Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation

Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation

Franca Tecchio Ms1,2,*, Andrea Cancelli Ms 1,3, Carlo Cottone Ms 1,4, Giancarlo Zito MD PhD1,5,

Patrizio Pasqualetti Ms6,2, Anna Ghazaryan MD5, Paolo Maria Rossini MD3,2, Maria Maddalena

Filippi MD5

1 Laboratory of Electrophysiology for Translational neuroScience (LET’S) – ISTC – CNR,

Department of Neuroscience, Fatebenefratelli Hospital, Rome, Italy

2 Department of Neuroimaging, IRCCS San Raffaele Pisana, Rome, Italy

3 Institute of Neurology, Dept. of Geriatrics, Neurosciences & Orthopaedics, Catholic University

of Sacred Heart, Rome, Italy

4 Department of Neuroscience and Imaging, G. d’Annunzio University of Chieti – Pescara, Italy

5 Department of Clinical Neuroscience, Fatebenefratelli Hospital, Rome, Italy

6 Medical Statistics and Information Technology, Fatebenefratelli Foundation for Health

Research and Education, AFaR Division, Rome, Italy

Corresponding author: Dr. Franca Tecchio, LET'S Laboratory of Electrophysiology for

Translational neuroScience, ISTC-‐CNR, Dipartimento di Neuroscienze Cliniche, Osp.le

Fatebenefratelli, Isola Tiberina, Roma-‐00186. Tel +39 06 6837382, e-‐mail:

[email protected]

Tecchio et al MS fatigue relief by bilateral S1 tDCS

2

Abstract

Multiple sclerosis related fatigue is highly common and often refractory to medical therapy.

Ten fatigued multiple sclerosis patients received two blocks of 5-‐day anodal bilateral primary

somatosensory areas transcranial Direct Current Stimulation in a randomized, double blind

sham-‐controlled, cross-‐over study. The real neuromodulation by a personalized electrode,

shaped on the MR-‐derived primary somatosensory cortical strip, reduced fatigue in all patients,

by 26% in average (p=.002), which did not change after sham (p=.901). Anodal tDCS over

bilateral somatosensory areas was able to relief fatigue in mildly disabled MS patients, when

the fatigue-‐related symptoms severely hamper their quality of life. These small-‐scale study’s

results support the concept that interventions modifying the sensorimotor network activity

balances could be a suitable non- pharmacological treatment for multiple sclerosis fatigue.


3

Introduction

Approximately 80% of subjects with multiple sclerosis (MS) complain of excessive

fatigue; in half of them it is their most disabling symptom[10]. The few medications used to

treat MS fatigue are often of limited efficacy[12], and sometimes not officially indicated for it.

Much of the MS fatigue originates in the central nervous system, with a specific

involvement of the sensorimotor networks[29]. In particular, altered excitability properties

within the sensorimotor cortex have been documented. Consistent involvement of brain areas

devoted to motor planning with a failure of the inhibitory mechanisms in frontal and primary

motor (M1) cortex[15], a reduced intracortical inhibition (ICI) within M1 either pre and post

fatiguing exercise[16, 22], and an increase in M1 excitability [19, 27] were found in MS patients

complaining of fatigue more often than those without fatigue or than healthy subjects.

The aim of the present study was to fit to MS fatigued patients an intervention which has

already been proven to enhance endurance to fatigue when applied to healthy subjects[3]. A

neuromodulation procedure capable of inducing long-‐lasting effects was here applied to the

whole bilateral S1 strip instead of the hand sensorimotor areas alone[3]. Previous electro-‐ and

magneto-‐encephalographic (EEG and MEG) data from our laboratory showed a disruption of

primary somatosensory network patterning in MS[6, 26] as a possible substrate for central

fatigue[28]. In particular, we found that an altered functional communication within the

central-‐peripheral nervous systems, namely involving S1 and M1, was sensitive to tiny

alterations of neural networking leading to fatigue, well before the appearance of impairments

of the communicating nodes[28]. Linking these functional indications to cortical atrophy of the

parietal lobe observed in patients affected by multiple sclerosis fatigue,[20] we planned to


4

selectively modulate, via a transcranial Direct Current Stimulation (tDCS), the primary

somatosensory cortices excitability. We first decided to selectively target S1 instead of SM1,

since M1 is already more excitable in MS patients complaining of fatigue than in those without

fatigue and in healthy subjects[19, 27]. Furthermore, neither electrophysiological [6], nor

neuroimaging data [20], provided any evidence for mono-‐hemispheric prevalence in MS

fatigue so far. Furthermore, reduction of interhemispheric functional connectivity in fatigued

patients [21] suggested stimulating interventions aiming to restore a normal inter-‐hemispheric

dynamical balance. Besides, since lower limbs are typically involved in the disease, we opted to

bilaterally [17, 25] target the S1 surface along the whole extent of Rolandic sulci. We thus

exploited an ad-‐hoc procedure to properly shape and position the custom-‐sized S1 electrode

using individual brain MRI data [4] .

In the present study electrodes personalized to individual patients were employed, with the

aim of increasing bilateral S1 excitability in a group of mild MS patients complaining of fatigue.

Primary endpoint was a Modified Fatigue Impact Scale (MFIS) score reduction as a measure of

fatigue relief.


5

Methods

Participants

We enrolled patients with MS in a mild state (Expanded Disability Status Scale, EDSS

≤3.5) experiencing fatigue (MFIS > 38); they were depression-‐free (Beck Depression Inventory,

BDI<19) and in absence of clinical relapse or radiological evidence of disease activity for the last

three months. Patients were excluded if they were consuming symptomatic drugs that could

affect their level of fatigue, depression and anxiety. They were also excluded if they suffered

from epilepsy or other central/peripheral nervous system comorbidities, or any conditions that

could cause fatigue, including pregnancy.

Study design

To investigate the efficacy of the treatment by bilateral whole body S1 5-‐day anodal

tDCS we designed a randomized, double blind, sham-‐controlled, cross-‐over study AB/BA (real-‐

sham/sham-‐real). Primary outcome measure was MFIS. It is based on items derived from

interviews with patients concerning how fatigue impacts their lives, in terms of physical,

cognitive, and psychosocial functioning. Administration time is approximately 5-‐10 minutes and

is a self-‐report questionnaire that the patient can generally complete with little or no

intervention of an interviewer. All of our patients completed the questionnaire by themselves.

We applied a restricted randomization procedure, so that the two arms were balanced

(5 patients Sham!Real and 5 Real!Sham). Once a patient was recruited, the

neurophysiologist or the technician responsible for the tDCS delivery called the Statistical Unit

and received the indication of the assigned treatment, on the basis of the randomization list


6

prepared in advance and kept concealed. The patient was kept blind to the delivered

treatment. Being the patients themselves the outcome evaluator the study design is

double-‐blind.

The fatigue scale scores were collected before (T0), at the end of treatment (at least 4 hours

after the 5th day of tDCS, T1) and four (T4), eight (T8) weeks later, according to MFIS referred

to the past 4 weeks.

MFIS scores were collected, and the tDCS treatments were executed, in the early

afternoon.

Since the literature did not provide data about the duration of possible effects of our

tDCS treatment, we collected MFIS every 4 weeks even after T8 to wait a value similar to the

baseline before directing patients to the second treatment block. We defined as ‘washout’ a

difference from baseline < 50% of the effect, i.e. the ‘washout time, TW’ was:

!"#$ !"!!"#$ !"!"#$% !"#$%!"#$ !"!"#$% !"#$%

< 0.5 !"#$ !"!"#$% !"#$%!!"#$ !"!"#$% !"#$%!"#$ !"!"#$% !"#$%

. To minimize possible

fatigue increase due to hot weather[11], we avoided going every day for 1 week to the Hospital

in summertime, i.e. in the case the washout time occurred on July or August, September was

waited for the second block.

In addition to EDSS and BDI, a detailed clinical history was collected in baseline (Table 1).

In all cases, MFIS was collected either separately (in a different day) or before other clinical

scales. All patients underwent brain magnetic resonance imaging (MRI) to agree with

inclusion/exclusion criteria and to tailor the S1 personalized electrode [25].

The Ethics Committee of the ‘S. Giovanni Calibita’ Fatebenefratelli Hospital in Rome approved

the protocol. All patients signed an informed consent form before their recruitment.


7

Sample size

To calculate the sample size we used the repeatability of MFIS scores before neuromodulation

treatment started. We collected MFIS twice one week apart in 10 patients with mild MS. The

average MFIS pre-‐post difference resulted 0.1 ± 1.9 (Table 1), with the Intra-‐Class Correlation

indicating a very high agreement (ICC=0.96; p<0.001). We assumed that the sham stimulation

would not induce any change and that a fatigue reduction of at least 3 points could be

considered clinically relevant and plausibly induced by our treatment. According to cross-‐over

design, a sample size of 10 patients allowed us to recognize as significant (at a bilateral alpha

level of 0.05) this large standardized effect size (3/1.9=1.6), with a power above 0.90. This

sample size will not have enough power to test the main Duration effect and the

Duration*tDCS Treatment interaction, to be tested in a larger incoming study.

Experimental Procedure

Brain MR images were collected from a standard scanner operating at 1.5 Tesla (Philips

Medical Systems, Best, The Netherlands). A semi-‐automated region of interest approach was

used to trace hyperintense lesions upon white matter (Jim 6.0, Xinapse Systems Ltd, Colchester,

UK), and the lesion relative factor (LrF) was calculated normalizing for brain parenchymal

volume[26].

SofTaxic Neuronavigation System ver.2.0 (www.softaxic.com, E.M.S., Bologna, Italy) was

used to elaborate individual brain MRI data to guide the stereotaxic procedure for the

electrode’s personalization. We shaped the bilateral S1 electrode as a 2-‐cm-‐width band along


8

the central sulcus trace (setting the electrode area to 35 cm2[25] Figure 1A). SofTaxic navigation

was also used to place the S1 electrode 5 mm anteriorly in line with the central sulcus (Figure

1B). The reference electrode (7 x 10 cm2) was centered on Oz, with the longer side pointing in

the left-‐right direction (Figure 1C).

tDCS was delivered through the electrodes wired to an electrical stimulator (BrainSTIM,

EMS srl, Bologna, Italy). The customized S1 was the anode. A constant current of 1.5 mA

intensity was applied for 15 minutes a day for 5 consecutive days. Sham condition consisted of

4 s of active stimulation at the beginning and the end of each daily 15 minute-‐stimulation. At

debriefing patients were explicitly asked if they felt the stimulation and no subject reported

feeling any difference across tDCS blocks.

Statistical analysis

After fitting a Gaussian of MFIS scores distribution (checked by the Shapiro-‐Wilk test), tDCS

effects were studied by submitting MFIS to an Analysis of Variance (ANOVA) with

tDCS Intervention (Pre T0, Post T1) and Stimulation (Real, Sham) as within-‐subjects factors.


9

Results

The MS patients presented a mild clinical picture and no sign of depression (Table 1).

Seven of them had relapsing-‐remitting, 1 secondary-‐ and 2 primary-‐ progressive MS. The lesion

load did not associate to any clinical or fatigue-‐related measure (LrF with EDSS, BDI, MFIS

p>.200 consistently).

One patient (P6) did not come back for the second block-‐sham stimulation. Real and sham

stimulation block induced effects lasting differently. As mentioned above, we considered the

washout ‘completed’ when the percentage MFIS difference from baseline became smaller than

0.5 of the induced effect. Subjects receiving sham as first intervention block returned below the

washout threshold in 4.8 ± 1.8 weeks, while those undergoing real stimulation as first did the

same in 9.6 ± 3.6 weeks (independent sample t-‐test p=.028). The washout time correlated to

the dimension of the effect (Pearson’s correlation r=.816, p=.004). The second block started 3.3

± 1.3 months after the first block. The mean MFIS percentage difference at the second block

baseline with respect to the first block baseline was -‐10% ± 6% of the induced effect.

The Shapiro-‐Wilk test indicated that the MFIS scores distribution did not differ from a Gaussian

(p>.500). ANOVA indicated that the MFIS changes depended on the type of stimulation

[Stimulation*tDCS Intervention F[1,8]=9.692, p=.014, Figure 2], with a reduction of fatigue after

Real stimulation (post-‐hoc comparison p=.002, 31.0 ± 4.0 post-‐ vs. 42.1 ± 2.6 pre-‐stimulation)

and no change after Sham (post-‐hoc comparison p=.901, 34.8 ± 3.5 post-‐ vs. 37.2 ± 2.4 pre-‐

stimulation). Slightly different baseline levels of Real and Sham blocks were observed

(F(1,8)=4.665, p=.063), but baseline levels did not correlate with the observed changes

(p>.200).


10

After real stimulation the mean fatigue reduction was 28% of the baseline (range between 2%

and 76%), and 8% after sham (range between -‐11% and 38%, paired-‐samples t-‐test real vs.

sham, p=.016). No patient was classified as an outlier (Figure 2). Noteworthy, when excluding

the patient who displayed the 76% of amelioration, the overall fatigue improvement after real

tDCS among the remaining subjects was confirmed, being 21% in average, ranging between 2-‐

40% (paired-‐samples t-‐test real vs. sham, p=.038).

Neither MFIS nor its changes associated with BDI or EDSS (p>.500 consistently).


11

Discussion

We documented that an innovative personalized electrode targeting 5-‐day anodal tDCS

on bilateral S1 encompassing the whole body representation induced a relevant reduction of

MS fatigue symptoms.

Clinical relevance of personalized neuromodulation

Fatigue is the single symptom that MS patients identify as interfering most with their

daily activities [12]. It is agreed in literature that treatment of fatigue requires a

multidisciplinary approach, with appropriate strategies including graded exercise programs,

behavior modification therapy, or medication. Nevertheless fatigue remains a challenging

problem with only incremental improvements in developing effective drug therapies [5, 12].

Currently available medications include amantadine, acetyl L-‐carnitine, aminopyridines (3-‐4-‐

diaminopyridine, 4-‐aminopyridine) that did not prove a definite efficacy and presented various

grade of side-‐effects [7, 12] .

The proposed neuromodulation intervention, if confirmed efficacious in larger cohorts of

patients, will represent a simple, low cost and risk-‐free procedure [2]

Whole body-‐S1 tDCS to relief MS fatigue

Our working hypothesis about the mechanisms behind beneficial tDCS effects stands on

the indications that a site of MS fatigue is upstream from the cortico-‐spinal tract [24] and that

tDCS can modify complex cortical and systemic excitability and connectivity properties. The

effects of non-‐invasive brain stimulation, in fact, are not limited to the directly targeted brain

regions, but are spread trans-‐synaptically to distant cortical and subcortical structures in a


12

networking mode [1, 14]. In particular, our previous data on impoverished S1 functional

projection to M1 posed the hypothesis of greater relief from fatigue through an intervention

predominantly impacting S1 excitability. It can be speculated that anodal tDCS inducing a

prolonged facilitation of cortical pyramidal S1 neurons can enhance parieto-‐frontal projections

[23] without significantly affecting M1’s excitability (already over-‐expressed in fatigued MS

patients [19, 27, 29] ). tDCS may also be responsible of important neuroplastic effects, partly

dependent on intracortical NMDA receptors activity and on stimulation parameters (duration

and intensity). Studies applying tDCS for multiple consecutive days,[9] beyond establishing the

safety of the procedure, showed that the final effects are cumulative, lasting 24 hours at least.

This supported the proposed application of tDCS on 5 consecutive days, in order to achieve a

neural modulation outlasting the stimulation session, leading to fatigue improvement. In our

observations, the effects were evident immediately following the fifth day of real stimulation

block and lasted at least 2 months (MFIS at T8 did not differ from T1 and differed from

baseline).

tCS electrode personalization

While an overall lack of efficacy was found for tDCS over bilateral sensorimotor hand

cortex [8] we documented beneficial effects when focusing the cortical target over bilateral S1,

in line with our working hypothesis. This indicates that it is possible to boost tCS efficacy by

properly tuning the stimulation parameters.

A tailoring procedure to personalize specific cortical targeting was used. In the present

study, following our working hypothesis, the procedure took into account the realistic


13

individual central sulcus shape, which was reconstructed by means of a structural brain MRI of

the patient. Furthermore, an MRI-‐guided neuronavigation system was used to precisely locate

the electrodes through the subject's scalp onto the target cortical patches. The present results

strengthen the notion that it is possible to enhance the effects of transcranial current

stimulations on specific cortical areas by properly shaping and positioning the electrodes.

The proposed workflow needs a precise neuronavigation to shape and position the

personalized electrode. This is the only step requiring special attention and we are working on

automatizing both the electrode's shaping from the individual brain MRI and its positioning, in

view of future applications at home.

Bilateral stimulation

The implemented targeting of the whole bilateral [13, 18, 25] S1 covering the cortical

convexity from left to right medio-‐lateral areas, where face, upper, and lower limbs of both

body sides are represented, can be a further motivation for explaining the greater efficacy of

the present treatment compared to the selected bilateral hand sensorimotor region

stimulation[8].

Conclusion

A beneficial tDCS effects against fatigue in MS patients with mild disability, when the

fatigue-‐related symptoms could be identified as the main cause of the reduced quality of life, is

the main outcome of the present report. Our findings support the notion that changing

reciprocal excitability balances within the neural system implicated in MS fatigue can produce


14

beneficial effects. This result sustains neuroscientists’ efforts in developing proper

neuromodulation interventions, in terms of cortical targeting, reference electrode dimension

and positioning, induced current amplitude, and time modulation.


15

Acknowledgement

The Authors wish to thank NT Marina Di Giorgio for her technical contributions.

This work was supported by: 1) FISM – Fondazione Italiana Sclerosi Multipla –Cod.2011/R/32

[FaReMuSDiCDiT], 2) Ministry of Health Cod. GR-‐2008-‐1138642 [ProSIA] and 3) MIUR Prot.

2010SH7H3F 'Functional connectivity and neuroplasticity in physiological and pathological aging

[ConnAge]'.

Conflict of interest

The authors have no conflicts of interest or financial ties to disclose.


16

Table 1. MS patient demographic and clinical profile

M=male, F=female; Mean or Median in italics and SD=standard deviations () or ranges [min,

max] across the group of: Dis Dur=disease duration; ARR= annual relapse rate; Scores of:

EDSS=Expanded Disability Status Scale, BDI=Beck Depression Inventory, LrF=lesion relative

factor, MFIS=modified fatigue impact scale, and 9-‐HPT=time (s) to execute right hand

9-‐Hole Peg Test at baseline. * MFIS 1�week apart repetition was 41.5, SD 6.1 (see study design).

Sex Age

Dis Dur

ARR EDSS BDI LrF MFIS 9-‐HPT

Mean/Median 7F/3M

45.8 7.1 0 1.5 12.7 0.38 41.6* 20.8

SD/Range (7.6) (8.2) [0-‐2] [0-‐3.5] (3.5) (0.48) (6.4)* (4.9)


17

Figures/Figure legends

Figure 1 Experimental procedure and design

Main steps of the experimental procedure: personalized electrode shaping (ES, A) performed

once for each patient (see the sequence of the operations sketched for the two consecutive

blocks in the bottom part of the figure) and electrode positioning (EP, B) for tDCS stimulation

(C) repeated for the 5-‐day treatment.


18

Figure 2 Bilateral S1 AtDCS effects on MS fatigue

Left Individual MFIS scores before (Pre-‐) and after (at least 4 hours after day 5 tDCS, Post1-‐)

five-‐day bilateral S1 anodal tDCS either real or sham (filled symbols). Post4 and Post8, which did

not enter the main analysis (see methods), are presented for descriptive purposes. Patient who

underwent sham stimulation first are listed in bold (patients 3, 4, 5, 6, 7). In all patients MFIS

decreased after real stimulation. Subject P6 did not come for the second session. Middle The

MFIS post1-‐pre difference and its standard deviation is plotted for real and sham stimulations.

Right The box and whiskers plot is used for percentage MFIS changes, showing that no outlier

was found, according to Tukey’s method: no values were below [Quartile1 – 1.5×Inter Quartile

Range, IQR] or above [Quartile3 + 1.5×IQR].


19

References

1. Baudewig J, Nitsche MA, Paulus W, Frahm J (2001) Regional modulation of BOLD MRI

responses to human sensorimotor activation by transcranial direct current stimulation.

Magn Reson Med 45:196-‐201

2. Brunoni AR, Amadera J, Berbel B, Volz MS, Rizzerio BG, Fregni F (2011) A systematic

review on reporting and assessment of adverse effects associated with transcranial

direct current stimulation. The international journal of neuropsychopharmacology /

official scientific journal of the Collegium Internationale Neuropsychopharmacologicum

14:1133-‐1145

3. Cogiamanian F, Marceglia S, Ardolino G, Barbieri S, Priori A (2007) Improved isometric

force endurance after transcranial direct current stimulation over the human motor

cortical areas. Eur J Neurosci 26:242-‐249

4. Cottone C, Tomasevic L, Porcaro C, Filligoi G, Tecchio F (2013) Physiological aging

impacts the hemispheric balances of resting state primary somatosensory activities.

Brain topography 26:186-‐199

5. Courtney AM, Castro-‐Borrero W, Davis SL, Frohman TC, Frohman EM (2011) Functional

treatments in multiple sclerosis. Current opinion in neurology 24:250-‐254

6. Dell'Acqua ML, Landi D, Zito G, Zappasodi F, Lupoi D, Rossini PM, Filippi MM, Tecchio F

(2010) Thalamocortical sensorimotor circuit in multiple sclerosis: an integrated

structural and electrophysiological assessment. Hum Brain Mapp 31:1588-‐1600

7. DeLuca J, Nocentini U (2011) Neuropsychological, medical and rehabilitative

management of persons with multiple sclerosis. NeuroRehabilitation 29:197-‐219


20

8. Ferrucci R, Vergari M, Cogiamanian F, Bocci T, Ciocca M, Tomasini E, De Riz M, Scarpini

E, Priori A (2013) Transcranial direct current stimulation (tDCS) for fatigue in multiple

sclerosis. NeuroRehabilitation

9. Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR,

Riberto M, Freedman SD, Nitsche MA, Pascual-‐Leone A (2006) A sham-‐controlled, phase

II trial of transcranial direct current stimulation for the treatment of central pain in

traumatic spinal cord injury. Pain 122:197-‐209

10. Giovannoni G (2006) Multiple sclerosis related fatigue. Journal of neurology,

neurosurgery, and psychiatry 77:2-‐3

11. Guidelines MSCfCP (1998) Fatigue and multiple sclerosis: evidence-‐based management

strategies for fatigue in multiple sclerosis Clinical Practice Guidelines:6

12. Kesselring J, Beer S (2005) Symptomatic therapy and neurorehabilitation in multiple

sclerosis. Lancet neurology 4:643-‐652

13. Koenigs M, Ukueberuwa D, Campion P, Grafman J, Wassermann E (2009) Bilateral

frontal transcranial direct current stimulation: Failure to replicate classic findings in

healthy subjects. Clin Neurophysiol 120:80-‐84

14. Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN,

Frackowiak RS (2005) How does transcranial DC stimulation of the primary motor cortex

alter regional neuronal activity in the human brain? Eur J Neurosci 22:495-‐504

15. Leocani L, Colombo B, Magnani G, Martinelli-‐Boneschi F, Cursi M, Rossi P, Martinelli V,

Comi G (2001) Fatigue in multiple sclerosis is associated with abnormal cortical

activation to voluntary movement-‐-‐EEG evidence. Neuroimage 13:1186-‐1192


21

16. Liepert J, Mingers D, Heesen C, Baumer T, Weiller C (2005) Motor cortex excitability and

fatigue in multiple sclerosis: a transcranial magnetic stimulation study. Mult Scler

11:316-‐321

17. Marshall L, Molle M, Hallschmid M, Born J (2004) Transcranial direct current stimulation

during sleep improves declarative memory. J Neurosci 24:9985-‐9992

18. Marshall L, Molle M, Siebner HR, Born J (2005) Bifrontal transcranial direct current

stimulation slows reaction time in a working memory task. BMC Neurosci 6:23

19. Nielsen JF, Norgaard P (2002) Increased post-‐exercise facilitation of motor evoked

potentials in multiple sclerosis. Clin Neurophysiol 113:1295-‐1300

20. Pellicano C, Gallo A, Li X, Ikonomidou VN, Evangelou IE, Ohayon JM, Stern SK,

Ehrmantraut M, Cantor F, McFarland HF, Bagnato F (2010) Relationship of cortical

atrophy to fatigue in patients with multiple sclerosis. Arch Neurol 67:447-‐453

21. Peltier SJ, LaConte SM, Niyazov DM, Liu JZ, Sahgal V, Yue GH, Hu XP (2005) Reductions in

interhemispheric motor cortex functional connectivity after muscle fatigue. Brain

research 1057:10-‐16

22. Perretti A, Balbi P, Orefice G, Trojano L, Marcantonio L, Brescia-‐Morra V, Ascione S,

Manganelli F, Conte G, Santoro L (2004) Post-‐exercise facilitation and depression of

motor evoked potentials to transcranial magnetic stimulation: a study in multiple

sclerosis. Clin Neurophysiol 115:2128-‐2133

23. Polania R, Nitsche MA, Paulus W (2011) Modulating functional connectivity patterns and

topological functional organization of the human brain with transcranial direct current

stimulation. Hum Brain Mapp 32:1236-‐1249


22

24. Sheean GL, Murray NM, Rothwell JC, Miller DH, Thompson AJ (1997) An

electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain

120:299-‐315

25. Tecchio F, Cancelli A, Cottone C, Tomasevic L, Devigus B, Zito G, Ercolani M, Carducci F

(2013) Regional personalized electrodes to select transcranial current stimulation target.

Frontiers in human neuroscience 7:131

26. Tecchio F, Zito G, Zappasodi F, Dell' Acqua ML, Landi D, Nardo D, Lupoi D, Rossini PM,

Filippi MM (2008) Intra-‐cortical connectivity in multiple sclerosis: a neurophysiological

approach. Brain 131:1783-‐1792

27. Thickbroom GW, Sacco P, Kermode AG, Archer SA, Byrnes ML, Guilfoyle A, Mastaglia FL

(2006) Central motor drive and perception of effort during fatigue in multiple sclerosis. J

Neurol 253:1048-‐1053

28. Tomasevic L, Zito G, Pasqualetti P, Filippi M, Landi D, Ghazaryan A, Lupoi D, Porcaro C,

Bagnato F, Rossini P, Tecchio F (2013) Cortico-‐muscular coherence as an index of fatigue

in multiple sclerosis. Mult Scler 19:334-‐343

29. Yusuf A, Koski L (2013) A qualitative review of the neurophysiological underpinnings of

fatigue in multiple sclerosis. Journal of the neurological sciences 330:4-‐9

Documents

Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation