderson HS, et al., Cardiorespiratory fitness and brain atrophy in early Alzheimer disease, Neurology, 2008;71:210–6.
70. Prakash RS, Snook EM, Erickson KI, et al., Cardiorespiratory fitness: A predictor of cortical plasticity in multiple sclerosis, Neuroimage, 2007;34:1238–44.
71. Prakash RS, Snook EM, Motl RW, et al., Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis, Brain Res, 2010;1341:41–51.
72. Kalron A, Zeilig G, Efficacy of exercise intervention programs on cognition in people suffering from multiple sclerosis, stroke and Parkinson’s disease: A systematic review and meta-analysis of current evidence, NeuroRehabilitation, 2015;37:273–89.
73. Mark VW, Taub E, Bashir K, et al., Constraint-Induced Movement therapy can improve hemiparetic progressive multiple sclerosis. Preliminary findings, , 2008;14:992–4.
74. Arya KN, Pandian S, Verma R, et al., Movement therapy induced neural reorganization and motor recovery in stroke: a review, J Bodyw Mov Ther, 2011;15:528–37.
75. Beer S, Aschbacher B, Manoglou D, et al., Robot-assisted gait training in multiple sclerosis: a pilot randomized trial, Mult Scler, 2008;14:231–6.
76. Sastre-Garriga J, Alonso J, Renom M, et al., A functional magnetic resonance proof of concept pilot trial of cognitive rehabilitation in multiple sclerosis, Mult Scler, 2011;17:457–67.
77. Rosti-Otajarvi EM, Hamalainen PI, Neuropsychological rehabilitation for multiple sclerosis, Cochrane Database Syst Rev, 2014;CD009131.
78. Stutzer P, Kesselring J, Wilhelm Uhthoff: a phenomenon 1853 to 1927, Int MS J, 2008;15:90–3.
79. Schauf CL, Davis FA, Impulse conduction in multiple sclerosis: a theoretical basis for modification by temperature and pharmacological agents, J Neurol Neurosurg Psychiatry, 1974;37:152–61.
80. Humm AM, Beer S, Kool J, et al., Quantification of Uhthoff’s phenomenon in multiple sclerosis: a magnetic stimulation study, Clin Neurophysiol, 2004;115:2493–501.
81. Meyer-Heim A, Rothmaier M, Weder M, et al., Advanced lightweight cooling-garment technology: functional improvements in thermosensitive patients with multiple sclerosis, Mult Scler, 2007;13:232–7.
82. Tamburin S, Lacerenza MR, Castelnuovo G, et al., Pharmacological and non-pharmacological strategies in the integrated treatment of pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation, Eur J Phys Rehabil Med, 2016;52:741–52.
83. Castelnuovo G, Giusti EM, Manzoni GM, et al., Psychological Treatments and Psychotherapies in the Neurorehabilitation of Pain: Evidences and Recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation, Front Psychol, 2016;7:115.
84. Beer S, Khan F, Kesselring J, Textbook of Neurorehabilitation, 2nd edition, Cambridge UK: Cambridge University Press, 2014.
85. Kesselring J, Neurorehabilitation in multiple sclerosis--what is the evidence-base?, J Neurol, 2004;251(Suppl 4):IV25–9.
86. Embrey N, Multiple sclerosis: managing a complex neurological disease, Nurs Stand, 2014;29:49–58.
87. Gallien P, Gich J, Sanchez-Dalmau BF, et al., Multidisciplinary management of multiple sclerosis symptoms, Eur Neurol, 2014;72(Suppl 1):20–5.
88. Khan F, Turner-Stokes L, Ng L, et al., Multidisciplinary rehabilitation for adults with multiple sclerosis, Postgrad Med J, 2008;84:385.
89. Skovgaard L, Bjerre L, Haahr N, et al., An investigation of multidisciplinary complex health care interventions--steps towards an integrative treatment model in the rehabilitation of people with multiple sclerosis, BMC Complement Altern Med, 2012;12:50.
90. Weinshenker B, Multiple Sclerosis and its Management: The multidisciplinary team approach to management, Can Fam Physician, 1992;38:2084–92.
91. Khan F, Turner-Stokes L, Ng L, et al., Multidisciplinary rehabilitation for adults with multiple sclerosis,Cochrane Database Syst Rev, 2007;CD006036.
92. Feinstein A, Freeman J, Lo AC, Treatment of progressive multiple sclerosis: what works, what does not, and what is needed, Lancet Neurol, 2015;14:194–207.
93. European Multiple Sclerosis Platform, MS Barometer 2013. Available at: www.emsp.org/wp-content/ uploads/2015/06/130530-MS-Barometer-2013.pdf (accessed 15 July 2016).
94. Veauthier C, Hasselmann H, Gold SM, et al., The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue, EPMA J, 2016;7:25.
Multiple sclerosis, resilience, neurorehabilitation, neuroplasticity