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Non-invasive Brain Stimulation Therapy in Multiple Sclerosis: A Review of tDCS, rTMS and ECT Results

Brain Stimulation, 6, 7, pages 849 - 854

Abstract

Background

Multiple sclerosis (MS) is a disabling neurological disorder presenting a variety of symptoms which are hard to control by actual drug regimens. Non-invasive brain stimulation (NIBS) techniques have been investigated in the past years for the improvement of several neurologic and psychiatric disorders.

Objective

Here, we review the application of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (rTMS, iTBS) and electroconvulsive therapy (ECT) in MS patients.

Methods

Articles were searched in common literature databases. Crosslinks were reviewed.

Results

ECT was shown to be efficacious for the treatment of severe psychiatric disorders in 21 case reports. The results of tDCS and TMS for the treatment of depressive symptoms, fatigue, tactile sensory deficit, pain, motor performance, and spasticity were assessed in several studies and showed mixed results.

Conclusions

Overall, data for the treatment of MS with NIBS is sparse regarding TMS and tDCS. Treatment of severe psychiatric disorders with ECT is only reported in single cases. More studies are needed to elucidate the potential role of NIBS in MS treatment.

Highlights

 

  • ECT is useful for the treatment of concomitant psychiatric disorders.
  • rTMS, iTBS, and tDCS show mixed results in MS symptoms.
  • More studies are needed to explore NIBS in MS.

Keywords: Electroconvulsive therapy, Multiple sclerosis, Non-invasive brain stimulation, Repetitive transcranial magnetic stimulation, Theta burst stimulation, Transcranial direct current stimulation, Treatment.

Introduction

Multiple sclerosis (MS) is a very frequent neurological disorder and the most common cause of disability in young subjects [1] . MS affects adults during their most productive years, influencing several crucial decisions of their life, like academic studies, careers, marriage and others [2] . It decreases their physical ability and raises serious financial concerns, resulting in a significant economic burden on subjects, families, society and health care systems [3] . MS course is characterized by a progressive neurological deterioration due to the accumulation of several neurological dysfunctions including motor deficit, sensory dysfunction, and sphincter disorders [2] . Furthermore, several comorbidities, like tremor, spasticity, fatigue, pain, affective and cognitive disorders can appear and worsen the course of illness[4], [5], [6], [7], [8], [9], [10], and [11]. Although fatigue has been widely studied in the literature, pain and psychiatric symptoms remain poorly evaluated in this disease. Recently, special attention has been paid on the diagnosis and management of these symptoms. Painful syndromes encountered in MS patients have been well described and divided in four major categories: trigeminal neuralgia, spasticity, neuropathic and musculoskeletal pain syndromes [12] . In addition, depression and anxiety usually associated with chronic health problems have been investigated over the last few years. For instance, it was found that up to 50% of MS patients suffer from depressive symptoms or depressive disorders[13], [14], and [15]. Emergence of depressive and anxiety symptoms was attributed to the incertitude of illness progress [16] . Furthermore, the loss of social functioning seems to play a greater role on the onset of depressive disorders than the loss of physical function [17] . Although several pharmacological solutions exist, neuropathic pain, spasticity as well as depression and anxiety remain difficult to be fully controlled. Therefore, new approaches are needed in MS population.

Non-invasive brain stimulation (NIBS) techniques are relatively new therapeutic options that proved to be beneficial in several neurological and psychiatric disorders, like chronic neuropathic pain syndrome, major depressive and general anxiety disorders. The potential mechanisms of action of transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) in MS are related to processes of neuronal plasticity, such as long term potentiation (LTP) or depression (LTD) of synaptic transmission, and focal changes in brain network activities. These effects can be measured, for example after tDCS application, by functional magnetic resonance imaging (MRI) [18] or electroencephalography (EEG) [19] . The modulation of neuronal activities by NIBS techniques supports their use in the treatment of cognitive and mood symptoms in depression[20], [21], and [22], or for motor rehabilitation after stroke [23] , for examples. The same concepts apply to MS patients to ensure the treatment of various neurological symptoms and psychiatric comorbidities occurring in this disease. However, the stimulation settings and targeted cortical regions are heterogenous, according to the given neurological and psychiatric symptoms, thereby precluding the existence of a unique protocol in this clinical condition, in which, moreover, structural brain lesions could hamper the modulatory effects and outcome of NIBS therapy. The rationale for using ECT differs from that of tDCS and rTMS, mostly because its mechanism of action is based on a widespread seizure-induced release of a variety of neurotransmitters. This non-focality might be the most prominent reason for a lack of action in specific neurological symptoms, whereas ECT can act on severe psychiatric disorders due to a complex dysfunction of a combination of neuronal circuits.

Thus, the application of these techniques in MS patients could be of help for therapeutic purpose but needs to be studied carefully, according to the technique and the treated symptoms in this multi-aspect disease. In this paper, we review the potential benefits of NIBS treatment on various disabling symptoms encountered in MS patients, in either the neurological (e.g. pain, fatigue, or spasticity) or the psychiatric (e.g. anxiety or depression) domain. Our review focuses on transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), including its theta burst stimulation (TBS) variant, as well as the application of electroconvulsive therapy (ECT). For this article, a PubMed search was done for relevant articles concerning the application of all these modalities of NIBS in MS patients. Reviews and editorials were excluded but we have accepted all study design, including open-label studies and case reports.

Transcranial direct current stimulation (tDCS)

The use of tDCS as a NIBS technique for the treatment of neuropsychiatric disorders is exponentially growing in the past years [24] . During tDCS, a weak constant current (1–2 mA) is delivered by sponge electrodes applied to scalp. Classically, anodal tDCS increases cortical excitability, whereas cathodal tDCS reduces it, both leading to long-lasting changes in neuronal activities of specific brain circuits (neuromodulation) [25] . In neurorehabilitation, tDCS yields promising results in post-stroke recovery for example [26] . In psychiatric domain, tDCS has proven to ameliorate depressive disorders; however, results are still inconsistent[22] and [27]. Recent research focused on the analgesic effects of tDCS in patients with various pain syndromes, suggesting different mechanisms of action according to the targeted brain structure (e.g. primary motor cortex, somatosensory cortex, dorsolateral prefrontal cortex) and the related neuronal circuits which are activated [28] .

A PubMed search (keywords: tDCS AND multiple sclerosis) found 6 papers aiming to ameliorate pain [29] sensory deficit [30] , fatigue[31] and [32], and altered motor performance[33] and [34]( Table 1 ).

Table 1 tDCS and TMS/TBS results in multiple sclerosis.

Author (year) Stimulation method/study design Number of participants/MS type Targeted brain region Targeted symptom/measurement Results
tDCS
Mori et al. (2010) [29] Anodal/sham tDCS 2 mA, 20 min, 5 sessions/double blind, placebo-controlled 19/RRMS C3/C4 contralateral to painful somatic area Pain, anxiety/visual analog scales, questionnaire Significant pain relief in the active group compared to sham, no differences in anxiety
Mori et al. (2013) [30] Anodal/sham tDCS 2 mA, 20 min, 5 sessions/double blind, placebo-controlled 20 (10 active, 10 sham)/RRMS S1 contralateral to hypesthetic upper limb Tactile perception/grating orientation task, questionnaire Active tDCS reduced sensory threshold compared to sham
Ferrucci et al. (2014) [31] Anodal/sham tDCS 1.5 mA, 15 min, 5 sessions/double blind, placebo-controlled 25/RRMS, SPMS C3/C4 Fatigue/questionnaire 1/3 non-responders and 2/3 responders after active tDCS, no change after sham
Saiote et al. (2014) [32] Anodal/sham tDCS 1 mA, 20 min, 5 sessions/double blind, placebo-controlled 13/RRMS Left DLPFC Fatigue, depression/questionnaires, correlation to magnet resonance imaging No difference of active and sham tDCS in fatigue and depression outcome. Correlation of lesion load and response to tDCS
Cuypers et al. (2013) [33] Anodal/sham tDCS 1 mA, 20 min, single session/double blind, placebo-controlled 10/N.A. M1 (FDI muscle region) contralateral to impaired hand Corticospinal excitability/TMS-EMG montage, MEP measures Increased corticospinal output and projections strength after active tDCS
Meesen et al. (2014) [34] Anodal/sham tDCS 1 mA, 20 min, single session/double blind, placebo-controlled 31/RRMS, SPMS M1 (FDI muscle region) contralateral to exercised hand Motor performance/finger tapping test No difference between active and sham group
TMS/TBS
Koch et al. (2008) [43] Real/sham 5 Hz rTMS, single session, 900 pulses, 15 min, placebo-controlled 8/RRMS M1 (arm region), contralateral to the most affected hand Hand dexterity/nine-hole pegboard task Active rTMS improved hand dexterity in MS patients and not in healthy subjects
Centonze et al. (2007) [44] 5 Hz active rTMS, 10 sessions (2 week protocol), 1000 pulses, 16 min. 10/N.A. M1 (leg region), contralateral to the most affected spastic leg Lower Urinary tract symptoms/urodynamic measures Active rTMS ameliorates voiding phase of micturation cycle
Centonze et al. (2007) [45] Real/sham 5 Hz rTMS, 10 sessions (2 week protocol), (900 pulses, 15 min), placebo-controlled 19/RRMS M1 (Leg region) Lower limb spasticity/H/M amplitude of soleus H reflex, MAS Active rTMS reduced spasticity compared to sham. Effects lasted for at least 7 days after the end of stimulation protocol
Mori et al. (2010) [46] Real/sham iTBS, 10 sessions (2-week protocol), ten bursts (600 pulses), placebo-controlled 20/RRMS M1 (leg region) contralateral to the most affected limb Lower limb spasticity/H/M amplitude ratio of the Soleus H reflex, MAS Reduction of H/M amplitude ratio and MAS scores following active stimulation. Effects persisted 2 weeks after the end of stimulation protocol
Mori et al. (2011) [47] Real/sham iTBS ± ET, 10 sessions (2-week protocol), ten bursts (600 pulses), placebo-controlled 30/RRMS M1 (leg region) contralateral to the most affected limb Spasticity, fatigue and daily life activity/MAS, MSSS-88, FSS,Barthel index and MSQoL-54 questionnaires iTBS associated with ET could significantly reduce spasticity and fatigue, and ameliorate quality of life

iTBS alone could decrease spasticity, without any effect on fatigue

No significant changes were observed after sham iTMS plus ET

N.A. = Not Available; RRMS = Relapsing Remitting Multiple Sclerosis; SPMS = Secondary Progressive Multiple Sclerosis; M1 = primary motor cortex; S1 = primary somatosensory cortex; FDI = First Dorsal Interosseous, MEP = Motor Evoked Potential; ET = Exercise Therapy; MAS = Modified Ashworth Scale; MSSS-88 = 88 items Multiple Sclerosis Spasticity Score, FSS = Fatigue Severity Scale; MSQoL-54 = 54 items Multiple Sclerosis Quality of life inventory.

The effects of tDCS on pain and tactile sensory deficit were assessed in MS patients in two studies conducted by the same group. Mori et al. [29] investigated the effect of five tDCS sessions (2 mA, 20 min/day) on chronic, drug-resistant neuropathic pain in 19 patients with relapsing remitting MS (RRMS) in a randomized double-blind placebo-controlled parallel group design. Stimulation was applied over the primary motor cortex (C3–C4 in the 10-20 EEG international system). This study showed significant pain improvement after anodal tDCS compared to sham tDCS. Conversely, the scores for anxiety on a visual analog scale (VAS) and for depression on the Beck depression inventory (BDI) did not show significant differences between the active and sham conditions, although there was a decline in the mean BDI score from 11.5 to 8 points in the active group. In a second trial, Mori et al. [30] investigated the effect of five tDCS sessions (2 mA, 20 min/day) on tactile sensory deficit in 20 RRMS patients without peripheral neuropathy or recent disease activity in a randomized double-blind placebo-controlled parallel group design. Stimulation was applied over the primary somatosensory cortex (2 cm posteriorly to C3–C4). This study showed significant improvement of tactile discriminatory thresholds in the grating orientation task (GOT) and increased sensation scores (visual analog scale, VAS) after active tDCS compared to sham stimulation. Again, there was no significant difference in BDI ratings between active and sham condition. Thus, in both studies, there was no antidepressant effect of tDCS delivered over the primary motor or somatosensory cortex, but mood improvement is rather expected after the stimulation of the dorsolateral prefrontal cortex [35] . Conversely, these studies open perspectives for the use of tDCS of the primary somatosensory cortex to modulate noxious and innocuous sensations in MS patients.

Concerning fatigue, the effect of tDCS was assessed in two sham-controlled studies. In a randomized double-blind placebo-controlled cross-over study, Ferrucci et al. [31] investigated 22 RRMS and 3 secondary progressive MS (SPMS) patients with chronic fatigue for at least 6 months, who were clinically stable for at least 2 months and did not receive specific drugs for fatigue. A single session of 1.5 mA anodal tDCS delivered to the dorsolateral prefrontal cortex was performed. The patients did not improve after active tDCS compared to sham tDCS. However, tDCS seemed to have a beneficial effect in a subgroup of patients with higher lesion load in brain MRI. In a second study, Saiote et al. [32] investigated 13 RRMS patients with chronic fatigue for at least 8 weeks, who were clinically stable and did not receive psychotropic drugs. A series of five sessions of 1.5 mA anodal tDCS delivered to the primary motor cortex was performed. Fatigue improved after active tDCS compared to sham tDCS, with after-effects lasting for at least three weeks after the last tDCS session. Baseline fatigue scores did not correlate to depression scores or MRI lesion load at baseline, however, subjective fatigue improvement after tDCS correlated with higher lesion load.

Motor performance was assessed in a randomized double-blind placebo-controlled cross-over study conducted by Cuypers et al. [33] . They investigated 9 patients with RRMS and 1 patient with primary progressive MS (PPMS) who did not receive psychotropic drugs. In this study, anodal tDCS (1 mA 20 min) was delivered over the motor cortex contralateral to the most impaired hand. Active tDCS increased the corticospinal motor output strength, as assessed by the size of the motor evoked potentials (MEP) elicited by single-pulse TMS and recorded from the first dorsal interosseous (FDI) muscle of the hand. The authors suggested that tDCS could be considered for motor training protocols in rehabilitation of MS patients. In a randomized double-blind placebo-controlled cross-over study, Meesen et al. [34] investigated 31 patients with RRMS, SPMS, or PPMS. These authors assessed the add-on value on motor performance of a single session of anodal tDCS (1 mA, 20 min) delivered to the motor cortex contralateral to the most impaired hand. They did not find any difference in a unimanual motor task of finger tapping between active and sham stimulation. There were also no significant changes in attention, fatigue, pain, and sleep quality and duration between the active and sham conditions. However, this study, like that of Ferruci et al. for example, was based on a single tDCS session. More significant effects on motor performance or fatigue should result from the application of a series of daily tDCS sessions, but further studies are awaited to support this hypothesis.

Finally, we have to mention that tDCS is a very safe technique, producing no significant adverse event. Only mild side effects are reported, such as headache or subjective sensory sensation at scalp level [35] , or eventually small, local skin burns at electrode placement, which was already reported in 3 MS patients[30] and [31].

Repetitive transcranial magnetic stimulation (rTMS), including its theta burst stimulation (TBS) variant

The level of evidence of therapeutic efficacy of rTMS has been recently reviewed by an European group of experts [20] , especially highlighting the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex and the antidepressant effect of HF rTMS of the left dorsolateral prefrontal cortex. In addition, promising results have been obtained in various other neuropsychiatric conditions, such as schizophrenic symptoms or motor stroke. It has been demonstrated that rTMS could modulate cortical plasticity and brain network activities via the production of electromagnetic currents delivered by a coil placed over the scalp. The resulting clinical effects depend on the targeted cortical region and various stimulation parameters, such as stimulation intensity, pattern, and frequency[36], [37], and [38]. For example, when applied over the motor cortex of normal subjects, HF rTMS (≥5 Hz) has facilitatory effects on motor cortex excitability, whereas low-frequency (LF) stimulation (≤1 Hz) reduces cortical excitability[39] and [40].

Among the recently developed rTMS protocols, theta burst stimulation (TBS) is probably the most frequently used and studied in clinical applications. Usually, TBS consists of bursts of three stimuli with inner frequency of 50 Hz and repeated at 5 Hz. TBS showed prolonged after-effects on motor cortex excitability when applied over the primary motor cortex of healthy subjects [41] . The modulating effect depends on the pattern of the stimulation: corticospinal excitability was found to be reduced by a continuous train of 100 bursts (cTBS), but increased by an intermittent stimulation (iTBS), consisting of 20 trains of 10 bursts each, given at 8-second interval [41] . However, the functional responses to TBS protocols are highly variable between individuals [42] .

A PubMed search (keywords: rTMS/TBS AND multiple sclerosis) found 5 papers ( Table 1 ). Three of them were performed to evaluate the therapeutic effects of “classical” protocols of rTMS and two focused on those of iTBS. All these studies were done by the same team. Cerebellar dysfunction was investigated in one study [43] , bladder dysfunction in another one [44] , while the last three studies, including TBS ones, addressed the issue of lower limb spasticity[45], [46], and [47].

First, Koch et al. [43] showed that the application of HF (5 Hz) rTMS over the primary motor cortex could be beneficial for MS patients with cerebellar symptoms. Active and placebo stimulation were applied on two consecutive days, in a pseudo-randomized order. Each session consisted of 900 pulses, delivered, over 15 min, on the hemisphere contralateral to the investigated hand. Compared to sham, active stimulation led to a significant improvement of hand dexterity in MS patients suffering from dysmetria as demonstrated by a reduced time needed to accomplish a nine-hole pegboard task. Such an improvement was not found in healthy subjects [43] . These preliminary results are interesting because cerebellar dysfunction is very frequent in MS patients, especially at the origin of tremor [48] . However, further studies, using repeated daily rTMS sessions are needed to confirm these results.

In another study, Centonze et al. [44] assessed the effect of HF (5 Hz) rTMS of the motor cortex on bladder dysfunction of MS patients with lower urinary tract symptoms. For five consecutive days over two consecutive weeks, a daily rTMS session (1000 pulses per session) was applied over the leg representation of the primary motor cortex. Urodynamic measures were performed one to five days before and three days after rTMS therapy. This study showed that HF rTMS improved the voiding phase, but not the filling phase; suggesting a modulation of the contractility of the detrusor rather than of the urethral sphincter. Again, these promising but preliminary results still need to be replicated.

The same authors assessed the modulating effect of the same rTMS protocol on lower limb spasticity in a series of 19 patients with RRMS [45] . The amplitude of the soleus H reflex (H/M ratio), a relevant biomarker of leg spasticity, was reduced after a single session of HF (5 Hz) rTMS of the lower limb motor cortex, but increased, after LF (1 Hz) rTMS. In a second phase of the study, the effect of a 2-week series of daily HF rTMS sessions was investigated, according to a placebo-controlled design. Stimulation was delivered to the leg representation of the primary motor cortex, contralateral to the most affected limb. Spasticity was significantly reduced after active stimulation, but not sham stimulation, with after-effects prolonged for at least 7 days after the last rTMS session [45] .

In a placebo-controlled study, Mori et al. [46] also investigated the effect of a 2-week series of daily iTBS sessions on lower limb spasticity in 20 MS patients. The application of active iTBS over the leg representation of the primary motor cortex significantly reduced lower limb spasticity, with after-effects prolonged for at least two weeks after the last rTMS session [46] . In a second study, the same authors assessed the effect of combining iTBS with exercise therapy on spasticity in 30 MS patients. They found that iTBS combined with exercise was superior to iTBS alone in reducing spasticity and that the effects of exercise therapy on perceived fatigue, daily living activity, and the physical component of MS-related quality of life questionnaire improved when primed by iTBS [47] .

All these results obtained in lower limb spasticity by applying various rTMS protocols over the lower limb representation of the motor cortex in MS patients deserve to be reproduced by independent teams. In addition, the approaches which have been tested (i.e., HF rTMS and iTBS alone or in combination with exercise) have not been compared directly. Much work remains to be done before considering the use of rTMS in clinical practice to treat such a common and disabling symptom presented by MS patients.

As tDCS, rTMS can be considered as a very safe technique, especially if the contra-indications are respected (intracranial metallic hardware, such as cochlear implants) and the safety instructions are followed, according to the international guidelines [49] . Thus, to our knowledge, no adverse event related to TMS/rTMS application has been yet reported in MS patients.

Electroconvulsive therapy (ECT)

ECT has been introduced as a powerful therapeutic option in severe psychiatric disorders about 70 years ago [50] . There are several case reports and case series of MS patients presenting psychiatric symptoms successfully treated by ECT, since the 1950s[51], [52], [53], [54], [55], [56], and [57]. These cases were reviewed by Mattingly et al. [58] and 6 additional publications were reported later[59], [60], [61], [62], [63], and [64]. Overall, the literature covers a total number of 21 MS patients treated by ECT ( Table 2 ). ECT was indicated because of depressive syndrome (n = 17), partially associated with psychotic and akinetic symptoms, mania (n = 1), or schizophrenic syndrome (n = 3). The site of stimulation is not reported in early papers, while later publications report that 7 patients received unilateral ECT and 6 received bilateral ECT. The psychiatric status improved in 19 patients, quite significantly in 16 cases, but, two patients had no change. Despite these positive results, ECT is still not a common treatment in psychiatric comorbidities occurring in MS patients. First, we must acknowledge that the literature may be biased because negative results are probably less taken into consideration for publication than positive results, and also there is a lack of large controlled data in this domain.

Table 2 ECT in patients with multiple sclerosis and comorbid psychiatric disorders.

Author (Year) Age/Gender MS active/inactive Psychiatric comorbidity number of ECTs/type Change in psychiatric status after ECT Change in neurologic status after ECT
Eicke (1951) [51] 49/F Active Psychosis, catatonia 1/n.a. Improved Left hemiparesis, right arm weakness
Savitsky (1953) [52] 39/F Active Depression 10/n.a. Unchanged Unchanged
27/F Active Depression 9/n.a. Improved Unchanged
45/F Unclear Psychotic depression 8/n.a. Improved Unchanged
Gallineck (1958) [53] 35/F Active Depression 8/n.a. Improved Unchanged
31/F Unclear Schizophrenia, catatonia 20/n.a. Improved Unchanged
Hollender (1972) [54] 23/F Active Schizophrenia 15/n.a. Improved Unchanged
Regestein (1985) [55] 38/M Inactive Bipolar disorder, depression 8/pulse RUL Slightly improved Dyscalculia, gait disturbance
Kwentus (1986) [56] 34/F Active Mania 7/pulse RUL Improved Unchanged
Coffey (1987) [57] 43/F Inactive Depression 6/pulse RUL Improved Unchanged
Mattingly (1992) [58] 45/F Active Depression 9/pulse RUL Improved Unchanged
35/M Active Psychotic depression 6/pulse RUL Slightly improved Delirium, urinary incontinence, localized muscle weakness
48/F Active Depression 10/pulse BIL Improved Unchanged
Scott (1995) [59] 25/F Active Akinetic mutism 1/n.a. Unchanged Unchanged
Corruble (2004) [60] 51/F Active Psychotic depression 14/pulse BIL Improved Unchanged
Fitzsimons (2007) [61] 43/F Active Bipolar disorder, depression Several series/pulse RUL Improved Unchanged
Rasmussen (2007) [62] 32/F Active Depression 8/RUL Improved Unchanged
61/F Inactive Depression 12/BIL Improved Unchanged
30/F Inactive Depression 117 (in 8 years)/BIL Improved Unchanged
Pontikes (2010) [63] 28/M Active Depression, catatonia 23/BIL Improved Unchanged
Urban-Kowalczyk (2014) [64] 46/F Active Psychotic depression 14/BIL Slightly improved Unchanged, 2 seizures after 14th ECT

n.a. = not available; RUL = right unilateral; BIL = bilateral.

More importantly, ECT requires general anesthesia and there are some reports of severe but transient adverse events following the application of anesthesia in MS patients, such as hyperpyrexia after administration of various anesthetic agents, e.g. thiopentone[65] and [66]. However, hyperpyrexia is not solely attributed to anesthetic agents such as thiopentone, but is rather a general result of the stress reaction during anesthesia and surgery procedure. Today, anesthetic management of MS patients is considered safe when controlling strictly for inflammation or hyperpyrexia [67] . The anesthetic agent chosen for ECT seems to have no impact on safety [68] . In addition, ECT is known to be at the origin of other potential severe side effects like asystolia, tachycardia, delirium, agitation, memory impairment and transient neurological motor deficit. In the 21 MS patients treated by ECT and reported in the literature, no neurological side effects were produced in the large majority of them. Conversely, neurological adverse events occurred in several patients, i.e., transient left hemiparesis and right arm weakness [51] , dyscalculia and gait disturbance [55] , delirium, urinary incontinence, and muscle weakness [58] , and seizures at a distance of the 14th ECT [64] . However, from these available data, there is no evidence that MS is a clinical condition that increases the risk of ECT-induced adverse events.

Overall, with respect to anesthesia constraints and usual contra-indications (recent myocardial infarction, severe cardiopulmonary disorder, hypertensive crisis, elevated intracranial pressure, recent apoplexia, intracranial tumor, and acute glaucoma), ECT could be considered as a treatment option in severe psychiatric symptoms occurring in MS patients, as for other patients with similar symptoms occurring in the absence of concomitant neurological disorder. However, the indication for ECT should be carefully discussed in the context of the course and prognosis of a chronic disabling condition, such as MS.

Conclusions and perspectives

Although literature data are sparse, mostly based on small sample size or open-label studies, the clinical application of NIBS has proven to be feasible and potentially efficacious in MS patients. Especially, results have been obtained for sensory symptoms, including pain, by tDCS, motor symptoms, including fatigue and spasticity, by tDCS and rTMS, and psychiatric symptoms, including severe depression with or without psychotic features, catatonia, and drug-refractory psychosis, by ECT.

In the development of NIBS therapies, it is of paramount importance to clarify the underlying pathophysiological mechanisms of the symptoms to treat, in order, for example, to determine the brain region or circuit to target. Thus, in the future, NIBS therapies must tend to a personalized approach, targeting distinct brain areas according to specific symptoms and individual data. This should include morphological and functional information of brain network alteration and dysfunction provided by neuroimaging techniques. Specific advantages of tDCS and related techniques, such as transcranial random noise stimulation (tRNS) and transcranial alternating current stimulation (tACS), are the low costs of the stimulating device, easy to manage and portable, opening the possibility for patients of performing at-home stimulation, even in severely disabled persons.

The main challenge for future applications is the design of the therapeutic NIBS protocol. Beyond the target that has to be defined for coil or electrode placement, there is a variety of parameters that have to be adjusted, such as stimulation intensity, duration, frequency, pattern, electrode polarity and size, or current or electromagnetic pulse waveform. Another crucial point is to consider that each NIBS technique can be applied as a single protocol in monotherapy or using a combination of protocols (priming strategies combining tDCS and rTMS for example). Furthermore, NIBS can also be combined with drugs or non-pharmacological treatments (e.g. physical therapy, cognitive tasks) to produce additive or potentiating clinical effects. Anyway, in the domain of MS, we are at the beginning of the story and we are lacking of sham-controlled studies performed on large sample size and replicated by independent teams, especially regarding rTMS. The use of ECT is limited by its contra-indications and potentially worrisome adverse events. In contrast, tDCS and rTMS are particularly appealing techniques, because they did not produce relevant side effects or deleterious interactions with pharmacotherapy, including specific disease-modifying drugs used in MS. Thus, these NIBS techniques are safe and promising and may be soon included in the armamentarium in addition to conventional therapy, for the challenging treatment of various disabling symptoms encountered in this disease. Efforts should be made to consider MS as a potentially powerful field of application of these techniques and to promote studies in this domain.

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Footnotes

a Department of Physiology, Henri Mondor Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, France

b EA 4391, Nerve Excitability and Therapeutic Team, Faculty of Medicine, Paris Est Créteil University, Créteil, France

c Department of Psychiatry, Psychotherapy and Psychosomatics, Ludwig-Maximilian University Munich, Munich, Germany

Corresponding author. Department of Psychiatry, Psychotherapy and Psychosomatics, Ludwig-Maximilian University Munich, Nussbaumstr. 7, 80336 Munich, Germany. Tel.: +49 89 4400 55511; fax: +49 89 4400 54749.

1 Both authors contributed equally to this work.

Conflict of interest: F.P. has received grants from neuroConn GmbH, Ilmenau, Germany. The other authors declare no conflict of interest.