https://doi.org/10.1177/1352458519865734 https://doi.org/10.1177/1352458519865734 MULTIPLE SCLEROSIS MSJ JOURNAL journals.sagepub.com/home/msj 1363 Multiple Sclerosis Journal 2019, Vol. 25(10) 1363–1371 DOI: 10.1177/ 1352458519865734 © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- permissions Introduction In the last decades, the treatment of multiple sclerosis (MS) has made enormous progress. Disease- modifying drugs are able to reduce the number of relapses and to slow the disease course, but still deserve the proper balancing of efficacy and safety. 1 The complexity and the heterogeneity of disease course and clinical symptoms of MS make compul- sory the search for the appropriate personalized treat- ment and disease management, including non-pharmacological interventions, particularly in the progressive form of the disease. The ultimate purpose of any form of rehabilitation is to ameliorate clinical symptoms by modulating neuronal activity. With this respect, the concept of rehabilitation in the context of MS has evolved from the classical motor rehabilitation to neuropsycho- logical and cognitive therapy, peripheral stimula- tion, or non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In this review, we will consider preclinical studies addressing the neurobiological basis of rehabilita- tion in MS and of NIBS, as well as NIBS clinical applications on people with multiple sclerosis (pwMS). The neurobiological basis for targeting neuronal activity in MS brain To appreciate the relevance of central stimulation- based interventions in MS treatment, we need to start from two basic principles of the neurobiology. First, synapses are highly plastic structures that easily respond and adapt to environmental stimulations, by fine-tuning their connectivity to their synaptic part- ners. Moreover, neurons can make synaptic contacts with other neurons that have lost part of their syn- apses in order to restore appropriate functioning of the circuitry and to avoid neuronal loss, thus playing a neuroprotective role. 2 Second, myelin formation and maintenance in the adult brain is a highly dynamic and complex process that continuously takes place to ensure the proper sheathing of axons and, more importantly, is tightly regulated by neuronal activity. 3 These simple neurobiological concepts of neuronal and myelin plasticity lay the ground for developing treatments for a neurological disorder like MS, where an early and progressive loss of synapses occurs in concomitance with demyelination. Therefore, neu- rons can be targeted to modulate neuronal circuitry and to promote remyelination, which, in fact, is a therapeutic strategy currently under investigation for MS treatment. The idea that neuronal activity can be modulated to modify the disease course and to mitigate the Beyond rehabilitation in MS: Insights from non-invasive brain stimulation Letizia Leocani , Raffaella Chieffo , Antonietta Gentile and Diego Centonze Abstract: Although the number of disease-modifying treatments for people with multiple sclerosis (pwMS) has meaningfully increased in the past years, targeting repair or compensation for central ner- vous system damage associated with the disease process remains an important clinical goal. With this aim, neurorehabilitation is a powerful approach targeting central nervous system plasticity. Another driver of brain plasticity is non-invasive brain stimulation (NIBS), receiving recent attention in neurology, particu- larly for its potential synergy with neurorehabilitation and as add-on treatment for several neurological conditions, from pain to fatigue to sensorimotor and cognitive deficits. In this review, we will resume the evidence exploring the neurobiological basis of NIBS and its applications to MS-related conditions. Keywords: Synaptic plasticity, neuromodulation, experimental autoimmune encephalomyelitis (EAE), transcranial magnetic stimulation, transcranial direct current stimulation Date received: 25 February 2019; revised: 24 April 2019; accepted: 27 April 2019. Correspondence to: L Leocani Neurorehabilitation Unit and INSPE-Institute of Experimental Neurology, San Raffaele Hospital, 20132 Milan, Italy. letizia.leocani@hsr.it Letizia Leocani Neurorehabilitation Unit and INSPE-Institute of Experimental Neurology, San Raffaele Hospital, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy Raffaella Chieffo Neurorehabilitation Unit and INSPE-Institute of Experimental Neurology, San Raffaele Hospital, Milan, Italy Antonietta Gentile Synaptic Immunopathology Lab, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Diego Centonze Synaptic Immunopathology Lab, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy/Neurology Unit, IRCCS Neuromed, Pozzilli, Italy 865734MSJ 0 0 10.1177/1352458519865734Multiple Sclerosis JournalL Leocani, R Chieffo research-article2019 2019 Special Issue Rehabilitation in MS