Handbook of Clinical Neurology, Vol.

184 (3rd series)

Neuroplasticity: From Bench to Bedside
A. Quartarone, M.F. Ghilardi, and F. Boller, Editors
https://doi.org/10.1016/B978-0-12-819410-2.00024-2
Copyright © 2022 Elsevier B.V. All rights reserved

Chapter 30

Multiple sclerosis: Inflammation, autoimmunity and plasticity

MARIO STAMPANONI BASSI1, ENNIO IEZZI1, AND DIEGO CENTONZE1,2*

1
Unit of Neurology & Neurorehabilitation, IRCCS Neuromed, Pozzilli, Italy
2
Laboratory of Synaptic Immunopathology, Department of Systems Medicine, Tor Vergata University, Rome, Italy

Abstract
In recent years, experimental studies have clarified that immune system influences the functioning of the
central nervous system (CNS) in both physiologic and pathologic conditions. The neuro-immune crosstalk
plays a crucial role in neuronal development and may be critically involved in mediating CNS response to
neuronal damage. Multiple sclerosis (MS) represents a good model to investigate how the immune system
regulates neuronal activity. Accordingly, a growing body of evidence has demonstrated that increased
levels of pro-inflammatory mediators may significantly impact synaptic mechanisms, influencing overall
neuronal excitability and synaptic plasticity expression. In this chapter, we provide an overview of pre-
clinical data and clinical studies exploring synaptic functioning noninvasively with transcranial magnetic
stimulation (TMS) in patients with MS. Moreover, we examine how inflammation-driven synaptic dys-
function could affect synaptic plasticity expression, negatively influencing the MS course. Contrasting
CSF inflammation together with pharmacologic enhancement of synaptic plasticity and application of
noninvasive brain stimulation, alone or in combination with rehabilitative treatments, could improve
the clinical compensation and prevent the accumulating deterioration in MS.

INTRODUCTION
Multiple sclerosis (MS) is an autoimmune-mediated
inflammatory and degenerative disorder of the central
nervous system (CNS), representing one of the most
common causes of neurologic disability among young
adults. The clinical course can vary from benign to
rapidly evolving forms, with most patients showing a
relapsing–remitting course (RR-MS), characterized by
recurrent manifestations of acute neurologic deficits fol-
lowed by complete or partial recovery. Clinical relapses
are correlated with the appearance of focal lesions dis-
closed by magnetic resonance imaging (MRI), although
newly developed lesions could be clinically silent. Nev-
ertheless, the association between the degree of brain
damage detectable at MRI and disability is fairly weak
(Filippi et al., 1995; Barkhof, 1999; Kappos et al.,
1999). In some cases, after a variable period of relapses
and remissions, the disease dramatically shifts towards a
slowly increasing accumulation of disability without
clear relapses (secondary progressive, SP-MS). In a
small portion of patients, the disease shows an essentially
progressive course from the onset (primary progressive,
PP-MS).
The ability of the CNS to compensate for new demy-
elinating lesions or neuronal loss importantly affects the
course of MS and could contribute to explain the differ-
ent disease phenotypes and the discrepancies observed
between MRI findings and disability. Long-term poten-
tiation (LTP) is one of the main neurophysiologic synap-
tic mechanisms involved in clinical recovery after
damage (Centonze et al., 2007a). Accordingly, it has
been proposed that efficiency of LTP-like plasticity
could critically influence the clinical course of MS
(Weiss et al., 2014; Stampanoni Bassi et al., 2019).

*Correspondence to: Diego Centonze, Unit of Neurology & Neurorehabilitation, IRCCS Neuromed, Via Atinense 18, 86077
Pozzilli, (IS), Italy. Tel: +39-0865-929170, Fax: +39-0865-929259, E-mail: centonze@uniroma2.it
458 M. STAMPANONI BASSI ET AL.
Experimental studies in animal models (i.e., experi-
mental autoimmune encephalomyelitis, EAE) and in
MS patients have shown that specific proinflammatory
cytokines involved in the pathogenesis of MS also alter
synaptic transmission and plasticity, negatively affecting
the disease course (Centonze et al., 2009; Di Filippo
et al., 2013; Nisticò et al., 2013; Stampanoni Bassi
et al., 2019). MS could therefore represent a useful model
to investigate how the immune system regulates neuronal
functioning and vice-versa.
NEURO-IMMUNE CROSSTALK IN MS
MS has been classically considered a white matter
pathology characterized by inflammatory demyelin-
ation, while atrophy is observed in late phases in
response to diffuse axonal transection and retrograde
neuronal death. Adaptive immune response has a pivotal
role in the pathogenesis of MS and autoreactive T cells
and autoantibodies represent the key players that induce
and maintain the inflammatory process and mediate
demyelination (Chitnis, 2007; Arneth, 2019). Specific
inflammatory mediators, including tumor necrosis factor
(TNF), interleukin (IL)-1b, and IL-6, released by acti-
vated T lymphocytes and resident immune cells promote
the entry of infiltrating lymphocytes into the CNS, alter
the blood brain barrier and amplify the immune response
(Larochelle et al., 2011; Arneth, 2019).
Studies in animal models and in MS patients have
demonstrated that the same inflammatory molecules
significantly affect synaptic transmission and plasticity
(Centonze et al., 2009; Stampanoni Bassi et al., 2017a),
suggesting that inflammatory synaptopathy may repre-
sent a specific feature of MS (Mandolesi et al., 2015).
In recent years, experimental studies have contributed
to clarify the relationship between the immune system
and the CNS. Although peripheral immune cells have
limited access to the brain under physiologic conditions,
the relatively recent discovery of its own lymphatic
drainage system, represented particularly in the menin-
ges, has led to a revision of the notion of CNS immune
privilege (Meyer et al., 2017; De Mesquita et al., 2018). It
has been observed that different cytokines and chemo-
kines, released by resident immune cells and lympho-
cytes, regulated neuronal functioning, suggesting that
immune mediators may represent a major communica-
tion system in the CNS together with neurotransmitters
and neurotrophins (Kipnis, 2016; De Mesquita et al.,
2018). This neuro-immune crosstalk plays a crucial role
in neuronal development and can be critically involved in
mediating the CNS response to neuronal damage.
It has been shown that TNF and IL-1b regulate the
physiologic expression of different forms of synaptic
plasticity, including Hebbian plasticity (i.e. LTP) and
homeostatic plasticity (i.e. synaptic scaling) (Schneider
et al., 1998; Beattie, 2002; Avital et al., 2003;
Stellwagen and Malenka, 2006). In pathologic condi-
tions, both acutely or chronically increased levels of
pro-inflammatory mediators may significantly impact
synaptic functioning, influencing the overall neuronal
excitability and synaptic plasticity expression.
SYNAPTIC INFLAMMATION IN MS:
PRECLINICAL STUDIES
Alterations of synaptic transmission have been
described in the striatum of EAE mice starting from
the early phases, together with increased concentrations
of pro-inflammatory molecules and microglial activa-
tion (Centonze et al., 2009). In particular, enhanced
excitatory synaptic transmission has been associated
with amplified expression and function of the a-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
glutamate receptor (Centonze et al., 2009). Synaptic
hyperexcitability has been related to excitotoxic neuro-
nal damage and dendritic spine loss, suggesting that
neurodegeneration in MS could primarily hinge on
inflammatory synaptopathy independently of demye-
lination. The proinflammatory cytokine TNF has been
identified as the major player of the excitotoxic-induced
neurodegeneration. Accordingly, in vitro TNF incuba-
tion reproduced the synaptic alterations observed in
EAE and the administration of TNF inhibitors or AMPA
receptor blockers reversed both the neurophysiologic alter-
ations and dendritic loss (Centonze et al., 2009). The pro-
inflammatory molecule IL-1b has also been consistently
associated to the synaptic alterations of EAE. One study
showed that IL-1b pathologically enhances glutamatergic
transmission in the cerebellum of EAE mice altering
the expression of the glutamate–aspartate transporter/
excitatory amino acid transporter 1 (GLAST/EAAT1) on
cerebellar astrocytes, thus reducing glutamate reuptake
(Mandolesi et al., 2013). In addition, impaired inhibitory
synaptic transmission has been reported in EAE. Specifi-
cally, TNF and IL-1b have been associated with reduced
GABAergic transmission (Rossi et al., 2011a; Mandolesi
et al., 2012), thus confirming the role of these molecules
in promoting hyperexcitability.
Inflammation also plays a role in the alteration of
synaptic plasticity observed in EAE. Different forms of
synaptic plasticity have been described and LTP repre-
sents the most studied. LTP consists in a long-lasting
enhancement of synaptic excitability and has been linked
to learning and memory processes (Bliss and Lømo,
1973, see also Chapter 2), as well as to clinical recovery
(Centonze et al., 2007a). LTP is associated to increased
size, density, and clustering of synaptic spines (Desmond
and Levy, 1986; Engert and Bonhoeffer, 1999;
 MULTIPLE SCLEROSIS: INFLAMMATION, AUTOIMMUNITY AND PLASTICITY
De Roo et al., 2008). LTP requires the activation of
the N-methyl-D-aspartate (NMDA) receptors (Bliss and
Collingridge, 1993) and could be induced by high-
frequency repetitive stimulation (Bliss and Lømo,
1973). Conversely, low-frequency stimulation is associ-
ated to long-term depression (LTD) of synaptic activity
(Mulkey and Malenka, 1992; Kirkwood and Bear, 1994).
Altered LTP induction has been demonstrated in the
hippocampus during the acute phase of EAE. One study
reported that impaired LTP induction is paralleled by
hippocampal microglia activation and increased expres-
sion of IL-1b (Di Filippo et al., 2013). Pathologically
increased LTP expression has also been described in
EAE: IL-1b incubation in control hippocampal slices
induced paradoxical LTP in response to an LTD-inducing
protocol, and this finding has been possibly related to
reduced GABAergic signaling (Nisticò et al., 2013). It
has also been shown that other pro-inflammatory mole-
cules modulate synaptic plasticity expression in vitro.
For example, IL-6 is a major pro-inflammatory cytokine
that has also been associated to LTP disruption when
incubated in mice hippocampal slices (Gruol, 2015;
Stampanoni Bassi et al., 2019).
Studies in EAE have shown that, in addition to
LTP and LTD, other forms of synaptic plasticity, partic-
ularly synaptic scaling, can be altered by inflammatory
cytokines. Synaptic scaling depends on increased or
decreased expression of AMPA receptors and represents
a homeostatic form of plasticity aimed at maintaining
neuronal excitability within physiologic ranges (Lissin
et al., 1998; Turrigiano et al., 1998). In EAE, TNF signal-
ing has been associated to pathologically increased
upscaling of excitatory synapses, leading to glutamate-
mediated excitotoxicity and synaptic loss (Centonze
et al., 2009; Rizzo et al., 2018). In addition, elevated
TNF levels have been found in the cerebrospinal fluid
(CSF) of patients with progressive MS (Rossi et al.,
2014a). Notably, it has been demonstrated that incubat-
ing the CSF of patients with progressive MS phenotype
in slices of control mice induced an increase of gluta-
matergic transmission and neuronal swelling caused by
TNF (Rossi et al., 2014a).
SYNAPTIC ACTIVITY
IN PATIENTS WITH MS
Synaptic activity and plasticity can be explored noninva-
sively in humans with transcranial magnetic stimulation
(TMS) (Rossini and Rossi, 2007; Ziemann et al., 2008;
Rossini et al., 2015). Different TMS protocols can be
used to probe the excitability of the primary motor
cortex (M1) to test the functionality of the cortico-spinal
tract and corpus callosum and to investigate the activity
459
of excitatory and inhibitory intracortical circuits
(Rossini et al., 2015).
Studies in patients with MS have demonstrated asso-
ciations between different TMS parameters and clinical/
demographic characteristics. For instance, prolonged
central motor conduction time (CMCT) and increased
resting motor threshold (RMT) have been previously
reported particularly in patients with progressive MS
phenotype (Conte et al., 2009; Ayache et al., 2015;
Neva et al., 2016). CMCT tests the integrity of the
cortico-spinal tract (Rossini et al., 2015), whereas
RMT provides information on pyramidal cells excitabil-
ity within M1 including the influence of neighboring
cortical neurons and the excitability of spinal motor
neurons (Rossini et al., 1999).
Moreover, increased cortical silent period (CSP) dura-
tion and reduced short-interval intracortical inhibition
(SICI) have been related to structural damage, clinical
disability, MS phenotype and the presence of fatigue
(Conte et al., 2009; Ayache et al., 2015; Nantes et al.,
2016a,b; Chaves et al., 2019). CSP, measured as an inter-
ruption of the voluntary electromyographic activity after
the TMS pulse, partly reflects the inhibitory activity
within M1 that is mediated by GABA-B receptors
(Fuhr et al., 1991; Inghilleri et al., 1993; Siebner et al.,
1998) and SICI, tested with a TMS paired-pulse para-
digm, evaluates the activity of GABA-A receptors
(Kujirai et al., 1993; Di Lazzaro et al., 2000). Other
paired-pulse TMS protocols are commonly used to test
the excitatory interactions within M1. Intracortical
facilitation (ICF) engages glutamatergic transmission
requiring the activation of NMDA receptors (Kujirai
et al., 1993; Ziemann et al., 1998; Schwenkreis et al.,
1999). In addition, short-interval intracortical facilitation
(SICF) could be mediated by facilitatory I-waves interac-
tions (Tokimura et al., 1996; Ziemann et al., 1998, 2015;
Hanajima et al., 2003), although the exact mechanisms
of SICF have not been completely elucidated (Paulus
et al., 2008; Van den Bos et al., 2018). In MS, a negative
correlation between clinical disability and SICF has been
found (Mori et al., 2013a). Although these measures
have clearly shown that also in patients with MS there
are alterations of inhibitory and excitatory transmission,
several differences between studies about MS pheno-
type, disability, and disease phase, complicate the inter-
pretation of the results.
Further results have convincingly suggested that
altered TMS measures of cortical excitability and synap-
tic activity in MS could be specifically linked to central
inflammation. One study reported both reduced CSP
duration and SICI in patients with relapsing MS, indicat-
ing that acute inflammation could specifically impair M1
inhibitory activity (Caramia et al., 2004). Similarly, it has
been demonstrated that CSF inflammation could affect
460 M. STAMPANONI BASSI ET AL.
M1 excitatory transmission. Enhanced IL-1b signaling
in patients with relapsing MS was positively correlated
with the extent of ICF, suggesting a link between inflam-
mation and glutamatergic transmission (Rossi et al.,
2012). Furthermore, higher CSF levels of the pro-
inflammatory molecule RANTES have been associated
to increased ICF and reduced SICI in patients with remit-
ting RR-MS (Mori et al., 2016). Conversely, it has been
shown that the CSF levels of the anti-inflammatory mol-
ecule IL-13 could exert beneficial effects, restoring SICI
(Rossi et al., 2011b). Overall, these data are in line
with findings in EAE animal models and suggest that
exacerbated central inflammation could promote cortical
hyperexcitability also in patients with MS.
SYNAPTIC PLASTICITY IN PATIENTS
WITH MS
TMS has been widely used to explore synaptic plasticity
in humans, particularly in the motor cortex (Ziemann
et al., 2008). The paired associative stimulation (PAS)
protocol, which combines electrical stimulation of the
peripheral nerve with TMS of M1, elicits either LTP-like
or LTD-like modifications depending on the time inter-
vals between the two types of stimuli (Stefan et al.,
2000) (see also Chapter 5). Another TMS protocol com-
monly used to explore M1 plasticity is theta burst
stimulation (TBS): in particular, continuous TBS (cTBS)
induces LTD-like effects, whereas intermittent TBS
(iTBS) is associated to long-lasting increase of M1 excit-
ability that resembles LTP-like plasticity (Di Lazzaro
et al., 2005; Huang et al., 2005) (see also Chapter 5).
TMS studies testing M1 plasticity in MS (Fig. 30.1A
and B) have shown that both PAS-induced LTP-like plas-
ticity and cTBS-induced LTD-like plasticity were similar
in patients with remitting MS and controls (Zeller et al.,
2010, 2012). Conversely, a simple repetitive motor task
produced a lower increase of MEP amplitude in patients
with RR-MS compared to healthy subjects (Stampanoni
Bassi et al., 2020).
Nevertheless, altered synaptic plasticity expression
has been associated to disease relapses, to CSF inflam-
mation and has been reported in progressive MS pheno-
types (Fig. 30.1C–E). Accordingly, in patients with
relapsing MS, iTBS protocols elicited LTP-like plasticity
that was reduced compared to controls but fully recov-
ered after 3-month treatment with interferon b-1a
(Mori et al., 2012). Moreover, a study reported that a
PAS protocol inducing LTD produced a paradoxical
LTP-like plasticity response in patients with relapsing
MS (Wirsching et al., 2018). Specific inflammatory cyto-
kines have been implicated in the alterations of synaptic
plasticity in patients with MS. In patients with RR-MS,
CSF levels of IL-1b positively correlated to the extent
of the paradoxical LTP-like response elicited by the
cTBS protocol (Mori et al., 2014a). These findings are
in line with the preclinical studies showing paradoxical
LTP induction in presence of IL-1b (Nisticò et al.,
2013), suggesting that this cytokine subverts LTP-like
plasticity mechanisms. Another proinflammatory cyto-
kine, IL-6, has also been recently associated to altered
synaptic plasticity in patients with MS, as the CSF levels
of this cytokine negatively correlated with the amount of
PAS-induced LTP-like plasticity (Stampanoni Bassi
et al., 2019). Conversely, other neurotrophins such as
the platelet-derived growth factor (PDGF) could enhance
the paradoxical LTP induction by cTBS in patients with
RR-MS, as the CSF levels of PDGF correlated with the
amount of LTP-like induced plasticity by cTBS (Mori
et al., 2013b).
It is worth mentioning that also the inflammation-
driven alteration of the metabolism of amyloid b (Ab)
could contribute to the dysfunctional plasticity found
in patients with MS (Lassmann, 2011; Gentile et al.,
2015; Stampanoni Bassi et al., 2017b). Indeed, exacer-
bated inflammatory milieu has been specifically associ-
ated to altered Ab homeostasis, as in the CSF, levels of
different pro-inflammatory molecules positively corre-
late with the Ab1–42 levels, while anti-inflammatory mol-
ecules showed a negative correlation with Ab1–42 levels
(Stampanoni Bassi et al., 2017b, 2019). Accordingly,
reduced Ab1–42 CSF levels in patients with MS have
been linked to the presence of MRI gadolinium-
enhancing lesions. In addition, a negative correlation
was observed between the CSF levels of Ab1–42 and
the amount of iTBS-induced LTP-like plasticity (Mori
et al., 2011a).
SYNAPTIC PLASTICITY EXPRESSION
AND CLINICAL RECOVERY IN MS
It has been demonstrated that synaptic plasticity phe-
nomena, especially LTP, critically contributes to the
compensation of symptoms following brain damage. In
animal models, clinical recovery after experimental brain
ischemia is strongly predicted by the amount of long-
lasting increase of synaptic activity occurring in the
neighboring, spared neurons (Centonze et al., 2007a).
A similar role of LTP-like plasticity mechanisms has
been demonstrated in humans using TMS. In patients
with ischemic brain stroke, the efficiency of iTBS-
induced LTP-like plasticity in the acute phase correlated
with the amount of clinical recovery tested 6 months
later (Di Lazzaro et al., 2010). Similar results have also
been reported in patients with relapsing RR-MS using the
PAS protocol (Mori et al., 2014b).
Physical rehabilitation represents the most useful
approach to promote recovery after neurologic injuries.
 MULTIPLE SCLEROSIS: INFLAMMATION, AUTOIMMUNITY AND PLASTICITY 461

Fig. 30.1. Summary of TMS studies exploring synaptic plasticity in MS. LTP-like and LTD-like effects of different plasticity-
inducing protocols, TBS (black) and PAS (red). (A) Normal LTP-like plasticity: iTBS-induced and PAS-induced LTP-like plas-
ticity of patients with remitting MS was comparable to controls (Zeller et al., 2010; Mori et al., 2013b). (B) Normal LTD-like
plasticity: cTBS-induced LTD-like plasticity was similar in both patients with remitting MS and controls (Zeller et al., 2012).
(C) Reduced/absent LTP-like plasticity: in patients with relapsing MS, iTBS-induced LTP-like plasticity was reduced (Mori
et al., 2012) and correlated with reduced CSF Ab1–42 (Mori et al., 2011a). In patients with RR-MS, reduced PAS-induced
LTP-like plasticity correlated with increased CSF IL-6 levels (Stampanoni Bassi et al., 2019). In progressive MS patients
LTP-like plasticity induced by both iTBS and PAS was absent (Mori et al., 2013b; Nicoletti et al., 2019). (D) Abnormal LTP-like
plasticity: in remitting MS patients paradoxical LTP-like in response to an LTD-inducing protocol (cTBS) was correlated with
increased CSF PDGF levels (Mori et al., 2013b). In RR-MS patients paradoxical cTBS-induced LTP-like response was also cor-
related with increased CSF IL-1b levels (Mori et al., 2014a). In relapsing MS patients an LTD-inducing protocol (PAS10) elicited
LTP-like plasticity (Wirsching et al., 2018). (E) Absent LTD-like plasticity: no effect of an LTD-inducing plasticity protocol (cTBS)
in progressive MS patients (Mori et al., 2013b). Abbreviations: Ab1–42, amyloid-beta-1-42; CSF, cerebrospinal fluid; cTBS, contin-
uous TBS; IL, interleukin; iTBS, intermittent TBS; LTD, long-term depression; LTP, long-term potentiation; MS, multiple sclerosis;
PAS, paired associative stimulation; PDGF, platelet-derived growth factor; RR, relapsing–remitting; TBS, theta burst stimulation;
TMS, transcranial magnetic stimulation.
462 M. STAMPANONI BASSI ET AL.
The beneficial effects of rehabilitation on clinical recov-
ery have been previously explored in animal models.
Exposing rats with focal brain ischemic damage to
enriched rehabilitation strongly improved motor func-
tion with a specific increase in dendritic arborization
and number of spines in surviving neurons (Biernaskie
and Corbett, 2001). Similarly, physical exercise dramat-
ically improved the clinical impact of EAE, reducing the
dendritic spine loss and the typical synaptic alterations
(Rossi et al., 2009). The relationship between motor
activity and LTP-like plasticity in humans has been
explored with TMS: following motor practice, PAS-
induced LTP plasticity did not develop, suggesting a sat-
uration effect due to metaplasticity (Ziemann et al., 2004;
Stefan et al., 2006). Remarkably, it has been highligh-
ted that motor exercise interacted with PAS-induced
LTP-like plasticity only in presence of motor learning
(Ziemann et al., 2004), suggesting that the beneficial
effects of physical rehabilitation could be linked to
practice-dependent LTP.
INFLAMMATION NEGATIVELY
INFLUENCES THE COURSE OF MS
There is good evidence that inflammation that alters
the expression of synaptic plasticity may influence the
mechanisms of brain damage compensation, therefore
worsening the disease course. Different studies have
shown that elevated CSF levels of specific pro-
inflammatory molecules at the time of diagnosis, includ-
ing IL-1b, IL-6, and IL8, were associated to enhanced
disease activity and prospective disability (Rossi et al.,
2014b, 2015; Stampanoni Bassi et al., 2019). In a group
of patients with RR-MS, elevated CSF levels of IL-6 at
the time of diagnosis predicted a greater number of symp-
tomatic relapses, thus indicating an impaired ability to
compensate for the appearance of new brain lesions
(Stampanoni Bassi et al., 2019). Notably, the detrimental
effect of IL-6 was accompanied by specific disruption of
LTP-like plasticity induced by PAS. Conversely, it has
been proposed that some anti-inflammatory molecules
and neurotrophins could exert positive effects on the
MS course (Sarchielli et al., 2002; Astier et al., 2006;
Vana et al., 2007; Mayo et al., 2016). In fact, elevated
CSF levels of PDGF could favor a stable disease course
(Stampanoni Bassi et al., 2018): PDGF can promote LTP
induction both in vitro (Peng et al., 2010) and in patients
with RR-MS (Mori et al., 2013b), while PDGF expres-
sion is absent in the CSF of patients with progressive
MS (Mori et al., 2013b). Indeed, in patients with progres-
sive MS, LTP-like plasticity is absent with different
TMS protocols (Mori et al., 2013b; Nicoletti et al.,
2019). Therefore, it is likely that, in progressive MS,
the absence of LTP may express the disruption of
synaptic compensatory mechanisms, causing increased
disability load even without new lesions (Mori et al.,
2013b; Stampanoni Bassi et al., 2017a).
POSSIBLE APPROACHES TO BOOST
SYNAPTIC PLASTICITY IN MS
The key role of LTP in favoring clinical recovery after
neurologic injuries makes LTP modulation an appealing
treatment option. The observation that physical exercise
can enhance LTP by influencing the expression of neuro-
trophins, cannabinoids, and inflammatory cytokines,
strongly supports the use of physical rehabilitation as
an active treatment, in both acute relapses and progres-
sive MS phenotypes. It has been recently suggested
that practice-dependent LTP in M1 following motor
learning of a simple task is reduced, in nondisabled
patients in early stages of RR-MS (Stampanoni Bassi
et al., 2020). This highlights the need for additional inter-
ventions specifically aimed at increasing the expression
of LTP in MS.
In different neurologic conditions, it has been shown
that pharmacologic enhancement of LTP could promote
recovery alone or in combination with rehabilitative
treatments (Dam et al., 1996; Scheidtmann et al., 2001;
R€osser et al., 2008). Synaptic plasticity mechanisms
are regulated by different signaling pathways that have
been extensively investigated in experimental studies,
including NMDA receptors and endocannabinoids. Both
in vitro and in vivo studies have clearly demonstrated
that stimulation of NMDA receptors is critical for induc-
ing LTP (see Chapter 2) (Bliss and Collingridge, 1993).
Accordingly, the administration of memantine, a NMDA
receptor antagonist, causes blockade of iTBS-induced
LTP in healthy humans (Huang et al., 2007) and the reap-
pearance of clinical signs and symptoms in patients with
RR-MS (Villoslada et al., 2009). NMDA receptors activ-
ity is strongly regulated by the D-amino D-aspartic acid
(D-Asp). Preclinical studies have shown that D-Asp is
involved in LTP induction and dendritic spines formation
in the hippocampus (D’Aniello et al., 1993; Errico et al.,
2014). It has been recently suggested that D-Asp admin-
istration may represent a useful approach to promote LTP
expression in MS patients. Accordingly, in patients with
progressive MS, a 4-week administration of D-Asp par-
tially restored LTP-like plasticity explored with PAS
(Nicoletti et al., 2019), thus opening the way for inves-
tigating its clinical effectiveness to limit the disability
progression in these patients.
The cannabinoid system is also involved in the
regulation of LTP mechanisms. In particular, stimulation
of cannabinoid type 1 receptors (CB1Rs) is required for
the induction of LTP, which is absent in mice lacking the
CB1Rs (Heifets and Castillo, 2009; Madroñal et al., 2012).
Table 30.1
Studies using noninvasive brain stimulation to treat MS-related symptoms

Study Patients Protocol Area Symptom Main clinical finding

Nielsen et al. (1996) RR-MS (remitting) rTMS (25 Hz) 7-days Thoracic spinal cord Spasticity rTMS reduced spasticity
Centonze et al. (2007b) RR-MS (remitting) rTMS (5 Hz) 10-days Leg M1 Spasticity rTMS induced long-lasting improvement of spasticity
Centonze et al. (2007c) RR-MS (remitting) rTMS (5 Hz) 10-days Leg M1 Urinary rTMS improved urinary symptoms with beneficial
effects on the bladder voiding phase
Koch et al. (2008) RR-MS (remitting) rTMS (5 Hz) single M1 Hand dexterity rTMS improved hand dexterity in patients with
session cerebellar symptoms
Mori et al. (2010a) RR-MS (remitting) TDCS 5-days M1 Pain Anodal TDCS reduced chronic central pain
Mori et al. (2010b) RR-MS (remitting) iTBS 10-days Leg M1 Spasticity iTBS reduced spasticity
Mori et al. (2011b) RR-MS (remitting) iTBS  ET 10-days Leg M1 Spasticity iTBS + ET reduced spasticity and improved quality of
life and functional measures more consistently than
iTBS alone
Mori et al. (2013c) RR-MS (remitting) TDCS 5-days Somatosensory Sensory Anodal TDCS improved sensory deficits
Deficits
Leocani et al. (2012) Progressive MS rTMS (20 Hz) Leg M1 Spasticity 3-week treatment with rTMS using H-coil over
11 sessions bilateral leg M1 improved spasticity and walking
Ferrucci et al. (2014) RR-MS TDCS 5-days M1 Fatigue Bilateral anodal TDCS reduced fatigue
Tecchio et al. (2015) RR-MS (remitting) TDCS 5-days Somatosensory Fatigue Bilateral anodal TDCS reduced fatigue
Saiote et al. (2014) RR-MS (remitting) TDCS 5-days Left DLPFC Fatigue Anodal TDCS had no effect on fatigue
Mattioli et al. (2015) RR-MS (remitting) TDCS 10 sessions Left DLPFC Cognitive Anodal TDCS during cognitive training improved
attention and executive functions
Burhan et al. (2015) RR-MS rTMS (6-Hz) 4 Left DLPFC Gait rTMS improved gait parameters in a single patient
sessions
Tecchio et al. (2015) RR-MS (remitting) TDCS 5-days Somatosensory/hand Fatigue Bilateral whole-body somatosensory stimulation
sensorimotor reduced fatigue
Iodice et al. (2015) RR-MS (remitting) TDCS 5-days M1 Spasticity Anodal tDCS had no effect on spasticity
Ayache et al. (2016) RR/SP/PP-MS TDCS 3-days Left DLPFC Pain Anodal tDCS reduced neuropathic pain
Elzamarany et al. RR/SP-MS rTMS (5 Hz) M1 Hand dexterity rTMS improved hand dexterity in patients with
(2016) 2- sessions cerebellar symptoms
Boutière et al. (2017) RR-MS iTBS 13-days Leg M1 Spasticity iTBS reduced spasticity
(remitting)/
SP-MS
Chalah et al. (2017a) RR-MS (remitting) TDCS 4-weeks Left DLPFC Fatigue Anodal tDCS reduced fatigue in a single patient
Chalah et al. (2017b) RR-MS (remitting) TDCS 5-days Left DLPFC/Right Fatigue Anodal tDCS over DLPFC reduced fatigue
PPC

Continued
Table 30.1
Continued

Study Patients Protocol Area Symptom Main clinical finding

Charvet et al. (2018a) RR-MS TDCS 10/20-sessions Left DLPFC Fatigue Anodal tDCS reduced fatigue
(remitting)/
SP/PP
Charvet et al. (2018b) RR (remitting)/ TDCS + CT Left DLPFC Cognitive Anodal tDCS improved complex attention and
SP/PP 10-sessions response variability
Cancelli et al. (2018) RR-MS (remitting) TDCS 5-days Somatosensory Fatigue Bilateral anodal whole-body somatosensory
stimulation reduced fatigue
Fiene et al. (2018) RR-MS TDCS single session Left DLPFC Fatigue Anodal tDCS reduced fatigue-related deterioration in
(remitting)/ cognitive performance
SP-MS
Cosentino et al. (2018) RR/SP-MS TDCS 5-days Right swallowing Dysphagia Anodal tDCS improved dysphagia
motor cortex
Restivo et al. (2019) RR (remitting)/ TDCS 5-days Dominant pharyngeal Dysphagia Anodal tDCS improved dysphagia in patients with
SP-MS motor cortex brainstem involvement
Korzhova et al. (2019) SP-MS rTMS (20 Hz)/iTBS Leg M1 Spasticity rTMS and iTBS reduced spasticity with a
10-days longer-lasting effect of iTBS
Berra et al. (2019) RR (remitting)/ TSDCS 10-days Thoracic spinal cord Pain Anodal tsDCS reduced neuropathic pain
SP/PP-MS

Abbreviations: CT, cognitive training; DLPFC, dorsolateral prefrontal cortex; ET, exercise therapy; iTBS, intermittent theta burst stimulation; MS, multiple sclerosis; M1, primary motor cortex (M1); PPC,
posterior parietal cortex; PP, primary progressive; RR, relapsing–remitting; rTMS, repetitive transcranial magnetic stimulation; SP, secondary progressive; TDCS, transcranial direct current stimulation;
TSDCS, transcutaneous spinal direct current stimulation.
 MULTIPLE SCLEROSIS: INFLAMMATION, AUTOIMMUNITY AND PLASTICITY
In addition, the administration of a cannabis-based med-
icine containing tetrahydrocannabinol and cannabidiol
(Sativex), was able to change in a group of RR-MS
patients the expected cTBS-induced inhibition into
LTP-like effect (Koch et al., 2009). It has been demon-
strated that the endocannabinoid system is involved in
mediating the beneficial effects of exercise (Heyman
et al., 2012; Raichlen et al., 2012). Notably, a polymor-
phism in the CB1R gene (long AAT) that reduces CB1R
protein expression, is also associated with reduced iTBS-
induced LTP and limited effect of motor rehabilitation
(Mori et al., 2014c).
Another interesting approach to increase synaptic
plasticity is the application of noninvasive brain stimula-
tion techniques. In the last decade, a number of studies
have explored the potential beneficial effect of repetitive
TMS and transcranial direct current stimulation on sev-
eral MS-related symptoms such as spasticity, pain, sensory
deficits, fatigue, cognitive disturbances and dysphagia,
with promising results (Table 30.1). In particular, it has
been shown that noninvasive brain stimulation techniques
can prime the effects of physical rehabilitation. Accord-
ingly, iTBS combined with exercise therapy led to a
greater improvement in motor function, fatigue, and qual-
ity of life, than exercise alone (Mori et al., 2011b).
CONCLUSIONS
Preclinical and clinical studies have shown that inflam-
matory synaptopathy alters synaptic plasticity mecha-
nisms negatively influencing the ability to compensate
for new demyelinating lesions or neuronal loss in MS.
Restoring synaptic plasticity could therefore represent
a useful therapeutic strategy to promote a stable disease
course in patients with MS. Contrasting CSF inflammation
together with pharmacologic enhancement of synaptic
plasticity and application of noninvasive brain stimulation,
alone or in combination with rehabilitative treatments,
could improve the clinical compensation and prevent the
accumulating deterioration in MS.
ACKNOWLEDGMENTS
This work was supported by the Italian Ministry of Health
(Ricerca Corrente—IRCCS Neuromed and 5 x 1000—
IRCCS Neuromed) and by FISM—Fondazione Italiana
Sclerosi Multipla- cod. 2019/S/1 to DC.
CONFLICT OF INTEREST STATEMENT
D.C. is an Advisory Board member of Almirall, Bayer
Schering, Biogen, GW Pharmaceuticals, Merck Serono,
Novartis, Roche, Sanofi-Genzyme, and Teva and received
honoraria for speaking or consultation fees from Almirall,
Bayer Schering, Biogen, GW Pharmaceuticals, Merck
465
Serono, Novartis, Roche, Sanofi-Genzyme, and Teva.
He is also the principal investigator in clinical trials for
Bayer Schering, Biogen, Merck Serono, Mitsubishi,
Novartis, Roche, Sanofi-Genzyme, and Teva. His preclin-
ical and clinical research was supported by grants from
Bayer Schering, Biogen Idec, Celgene, Merck Serono,
Novartis, Roche, Sanofi-Genzyme and Teva. The funders
had no role in the design of the study; in the collection,
analyses, or interpretation of data; in the writing of the
manuscript, or in the decision to publish the results.
M.S.B.: no conflict of interest.
E.I.: no conflict of interest.
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