A Pilot Trial of Remotely-Supervised Transcranial Direct Current Stimulation (RS-tDCS) to Enhance Motor Learning in Progressive Multiple Sclerosis (MS)
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: NYU Langone Health

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A Pil ot Tri al of Re m otel y -S u per vise d Tr a nscr a ni al Direct C urr e nt Sti m ul ati o n ( R S -t D C S) t o E n h a nce 
M ot or Le ar ni n g i n P r o gressi ve M ulti ple Scler osis  ( M S) 
 
P ri nci p al I n vesti g at or: Lei g h C h ar vet, P h. D.  
 
T his is a ra n d o mize d, d o u ble -bli n d pil ot cli nical tri al t o test a n o v el tr eat me nt a p pr o ac h t o r e ha bilit ate fi n e  
m ot or f u ncti o n i n i n di vi d uals li vi n g wit h pr o gressi ve m ulti ple scl er osis ( M S) usi n g a n o dal tra nscra nial dir ect  
c urre nt sti m ulati o n (t D C S) t o a u g me nt ma n ual d e xterit y trai ni n g. Tr eat me nt will be deli ver e d t o i n di vi d u als at 
h o me usi n g a state -of -t h e-art re m otel y -s u per vise d t el ere ha bilit ati o n pr ot oc ol, a maj or a d va nt a ge f or patie nts  
wit h res pect t o ease of a ccess, feasi bilit y, rei nf or ce m e nt le ar ni n g, a n d mi ni mal b ur de n of  i n-cli nic st u d y  visit 
partici pati o n. I m pr o ve me nts i n fi ne m ot or s kill will be assesse d at eac h r e m ot e sessi o n usi n g a n o vel  p ort a ble 
gri p de vic e t hat meas ures e x ec uti o n a n d a d a ptati o n or lear ni n g of fi n gerti p f orces d uri n g gras p, w hic h is  m ore 
se nsiti ve th a n sta n dar d meas ures of ha n d  f u ncti o n. 
 
B ac k gr o u n d   
M S is c haracterize d b y de m yeli nati o n, i m m u ne -m e di ate d i nfla m mati o n, a n d ne ur o de g e nerati o n wit hi n  t h e 
ce ntral ner v o us s yste m [ 1, 2]. M S is t he m ost c o m m o n de ge nerati ve ne ur ol o gic dis or der i n a d ults of  w or ki n g - 
a ge [ 3]. It is esti mate d t o aff ect m ore t h a n 2. 3 milli o n pe o ple w orl d wi de i ncl u di n g o ver 4 0 0, 0 0 0 i n di vi d u als  i n 
t he U S, c osti n g u p t o ~ $ 5 2, 0 0 0 per p ati e nt per ye ar [ 3, 4]. T he m ost c o m m o n s u bt y pe of M S is rela psi n g- 
re mitti n g a n d o v er half of t hese i n di vi d uals tr a nsiti o n t o a pr o gressi ve c o urse; t he re mai n d er ha ve a pr o gressi ve 
c o urse fr o m t he o nset  [ 5]. 
T his st u d y will f oc us o n t h ose wit h pr o gressi ve ( pri m ar y, sec o n d ar y) M S s u bt y pes . I n di vi d uals wit h 
pr o gressi ve s u bt y pes ha ve greater disa bilit y b ut fe wer t hera pe utic o pti o ns (i.e., m ost disease  m o dif yi n g 
t hera pi es are o nl y a v ail a ble f or t h ose wit h t h e rel a psi n g disease s u bt y pe) a n d are rel ati v el y u n derser v e d i n t he 
M S c o m m u nit y. A d diti o nall y, patie nts wit h pr o gr essi ve M S are e x pe cte d t o ha ve a s t a ble disease c o urse ( vs. 
ris k of rela pse wit h r ela psi n g M S) acr oss t he peri o d of st u d y. 
Re d uce d m a n u al de xterit y occ urs as a direct r es ult of de m yeli n ati o n, affects m ore t h a n 7 5 % of  all 
p atie nts wit h M S, a n d is a le a di n g c a use of dis a bilit y [ 6]. It is also o ne of t he earliest mar kers of t h e  dis ease  as 
meas ures of fi ne m ot or f u ncti o n ha ve b ee n f o u n d t o be m ore se nsiti ve t h a n t h ose of eit her a m b ulati o n  or 
c o g niti v e f u ncti o ni n g [ 6, 7]. T h e cli nical ma nifestati o ns of M S res ult fr o m c o m ple x i nter acti o ns bet wee n  tiss ue 
da ma ge, c orti cal re or g a niz ati o n a n d re pair, a n d recr uit me nt of a d diti o nal ne ural s u bstrates [ 8 -1 0]. W hile  d ecli n e 
i n a m b ul at or y f u ncti o n i n M S c orres p o n ds wit h atr o p h y of ce ntral brai n re gi o ns, decli ne i n h a n d f u ncti o n 
c orres p o n ds wit h atr o p h y of b ot h ce ntral a n d peri p heral brai n r e gi o ns [ 1 1]. Ha n d f u ncti o n t heref or e  decli n es 
wit h disease pr o gressi o n, a n d warra nts caref ul  assess me nt.  
I n cli ni cal setti n gs, t h e E x pa n de d Disa bilit y Stat us S cale ( E D S S) is use d t o br oa dl y rate t he l e vel of 
disa bilit y fr o m a sc or e of 1 ( n o disa bilit y) t o 1 0 ( deat h) [ 1 2 -1 4]. W hile t he E D S S pr o vi des i nf or mati o n a b o ut  a n 
i n di vi d ual’s m o bilit y l e vel, it pr o vi d es little i nf or mati o n re gar di n g h a n d f u ncti o n [ 1 5-1 7]. I m pair e d  m a n u al 
a bilit y is dire ctl y c orrelate d wit h pi nc h stre n g t h, w hi c h u n derli n es t he i m p orta nc e of fi ne m ot or c o ntr ol i n t he 
perf or ma nc e of e ve n t h e si m pl est acti vities of dail y li vi n g [ 1 8]. C o nse q ue ntl y, e ve n a mi n or re d u cti o n i n  ha n d 
f u ncti o n c a n c o m pr o mise q ualit y of life [ 1 9]. 
Re h a bilit ati o n is pr o misi n g a n d c a n be c o m plete d at h o me. I nter ve nti o ns t o i m pr o v e a n d/ or preser ve 
ma n ual d e xterit y are t h us of critical i m p orta nc e i n patie nts wit h M S. Alt h o u g h dise ase m o dif yi n g  t her a pies 
( D M T) ca n miti gat e t he pr o gressi o n of disa bilit y, i m paire d m a n ual d e xterit y re m ai ns a si g nifica nt pr o ble m f or a 
maj orit y of M S patie nts [ 2 0]. Re ha bilit ati o n a p pr oac hes wit h a f oc us o n m ot or lear ni n g [ 2 1], w hic h  har nesses  
ne ur o plasti cit y f or f u n cti o nal rec o v er y i n M S, are pr o misi n g e ve n i n patie nts wit h pr o gr essi ve disease [ 2 2].  F o r 
e xa m pl e, T o m assi ni a n d c ollea g u es [ 2 2] f o u n d t hat w he n c o m pare d t o healt h y c o ntr ols, alt h o u g h  M S  
partici pa nts ha d gr eater le vels of disa bilit y a n d p erf or me d m ore p o orl y at b aseli ne, e ve n t h e m ost  disa ble d 
patie nts ( E D S S sc ore > 4. 0, ma n y of w h o m ha d pr o gr essi ve f or ms of M S) re d uce t heir err ors t hr o u g h  tr ai ni n g 
e xercises [ 2 2]. F urt her, after j ust o n e wee k of at -h o m e trai ni n g, s o me partici pa nts were a ble t o ac hi e ve t h e  sa me 
N C T 0 3 4 9 9 3 1 4
N C T 0 3 4 9 9 3 1 4
NCT03499314

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perf or ma nc e le vels as t h ose of t he c o ntr ols at baseli n e  [ 2 2]. 
M ost rece ntl y, Ka m m a n d  c olle a g ues ha ve f or malize d a n at -h o m e pr o gra m of ma n ual d e xterit y  trai ni n g 
e xercises a n d d e m o nstrat e d t hat t his pr o gra m is s u peri or w he n c o m par e d t o stre n gt h -b ase d trai ni n g  e xer cises 
[ 2 3]. Partici p a nts wit h M S ( n = 3 9) were assi g ne d t o eit her at-h o me ma n ual  de xterit y or stre n gt h trai ni n g  ( usi n g 
t hera-ba n ds) f or 3 0 mi n utes a da y, f or fi ve da ys per wee k o ver 4 wee ks ( 2 0 sessi o ns). C o m pare d t o  str e n gt h 
trai ni n g, t he m a n ual d e xterit y trai ni n g l e d t o si g nific a nt i m pr o v e me nts o n t he 9-H ole Pe g Test  ( 9 H P T) [ 2 4]. 
Tr a nscr a ni al dire ct c urr e nt sti m ul ati o n (t D C S) c a n be t ar gete d t o e n h a nce m ot or le ar ni n g.  W hile 
pr o misi n g, re ha bilitati o n pr o gra ms re q uire i nt e nsi ve trai ni n g f or e ve n m o d est effects. If t he rate of  m ot or 
lear ni n g c o ul d be i ncrease d, r e ha bilit ati v e o utc o mes ca n be i m pr o ve d wit h gr eater b e nefit i n l ess ti me –  t his is 
es peciall y criti cal f or patie nts wit h pr o gressi ve M S t o re d uce t h e b ur de n of ac c u m ul ate d disa bilit y. T h us, we  will  
test t he ce ntr al h y p ot hesis t h at tr a nscr a ni al dire ct c urre nt sti m ul ati o n (t D C S) p aire d wit h m a n u al  d ext erit y  
tr ai ni n g will acc eler at e m ot or le ar ni n g i n p atie nts wit h M S . 
t D C S is a safe, [ 2 5] t hera p e utic a p pr oac h t hat utilizes l o w a m plit u d e dire ct c urre nts t o i n d uc e c ha n g es i n 
c ortic al e x cita bilit y, w hic h has s h o w n si g nific a nt eff ects o n m ot or s kill l ear ni n g a n d perf or ma n ce [ 2 6].  M ore 
s pecific all y, s ha m-c o ntr olle d st u di es of a n o dal t D C S ha ve bee n s h o w n t o i n crease t h e rat e of m ot or  se q u e nce 
lear ni n g i n healt h y partici p a nts [ 2 7], a n d sti m ulati o n of t he pri m ar y m ot or c orte x ( M 1) has bee n s h o w n  t o 
pr o m ote m ot or le ar ni n g a n d i n d uce b ot h p h ysi ol o gic al a n d be h a vi oral c ha n ges [ 2 8,  2 9].  
T h o u g h vari o us n o n -i n vasi v e ne ur o m o d ulati o n tec h n ol o gies are a vaila ble, s uc h as tra nscra nial ma g n eti c 
sti m ulati o n, t D C S has ma n y a d va nt a ges i ncl u di n g ease of use, l o wer c ost, a n d a n e xte nsi ve r ec or d of safet y  a n d 
t olera bilit y (e. g., it has n ot be e n ass ociat e d wit h t h e de vel o p m e nt of sei z ures). T he m ost c o m m o n si d e eff ects 
are s pecific t o t he el ect r o d e site a n d i ncl u de itc hi n g, ti n gli n g, a n d b ur ni n g. I nitial st u dies ha v e f o u n d t D C S t o be 
effecti ve i n a variet y of uses i n healt h y partici pa nts, as well as i n a r a n ge of cli nic al c o n diti o ns [ 3 0, 3 1] a n d  ma y  
be preferre d t o dr u g treat me nt i n s pecial p o p u lati o ns (s uc h as pre g na nt w o me n) d ue t o its safet y a d v a nta g es. 
t D C S is c o nsi dere d es peciall y pr o misi n g f or e n h a nci n g t he le ar ni n g pr oc ess i n pr oce d ural trai ni n g a n d m ot or 
re ha bilitati o n [ 3 2]. M ulti ple t D C S sessi o ns are re q uire d f or o pti m al be n efit, paire d wit h c o nti n u o us a cti vit y  [ 3 3, 
3 4]. T he c o m bi ne d a p pr oa c h ma y i ncre ase ret e nti o n a n d ha ve t h e a d diti o nal be nefit of c o nti n ue d  lear ni n g 
effects after tre at m e nt [ 3 5 -3 8]. H o we ver, t h e a p pr oac h of pairi n g t D C S wit h m a n ual d e xterit y tr ai ni n g  t o 
e n ha nce m ot or l ea r ni n g has n ot y et be e n test e d i n M S.  
We will e m pl o y n o vel a n d i n n o v ati ve a p pr o ac hes f or tre at me nt deli ver y a n d o utc o me  me as ure m e nt. 
T he pr o p ose d w or k feat ures t w o m aj or i n n o v ati o ns t hat re prese nt si g nifi ca nt a d v a nces fr o m st a n dar d c are  a n d 
will dire ctl y tr a nslate t o cli nical use a n d esta blis h met h o ds f or effecti ve telere h a bilitati o n f or t h ose li vi n g  wit h 
M S:  
• t D C S a n d m a n u al dexterity tr ai ni n g will be c o m pl ete d at h o me a n d be re m otel y-s u pervise d i n re al ti me 
usi n g a n i n n ov ati ve t elere h a bilit ati o n pr ot o c ol. W hil e t he c ell ular me c ha nis ms of t D C S re m ai n t o b e  f ull y 
u n derst o o d [ 3 9], w hat is esta blis he d is t h at s ustai n e d (se veral mi n utes of) t D C S ca n pr o d uc e lasti n g c ha n g es  i n 
brai n  e x cit a bilit y  a n d t h at t hese c h a n ges  are  c u m ulati ve w it h re p eat e d sessi o ns [ 4 0]. Re peate d  sessi o ns are  als o 
necessar y t o pr o d uce c u m ul ati v e effe cts as s h o w n i n ne ur o p h ysi ol o g y st u dies a n d cli nical tri als  f or 
ne ur o ps yc hiatric dis or ders a n d re h a bilitati o n [ 3 0, 4 1, 4 2]. H o we ver, dail y tr a vel t o a tre at m e nt fa ci lit y is a real- 
w orl d li mitati o n bec a use it is n ot feasi ble f or t h ose wit h a f ull w or k a n d fa mil y sc he d ule (re q uiri n g ti me  ta ke n 
fr o m r o uti ne o bli gati o ns), or li mit e d m o bilit y a n d/ or restrict e d tra ns p ort ati o n o pti o ns ( w hic h ca n b e es peci all y 
b ur de ns o me f or care gi vers). F or e xa m ple, t h e maj orit y of st u dies of t D C S use i n M S ha ve ha d  li mite d 
c o ncl usi o ns d ue t o v er y l o w sa m pl e sizes a n d fe w n u m ber of tre at m e nt sessi o ns [ 4 1, 4 3 -4 8]. C urre ntl y, t h e  o nl y 
p u blis he d st u d y t o date i n v ol vi n g t h e use of t D C S f or m ot or i m pr o v e me nt i n M S i ncl u d e d o nl y o ne sessi o n of 
t D C S [ 4 1]. 
T o st u dy t he m ulti ple a p plic ati o ns of t D C S i n M S, es peci ally w he n p airi n g sti m ul ati o n wit h a  re h a bilit ati o n 
pr o gr a m, M S p artici p a nts m ust be a ble t o ac cess t hese tre at me nts  fr o m h o me. We ha ve esta blis he d a m et h o d t o 
pair t D C S wit h at -h o me deli ver y of re h a bilitati o n f or c o ntr oll e d cli nic al trials i n M S. O ur R S -t D C S pr ot oc ol 
meets c o nse ns us g ui deli nes [ 4 9], a n d we ha v e vali date d it f or r e m ot e use [ 5 0, 5 1]. We ha v e als o  de m o nst r ate d 

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t he a bilit y t o recr uit patie nts ra pi dl y f or t his pr ot oc ol  
(li mite d o nl y b y d e vic e a vaila bilit y), wit h o ver  9 6 %  
c o m pli a nce r ate f or sessi o n a n d st u d y  c o m pleti o n  
[5 1]. Usi n g re m ote s u per visi o n, we h a ve a d mi nister e d  
> 5 0 0 t D C S ( Fi g. 1 ) sessi o ns ( nearl y matc hi n g t h e 
c o m bi ne d p u blis he d e x p erie nc e of t D C S i n M S)  i n 
partici pa nts ra n gi n g i n a ge fr o m 1 9 t o 6 9 ye ars a n d  i n 
disa bilit y fr o m mil d t o se v ere ( n o n -a m b ulat or y; E D S S  
sc ore 1. 0 t o 8. 0), a n d i n cl u di n g ma n y  parti ci pa nts  
wit h pr o gressi ve  disease.  
• Fi ne m ot or skill le ar ni n g will b e assesse d usi n g a n ovel i nstr u me nt e d p ort a ble gri p d evi ce a n d a  m o bile  
a p p acr oss t he tr ai ni n g  sessi o ns. 
Ha n d f u ncti o n i n M S is m ost c o m m o nl y meas ure d u si n g t he 9-h ole p e g test ( 9 H P T) [ 2 4], w hic h is o ne of  t hree 
c o m p o ne nts of t h e M ulti ple Scl er osis F u ncti o nal C o m p osite ( M S F C) [ 2 4, 5 2 -5 5]. T h e 9 H P T is a ti me d  m eas ure  
of de xterit y, b ut c a n n ot pr o vi de d etaile d i nf or mati o n a b o ut w het her t he i m pair me nt is i n g ras p e xe c uti o n,  
lear ni n g or b ot h. T he assess me nt of precisi o n gr as p wit h a n i nstr u m e nte d gri p de vi ce is a hi g hl y  se nsiti ve  
meas ure of fi n e m ot or c o ntr ol a n d m ot or l ear ni n g i n patie nts wit h ne ur ol o gic i m pair me nt fr o m str o k e a n d  M S  
[ 5 6-5 9]. It pr o vi des i nf or m ati o n a b o ut f u n da m e ntal as pects of ha n d f u ncti o n s uc h as gras p e xec uti o n,  a da ptati o n  
of gras p t o o bject pr o perties, a n d c o m p e nsat or y a dj ust me nt of gras p, w hic h ma y be affect e d t o vari o us  de grees  
de pe n di n g o n t h e u n derl yi n g C N S pat h ol o g y. A s c he mati c of t he pr ot ot y pe d e vice a n d t he k e y  vari a bles  
o btai ne d fr o m i nt eracti o n wit h t he de vi ce ar e s h o w n i n Fi g.  2 : 
( 1) T he prel o a d p hase d urati o n ( P L D) is t he d urati o n of  
fi n ger c o nt act u ntil t he o nset of p ositi ve l o a d f orce.  It 
assesses t he ti me ta ke n t o sta bilize gr as p a n d is a  r o b ust 
meas ure of gras p e xe c uti o n. W he n gras pi n g a n  o bj ect,  
t he gras pi n g a n d lifti n g f orces ha ve t o be t e m p orall y 
c o or di nat e d - a dela y bet we e n t he ti m e t o i niti ate  gras p  
a n d t he t i me t o i nitiate lift c o m pr o mises fi ne m ot or  
e xec uti o n a n d is c orrelat e d wit h pr ol o n g e d ti me  ta ke n 
o n de xterit y tas ks s uc h as t he 9 H P T ( 2). T he p ea k  l o a d 
f orce rat e ( p L F R) is a me as ure of a da ptati o n of  
fi n gerti p f or ces t o o bj ect wei g ht pri or t o o bject lift. It 
assesses lear ni n g of t he relati o ns hi p bet we e n t he wei g ht of t he o bj ect a n d t he a p pr o priat e fi n gerti p  f orc es 
nee de d t o lift it. I n dail y life o ne ne e ds t o e xert t he o pti mal a m o u nt of f orce t o gras p o bjects of differe nt  wei g hts  
a n d te xt ur es - hea vier a n d  s m o ot her o bjects re q uire f aster rat e of c ha n ge of fi n gerti p f orces c o m pare d  wit h  
li g hter a n d r o u g her o bj ects. Healt h y i n di vi d uals i n c o ntrast t o patie nts wit h ne ur ol o gical dis or ders, lear n t o d o  
s o wit hi n 1-2 trials. We will e xa mi ne t he rat e of le ar ni n g of fi n gerti p f orce c o or di nati o n t o o bj ects of diff ere nt  
wei g hts wit h acti ve v ers us s ha m t D C S ( 3) T he gri p f orce at o n -lift ( G F O) is t he gri p f orc e a p plie d w he n t he 
o bject is j ust lifte d. It assesses gri p f orce efficie nc y. T y picall y t h e gri p f orce at lift s h o ul d be j ust e n o u g h  t o 
o verc o me t he fricti o n at t he gri p s urface; h o we ver i n patie nts wit h M S, t he gri p f orc e is ofte n  e xc essi vel y  
i ncrease d. I n o ur pil ot fe asi bilit y st u d y i n 
patie nts wit h M S, q ua ntit ati v e  assess me nt  
of precisi o n gras p was f o u n d  t o se nsiti vel y 
ca pt ure i m pair me nts i n gras p  e xec uti o n  
a n d a da pt ati o n or lear ni n g of  fi n gerti p 
f orces t o o bje ct wei g ht i n hi g h f u ncti o ni n g 
patie nts ( M S hi g h) vers us l o w f u ncti o ni n g 
patie nts ( M S l o w), relati v e t o t h e 9 H P T ( Fi g. 3 ). We ha ve n o w de vel o pe d a p orta bl e  gri p  
   
   
  
  
 
 
 
 
  
 
  
  
 
 
 
  
 
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Fi g ure 2 . I nstru me nte d gri p  de v ice 

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Fi g ure 3. 9 H P T sc or es wer e n ot differe nt bet we e n M S hi g h a n d M Sl o w 
gr o u ps,  w her eas  me as ur es of gr as p e xe c uti o n ( Prel oa d p hase d urati o n) 
a n d a da ptati o n or lear ni n g  of  fi n gerti p f orc es t o o bje ct  wei g ht  ( Pe a k l oa d 
f or ce rate) s h o we d si g nifica nt differe nc es  

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Fi g ure 4 . P ort ab le gri p d e vice 
 
de vice t o q ua ntif y t he eff ect of ma n ual de xt erit y trai ni n g  o n  
m ot or le ar ni n g i n p ati e nts wit h M S usi n g a re m otel y  s u per vise d 
teler e ha bilit ati o n set u p via a la pt o p (Fi g. 4 ). T h e p orta ble gri p  
de vice h as bee n vali dat e d a gai nst t he gri p de vi ce use d i n  t he 
la b orat or y a n d t he d ata ar e f o u n d t o be acc ur ate a n d relia ble. 
 
O bjecti ve  
O ur o bjectiv e is t o t est t he exte nt t o w hi c h t D C S p air e d wit h m a n u al de xterity tr ai ni n g i m pr oves  fi ne 
m ot or exec uti o n a n d a d a pt ati o n or le ar ni n g t o use a p pr o pri ate fi n gerti p f orces ac c or di n g t o o bj ect  pr o perties  
o n a gr as p a n d lift  t ask. 
Partici p a nts ( n = 8 0) wit h pr o gressi ve M S ( pri m ar y or sec o n dar y) a n d m a n ual de xterit y  i m pair me nt 
( defi ne d b y sl o wi n g o n t h e 9 H P T i n t he d o mi na nt ha n d of at le ast 1 S D fr o m a ge-base d n or m ati v e dat a) will  be  
ra n d o ml y assi g ne d t o rec ei ve 2 0 × 2 0-mi n ut e sessi o ns of eit her a cti v e ( u p t o 2. 0 m A) or s ha m t D C S, o ver  f o ur 
wee ks (Fi g. 5 ). E nr oll m e nt criteri a ( Ta ble 1) is sel ect e d t o i de ntif y t h ose w h o will ha ve t he a bilit y t o  f ull y 
partici pat e i n t h e pr o gra m (i n cl u di n g d e vic e o perati o n).  
S pecific Ai m 1: T o d eter mi ne t h e e xt e nt t o w hi c h t D C S paire d wit h m a n ual d e xterit y trai ni n g i m pr o ves  fi ne 
m ot or e xe c uti o n o n a gras p a n d lift tas k. T h e pri m ar y o utc o me will be t he t e m p oral c o or di nati o n  bet wee n  
gras pi n g a n d lifti n g f orc es, as assesse d b y t he prel oa d p hase d urati o n  ( P L D). 
H y p ot hesis 1: We hy p ot hesize t h at active vs. s h a m t D C S p aire d wit h m a n u al dexterit y tr ai ni n g  ( pr ovi d e d 
c u m ul ativ ely) will le a d t o i m pr ove d fi ne m ot or e xec uti o n as assesse d by t he prel o a d p h ase d ur ati o n  d uri n g  
precisi o n  gr as p.  
S pecific Ai m 2: T o assess t he a da pt ati o n or lear ni n g of fi n gerti p f orces t o o bject wei g ht w he n t D C S is  paire d  
wit h ma n u al d e xterit y trai ni n g. T h e pri mar y o utc o m e will be t he differe n ce i n t he p ea k l oa d f or ce r ate  ( p L F R) 
bet wee n trials wit h t he li g ht vers us hea v y  o bje cts.  
H y p ot hesis 2: We hy p ot hesize t h at active sti m ul ati o n wit h t D C S vs. s h a m, a p plie d t o t he  c o ntr al at er al  
pri m ary m ot or c ortex ( M 1 -S 0), will p ote nti ate m ot or le ar ni n g f or i m pr ove d de xterity i n i n divi d u als li vi n g  wit h  
pr o gressive M S, as me as ure d by a d a pt ati o n or le ar ni n g of fi n g erti p f orc es t o o bje ct wei g ht, c o m p are d t o  
s h a m t D C S. 
Acti ve R S -t D C S ( n = 4 0) vs. S h a m R S-t D C S ( n = 4 0) 
+ At -H o me Ma n ual De xt erit y  Trai ni n g  
•  Bilat eral M 1 -S O ele ctr o de pl ace me nt  [ 2 9] 
•  Acti ve = a n o d al 2. 0 m A d ose × 2 0  mi n utes  
•  S ha m = desi g ne d t o e ns ure bli n di n g, i ncl u des i nitial a n d e n di n g “ra m p -u p/ d o w n” sti m ulati o n f or  6 0  
sec o n ds [ 6 0] 
•  At -h o me ma n u al de xterit y trai ni n g [ 2 3] pair e d wit h  t D C S 
•  Assess me nt of m ot or lear ni n g wit h n o vel de vic e use d t o meas ure t he ti mi n g a n d c o or di nati o n  of  
gr as pi n g a n d lifti n g f orc es ( bef ore a n d after e ac h dail y trai ni n g sessi o n)  [ 8]. 
 
St u d y Fe asi bilit y a n d  Desi g n  
Scree ni n g e v al uati o n s (T a ble 2 ) will i ncl u d e a ne ur ol o gical e xa m a n d me dical cle ara nc e b y t he  st u d y  
p h ysicia n  a n d brief scree ni n g e val uati o ns f or a bilit y t o o perate t he st u d y e q ui p me nt . Baseli n e a n d f oll o w-u p  
(st u d y e n d) assess me nts will i n cl u de meas ures of ma n ual de xt erit y a n d f u ncti o ni n g (T a ble 2 ). Det ail e d 
fi n gerti p f orc e dat a d uri n g a gr as p a n d lift tas k wit h o bjects of diff ere nt wei g hts will be o btai n e d re m otel y at 
eac h sessi o n usi n g t he d e vic e.  
 
 

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T a ble 1 . I ncl usi o n/ E xcl usi o n C rite ri a 
•  
I n cl usi o n: 
•  
A ges 1 8 -7 0, ri g ht ha n d  d o mi na nt  
•  
Defi nite M S dia g n osis,  pr o gressi ve s u bt y pe  
[ 6 1] 
•  
9 H P T sc ore at le ast 1 sta n dar d 
de viati o n bel o w a ge -base d n or mati ve 
sc ores [ 2 4] 
•  
S c ore of < 7. 5 or less o n t he E D S S [ 6 2]  ( wit h 
c are gi ver pr o x y re q uire d f or t h ose wit h 
sc ores of 6. 5  or  greater) *  
•  
A bilit y t o u n dersta n d t he i nf or me d c o nse nt  
pr oc ess  a n d pr o vi de c o nse nt t o partici pate i n 
t he st u d y 
•  
Ne gati ve uri ne pre g na nc y test f or w o me n of 
c hil d be ari n g p ote ntial 
•  
Has sta ble a n d c o nti n u o us acc ess t o  i nter net 
ser vic e at h o me c o m pati ble wit h t he st u d y 
la pt o p ( Wi-Fi or et her net ca ble)  
•  
A de q uate i nter net ca pacit y f or re m ote  
             m o nit ori n g, as teste d b y  
htt p:// w w w.s pee dtest. net/ ) 
•  
A de q uate h o me facilities (e n o u g h s pac e,  
             a c cess t o q uiet a n d distracti o n free area)  
•  
A ble t o c o m mit t o t he f o ur-we e k peri o d of 
trai ni n g sessi o ns wit h baseli ne a n d f oll o w -u p 
visits.  
•  
S y m b ol Di git M o dalities Test or S D M T [ 6 3] 
sc ore ≥3. 0 S D fr o m p u blis he d n or ms 
 
E xcl usi o n:  
• Pri mar y ne ur ol o gic, ps yc hiatric or ot her me dical dis or der  
ot her t ha n  M S  
• Use of u p per e xtre mit y B ot o x i nje cti o n wit hi n 3 m o nt hs  
• C urre nt use of i ntrat hec al Ba cl ofe n  
• Hist or y of seiz ure dis or der  
• Hist or y of hea d tra u ma i n t he past year or me dic al de vice i n 
he a d or  nec k  
• W R A T-4[ 6 4] re a di n g le vel bel o w a vera ge ( < 8 5)  (esti mate d 
ge neral i ntelle ct ual  f u ncti o n) 
•A n y s ki n dis or der/se nsiti ve ne ar sti m ulati o n  l oc ati o ns 
• Vis ual, a u dit or y a n d m ot or deficits t hat w o ul d  
pre ve nt f ull a bilit y t o u n dersta n d st u d y  i nstr ucti o ns or o perate 
t he t D C S de vice or st u d y la pt o p, as j u d ge d b y tre ati n g 
ne ur ol o gist  or st u d y staff  
• Rela pse or ster oi d use i n pre vi o us m o nt h 
• Hist or y of me ntal retar dati o n, per vasi ve  
de vel o p me ntal dis or der or ot her ne ur ol o gic al  
c o n diti o n ass ociate d wit h c o g niti ve  i m pair me nt 
• Hist or y of u nc o ntr olle d or la bile h y perte nsi o n.  
• Ot her seri o us u nc o ntr olle d me dical c o n diti o n  
(e. g., ca ncer or a c ute m y oc ar dial i nfarcti o n) 
• Alc o h ol or ot her s u bsta nc e use dis or der  
• Pre g na nt or bre astfe e di n g  
 
 
E x peri m e nt al A p pr o ac h : F oll o wi n g o ur esta blis he d re m otel y-s u per vise d, at-h o me t D C S cli nic al  tri al 
pr ot oc ol [ 5 0, 5 1], partici pa nts will be trai ne d at baseli ne a n d t h e n pr o vi de d wit h telere ha bilitati o n e q ui p m e nt t o 
ta ke h o m e f or st u d y c o m pleti o n. T he first t D C S sessi o n will be c o m plete d d uri n g t he baseli ne visit t o t est 
t olera bilit y a n d c h ec k f or u n dersta n di n g of pr oce d ur es. T he t D C S pr ot oc ol is u ni q uel y d esi g ne d f or re m ot el y- 
s u per vise d deli v er y a n d re q uir es a o ne-ti me use c o de pr o vi de d b y t he st u d y tec h nici a n t o u nl oc k t he de vic e f or 
o ne sti m ul ati o n sessi o n. T h e de vi ce will n ot o perate wit h o ut c orre ct he a dset pla ce m e nt a n d h as a  si n gle-b utt o n  
o pti o n t o a b ort t he sessi o n. T h e de vi ce will als o a ut o mati call y a b ort t he sessi o n if o pti mal sti m ulati o n 
c o n diti o ns ar e  n ot mai ntai ne d.  It r e p orts a n d rec or ds a c o m pl eti o n c o de f or ea c h  sessi o n. 
E q ui p m e nt: Partici pa nts will be pr o vi de d wit h a 1) prec o nfi g ure d l a pt o p c o m p uter; 2) a t D C S  d evi ce,  
he a d ge ar a n d s u p ply kit; 3) m a n u al dexterity tr ai ni n g m ateri als; a n d 4) t he p ort a bl e i nstr u me nte d gri p  d evic e . 
T he la pt o p will i ncl u d e a pr o gra m f or r e m ot e ac cess t o directl y pr o vi d e te c h nical s u p p ort ( Te a m Vie wer [ 6 4]) 
a n d pr o gra m m e d t o r u n t h e m o bile de vi ce a p p f or gr as p de vice meas ure m e nt. Det ail e d ma n u als of o perati o n  
will be use d b y b ot h t he partici pa nt a n d st u d y tec h ni cia n. C o pi es  of  pati e nt si g ne d d o c u me nts  a n d a n 
i nstr ucti o n al vi d e o will als o be  pr o vi de d.  
 
Mi ni -Cli nic al Tri als ( Mi ni -C T) t D C S devi ce: F or t his trial, we will use e q ui p me nt d e vel o pe d b y  S oteri x 
Me dical [ 6 5], a bi o m e dical e n gi n eeri n g c o m pa n y f o c use d o n pr o vi di n g t D C S de vic es t o cli nic al trials f or  n o n - 
i n vasi ve ne ur o m o d ulati o n. T h e mi ni-C T [ 6 5] ( Fi g. 5 ) is u ni q uel y desi g n e d f or re m otel y-s u per vise d deli ver y 
a n d re q uires a o n e -ti me use c o de pr o vi de d b y t h e st u d y tec h ni cia n t o 
u nl oc k 
t he de vi ce f or o ne sti m ulati o n sessi o n.  T his pr oce d ure is i de ntical f or b ot h  

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t he s ha m a n d acti ve c o n diti o n. T h e de vi ce is  batter y -p o were d 
(rec har gea ble lit hi u m i o n) a n d o p erat e d wit h a user-frie n dl y lar ge-b utt o n 
ke y pa d i nt erface. C ol or -c o de d ca bl es will be f use d t o t he de vi ce,  e ac h 
wit h a c orres p o n di n g electr o de at t he e n d. Ea c h de vi ce  c o ntai ns 
m o nit o ri n g a n d c o ntr ol s yste ms t hat u p dat e perf or ma nce a n d fe e d bac k 
o ver 1, 0 0 0 ti m es per sec o n d.  T his hi g h se nsiti vit y t o a n y c ha n ge  i n 
rea di n gs e ns ures safet y w hile a d mi nisteri n g t he treat me nt, a n d hel ps 
mai nt ai n sti m ulati o n efficac y. T he de vice h as se veral b uilt -i n f eat ur es f or 
 
Fi g ure 5. De vice a n d hea d gear  

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safet y a n d a cc urac y of r e m ot e a d mi nistrati o n.  If t h er e is a n y disr u pti o n i n t he c orrect plac e me nt of  t h e 
electr o des (e. g., t he h ea d ge ar is m o ve d), t he de vice will a ut o maticall y p o wer off ( gra d uall y de creasi n g  t h e 
c urre nt o ver 3 0 sec o n ds). T o disc o nti n u e a sessi o n at a n y p oi nt, t h e partici p a nt ca n pr ess t he a b ort “ 0” b utt o n  
t o als o tri g g er a n i m me diat e a n d gra d ual s h ut-off. Sessi o ns ca n n ot be restarte d wit h o ut a ne w u nl oc k c o de.  
T he de vi ce i n cl u des a n o ut p ut wit h e asil y i nter prete d rea di n gs t hat i n di cat e t he s ucc ess of t he sti m ulati o n after  
t he sessi o n. W he n t h e sessi o n is s uccessf ull y c o m plete d t he d e vic e will g e nerat e a c o m pleti o n c o d e t hat 
pr o vi des i nf or mati o n a b o ut  t he sessi o n d urati o n a n d q ualit y.  
 
He a d ge ar: We will use c ust o m -ma d e hea d g ear wit h t he g oal of  si m ple a n d c o nsiste nt plac e me nt acc or di n g t o 
t he M 1-S 0 m o nta ge [ 6 6, 6 7].  T his m o nt a ge offers ease of  relia ble ele ctr o de plac e me nt, a n d wi de t hera pe utic 
a p plic ati o n [ 6 6, 6 8]. B ase d o n t he t y pical sta n dar ds  esta blis he d a cr oss t D C S st u dies, we will tar g et 2. 0 m A f or 
2 0 mi n ute sessi o ns [ 6 6, 6 8]. T he ma n ual de xterit y  trai ni n g pr o gra m will be c o m pl ete d d uri n g sti m ulati o n. T he 
gri p de vic e me as ures wi ll be a d mi nist ere d i m me diat el y bef ore a n d after e ac h sessi o n. 
Electr o des will b e sec urel y att ac he d t o s pecific m ar ki n gs o n t he hea dset. F or plac e me nt,  pre -m oiste n e d o ne -
ti me use s p o n ges ar e attac he d t o t he h ea dset usi n g s n a p-c o n nect ors. T he el ectr o d es are t h e n pla ce d i nt o t h e 
m oiste ne d s p o n ge p o c kets a n d cli p pe d t o t he h ea d ge ar. T he s p o n ge p oc k ets are pr o vi d e d i n si n gl e -use pa c kets,  
a n d o nce o pe n e d, ca n be r ea dil y attac h e d i n t h e c orre ct pla ce m e nt t o t he hea d g ear. A nasi o n m ar ker  g ui des 
acc urate user pla ce m e nt of t h e hea d g ear.  
Acti ve vs. s h a m pr o gr a m mi n g : I n t his d o u ble-bli n d st u d y, de vices will be pr o gra m me d i n a d va nc e b y  a n  
 
T a ble 2. S u m mar y of Ke y  Meas ures  
A d mi nistere d Scree ni n g/ B aseli ne, St u dy E n d , E xte nsi o n E n d †  
•  
W R A T -4[ 6 9] Rea di n g (esti mate d ge neral c o g niti ve f u ncti o ni n g; scree ni n g, st u d y/e xte nsi o n e n d) 
•  
S D M T[ 6 3] (scree ni n g, st u d y/e xte nsi o n  e n d) 
•  
9 H P T[ 2 4, 7 0](scree ni n g, st u d y/e xte nsi o n  e n d) 
•  
M o difie d M o ber g test of stere o g n osis  f u ncti o n 
•  
M o n ofila me nt test f or fi n ger -ti p press ure se nsitivit y  
•  
S tatic a n d d y na mic 2-p oi nt discri mi nati o n tests t o assess q ualit y of fi ne discri mi nati ve  se nsati o n[ 7 2] 
•  
Ha n d gri p a n d pi nc h stre n gt hs usi n g t he sta n dar d J a mar D y na m o meter ( Pr o Me d pr o d ucts, Atla nta,  G A)  
•  
Test of E ver y da y C o g niti ve A bilit y ( T E C A) (ti me d i nstr u me ntal acti vities) 
•  
P R O MI S Fati g ue  S h ort -F or m[ 7 4]  
•  
P ositi ve a n d Ne gati ve Affect Sc he d ule  ( P A N A S)[ 7 5] 
•  
M S Q ualit y of  Life[ 7 6]  
•  
Ti me d 2 5 -F o ot Wal k  
•  
Ti me d U p & G o ( T U G)  
A d mi nistere d E ac h t D C S  Sessi o n  
•  
De vice -base d ( Fi g. 6 ) gras pi n g a n d lifti n g f orc es *( pre- a n d p ost -sessi o n) 
•  
Fati g ue  V A S[ 7 7]  
•  
Pai n V A S[ 7 8,  7 9]  
•  
M o o d  V A S[ 8 0]  
•  
T olera bilit y C hec klist ( base d o n c o m m o nl y re p orte d  si de-effects[ 8 1]) 
* Pri mar y o utc o me; † T h ose assi g ne d t o s h a m will be offere d 1 0 o pe n -l a bel active sessi o ns at st u dy e n d 
 
u n bli n de d st u d y t ea m me m b er ( data ass ociat e) t o pr o vi de eit her a cti ve or s ha m sessi o ns f oll o wi n g  c urre nt 
sta n dar ds f or bli n di n g [ 8 2, 8 3]. D uri n g a s ha m sessi o n, t he de vi ce is pr o gra m me d t o r a m p u p t o t he  d esire d 
i nte nsit y (tar get 2. 0 m A) a n d ra m p d o w n f or t h e i niti al 6 0 sec o n ds, wit h n o c urr e nt deli ver y d uri n g t he sessi o n, 
a n d t he n a g ai n at t he e n d of t he sessi o n. T hese brief peri o ds of sti m ul ati o n ser v e t o mi mi c t he eff ects of a  tr ue 
sti m ulati o n sessi o n. B ot h partici pa nts a n d st u d y tec h nicia n will be bli n d e d a n d will b e as ke d t o g uess  t he 
assi g ne d c o n diti o n at st u d y e n d.  

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At t he ti m e of u n bli n di n g at st u d y e n d, t h ose i n t h e s ha m c o n diti o n will b e offer e d t o c o m pl ete 1 0  o pe n - 
la bel acti ve R S-t D C S sessi o ns w hile c o nti n ui n g t he ma n ual d e xterit y tr ai ni n g pr o gra m. T he d ail y meas ur es  a n d 
a n a d diti o nal f oll o w -u p assess me nt will be c ollecte d f or e x pl orat or y  a nal yses.  
R S -t D C S sessi o n pr ot oc ol: Partici pa nts will c o m plet e a 2 0 mi n ute sti m ulati o n sessi o n s u per vise d b y  a st u d y 
tec h ni cia n t hr o u g h a vi de o c o nfere n ci n g pl atf or m, V See.  V See is a HI P A A c o m plia nt telec o nfere nci n g s oft ware 
t hat e ncr y pts data bef ore se n di n g, creati n g a sec ure c o n necti o n bet wee n t w o c o m p uters. T he tec h nicia ns are I R B 
a p pr o ve d st u d y te a m m e m bers w h o c o m pl ete d CI TI, HI P A A, a n d st u d y -s pecific trai ni n g i n R S-t D C S, Vsee, 
a n d Tea m Vie wer.   T he tec h nici a n will g ui de t h e ma n ual de xt erit y  tr ai ni n g r o uti ne t o be c o m plete d w hil e d uri n g 
t he t D C S acti vati o n (s ha m or a cti ve × 2 0 mi n utes) a n d c o nti n ue f or a n a d diti o nal 1 0 mi n utes after t he de vi ce has 
p o were d  off.  
 
All re m ot el y -s u per vise d sessi o ns will b e c o m plete d w hile c o n ne cte d t o a sec ure vi de o sessi o n wit h  t h e st u d y 
tec h ni cia n. T he pr ot oc ol is desi g ne d t o ha ve a decisi o n-tree seri es of c hec k p oi nts wit h “ S T O P” criteri a t h at 
m ust be cl eare d i n or der t o pr oc ee d at ea c h ste p. T h ese c hec k p oi nts a d dress c o m plia nce ( att e n da nc e,  a bilit y t o 
c o m plete t h e pr oce d ures as i nstr u cte d, f oll o wi n g t h e st u d y g ui deli n es) a n d t ol era bilit y ( at a n y ti me, if  a n y 
pre defi ne d e ve n ts are r e p orte d, or if pai n cr osses a t hres h ol d of 7 or m ore, partici pati o n will be disc o nti n u e d). 
F or sessi o ns 1 t hr o u g h 2 0 (a n d a n y a d diti o n al o pti o n al sessi o ns), partici pa nts  i n b ot h c o n diti o ns will c o m plete 
brief a d verse e v e nt re p orts bef ore a n d after t heir sessi o ns ( wit h ite ms deri ve d fr o m a list of t he m ost c o m m o n 
t D C S si de-effects i n pr e vi o us tri als [ 8 4]).  I n a d diti o n, partici pa nts  will c o m pl ete t he self -r e p ort me as ures t o 
a d dress t olera bilit y ( bef ore a n d after t he sessi o n), pai n ( bef ore, d uri n g  a n d after t h e sessi o n), a n d brief me as ures 
of fati g ue [ 7 4] a n d m o o d [ 7 5] ( T a ble  2 ). 
 
R a n d o miz ati o n:  
Partici p a nts will b e assi g ne d t o acti ve or s ha m t D C S usi n g a stratifie d ra n d o mizati o n pr oc e d ure.  Partici p a nts will 
be mat c he d a cc or di n g t o t heir d e gree of ma n u al de xt erit y i m pair me nt ( d efi ne d b y sl o wi n g o n t he 9 H P T of at le ast 
1 S D fr o m a ge -base d n or mati ve data) a n d n e ur ol o gi c ( m ot or) i m p air m e nt ( E x p a n de d Disa bilit y Stat us Scale or 
E D S S sc ore).  

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C li nicia n assess me nt f or me di cal clear a nce ma y oc c ur bef ore or o n t he da y of t he baseli ne visit. 
 
M a n u al de xterity tr ai ni n g t o b e p aire d wit h t D C S : As a b o ve, t he ma n u al de xterit y trai ni n g will be  base d o n t he 
at-h o me st u d y i n M S b y Ka m m  a n d c olle a g ues ( 2 0 1 5) [ 2 3], w here t he trai ni n g was c o m plet e d  b y partici p a nts i n 
t heir h o m es a n d de m o nstr ate d t o be s u peri or t o str e n gt h trai ni n g. T he trai ni n g pr o gra m is 
 
T a ble 3. M a n u al De xterit y T r ai ni n g  Pr o gr a m  
1.  
Fi n ger t a p pi n g : Partici pa nts la y t heir ha n d o n a  flat 
s urfac e a n d ta p t heir t h u m b a gai nst t he s urfac e t wice, 
f oll o we d b y t heir i n de x fi n ger t wice a n d fi nall y t heir 
mi d dle fi n ger  t wic e. 
 
 

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2.   
Circle c o m pleti o n : Partici pa nts are gi ve n a s ufficie nt 
n u m ber of circ ular gri ds f or t he d urati o n of t he  st u d y. 
Partici pa nts m ust c aref ull y mar k ea c h circle wit h  a  
writi n g ute nsil wit h o ut letti n g t heir res pecti ve  ar ms  
t o uc h t he ta ble. 
 
 
3.  
W as her fli ps : A set of was hers of differi n g  
circ u mfere nc es are pr o vi de d t o ea c h partici pa nt. T he  tas k 
is si m ple yet de ma n di n g, as t he y m ust fli p e a c h was her.  
A mi xt ure of lar ge a n d s mall was hers is t o be plac e d  
u p o n a pre -desi g ne d gri d b y e ac h partici pa nt  bef ore  
be gi n ni n g t he tas k t o e ns ure t he e xercise is  sta n dar dize d 
fr o m da y to  da y.  
 
 
4.   
B olt t hre a di n g : Partici pa nts are pr o vi de d a set of n uts  
a n d b olts of differi n g sizes. T he tas k is t o scre w t he  b olt  
o n a n d off of a n ut, t hree differe nt size d n uts a n d  b olts  
are pr o vi de d.  
 
 
5.   
Cl ay K ne a di n g : M o deli n g cla y of differi n g de nsities  is 
pr o vi de d f or tas ks 5 a n d 6. Tas k 5 re q uires  partici pa nts  
t o r oll t he cla y i nt o a ball wit h b ot h ha n ds, t he n t o flatte n 
t he ball wit h t he fi n gers of alter nati n g ha n ds. Partici pa nts  
m ust c o m plete t he e xercise 5 ti mes wit h ea c h  ha n d.  
 
 
6.   
Cl ay S h a pi n g : Partici pa nts r oll t heir m o deli n g cla y i nt o a  
l o g a n d use t he flat si de of alter nati n g ha n ds t o create  
n otc hes i n t he cla y l o g. T he y are t he n i nstr ucte d  t o 
briefl y pla ce t heir fi n gers se veral ti mes i nt o t he  ne wl y  
create d n otc hes. F oll o wi n g c o m pleti o n of o ne  re petiti o n, 
t he partici pa nt r olls t he cla y bac k i nt o a l o g. 
 
 
 
c o m plete d fi v e da ys per wee k f or f o ur wee ks, f or a p pr o xi mat el y 3 0 mi n utes e ac h sessi o n, wit h a r ot ati o n of  si x  
u p per e xtre mit y e xercises. T h e first 2 0 mi n utes will be paire d wit h t he t D C S sessi o n (acti ve or s ha m), a n d  t he n 
trai ni n g will c o nti n ue f or a n a d diti o nal 1 0 mi n ut es after t he sti m ul ati o n t o ma xi mi ze l ear ni n g p ote ntiati o n  
[ 2 9]. T he si m pl e tas ks are e ac h desi gn e d t o be sc ala bl e t o pr o vi de a c halle n ge t o patie nts a cr oss a ra n ge  of  
f u ncti o ni n g le vels. T he si m ple tr ai ni n g materials (T a ble 3 ) i ncl u de n uts a n d b olts, a set of varie d siz e d was hers,  
a n d a set of m o d eli n g cla y of diff eri n g de nsities. T h e st u d y  tec h nicia n  will b e i n li ve c o ntact wit h t h e parti ci pa nt 
t hr o u g h o ut t he d ur ati o n of t he sessi o n. A d diti o n all y, a ma n ual  is pr o vi de d wit h i ntri cate d etails of ea c h of t he 
e xercises, t o a d vise partici p a nts s h o ul d t he y h a ve q u esti o ns  bef ore  be gi n ni n g a  sessi o n. 
Assess me nt of gr as p ( Pri m ar y O utc o mes): Bef ore a n d after eac h m a n ual d e xterit y tr ai ni n g  sessi o n  
( wit h acti ve or s ha m sti m ul ati o n), t he p orta ble i nstr u me nte d gri p de vi ce will be use d t o assess gras p e xe c uti o n  
a n d lear ni n g. T his will e na ble me as ure me nt of i m pr o ve me nt i n fi ne m ot or e x ec uti o n a n d rat e of m ot or l ear ni n g 
t hr o u g h o ut t he d ur ati o n of t he st u d y. I n t his ma n ner, we will me as ure b ot h pre- a n d p ost-treat me nt c ha n g es as  
well as c u m ulati ve c ha n g es acr oss t he dail y sessi o ns. T his will pr o vi d e a r o b ust da ta set t o e xa mi ne l ear ni n g of  
fi ne m ot or c o ntr ol i n patie nts wit h pr o gressi ve M S. T he p orta ble gri p d e vice c o nsists of a s q uare pl atf or m o n  
w hic h a l oa d -cell fitte d wit h a str ai n ga u g e is m o u nt e d. T he ot her e n d of t he l oa d -cell c o ntai ns a 3 D  pri nt e d  
circ ul ar c oaster a n d plates f or mi n g  a   
 
 

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platf or m w here o bjects ca n be plac e d  t o 
me as ure l oa d f orc e ( Fi g. 6).  T he  se nsiti vit y 
of t he l oa d f orc e se ns or is 1 g,  
i.e. 0. 0 0 1 N. T he gri p f orce me as ure me nt  
se ns ors use t w o 9. 5 3 m m dia meter fle xi- 
f orce se ns ors fr o m Te ksca n c o n ne cte d  wit h a 
l o w-p o wer li near a m plifier.  T he  se nsiti vit y 
of t he gri p f orc e se ns ors is  5 g,  
i.e. 0. 0 5 N. T he gri p f orces o btai ne d  fr o m t he 
t w o se ns ors are a vera ge d t o yiel d t he 
gri p f orce. T he filtere d l oa d f orc e a n d gri p f orc e data are dire ctl y differe ntiate d o ver a 1 0 ms wi n d o w t o  o btai n  t he l oa d 
f orce a n d gri p f orce rates. Data are sa m ple d wit h a 1 0-bit a nal o g t o di gital c o n verter ( A D C)  a vaila ble  o n t he Ar d ui n o 
micr o micr oc o ntr oller. T he de vic e is fitte d wit h a start -st o p b utt o n t o be gi n data c olle cti o n. T he  i m ple me ntati o n of fle xi-
f orce se ns ors t o meas ure gri p f orc e pr o vi des versatilit y of usi n g re al-life o bje cts s uc h as  a ca n, jar, glass, or b ottle of 
vari o us wei g hts t o be use d as test o bje cts. F o ur test o bje cts of k n o w n  wei g hts,  bet we e n 5 0 g a n d 6 0 0 g (as t he l oa d f orc e 
se ns or has bee n cali brate d a cr oss t hese wei g hts) will be use d as “li g ht”  a n d “ hea v y” o bjects. T he gri p f orce se ns ors will be 
pla c e d o n a fi n ger -ti p i nterfa ce t hat will be attac he d t o t he fi n gers t o e na ble a c o nsta nt gri p s urfa ce w he n gras pi n g t he 
vari o us test o bje cts of differe nt wei g hts.  
I nstr ucte d b y t he st u d y te c h nicia n, partici pa nts will press t he start-st o p b utt o n o nc e t o be gi n data  c olle cti o n. T he y 
will re a c h a n d gras p t he test o bje ct ( of k n o w n wei g ht) plac e d o n t he c oaster usi n g t heir  t h u m b a n d i n de x fi n ger, lift it 
a p pr o xi matel y 5 c m fr o m t he c oaster, a n d h ol d it f or a p pr o x i matel y 3 sec o n ds bef ore  bri n gi n g it ba c k d o w n o n t he c oaster. 
Ea c h da y, partici pa nts will c o m plete t w o sets of te n lifts bef ore a n d after t he sti m ulati o n sessi o n a n d t he sets will ha ve 
desi g nate d wei g hts a n d te xt ures all oc ate d t o t he m base d o n a ra n d o mize d sc he d ule.  T he ti mi n g a n d a m plit u de of t he gri p 
a n d l oa d f orc es a n d f orc e rates  will  pr o vi de me as ures of gras p e xe c uti o n a n d lear ni n g of fi n gerti p f orc es as s h o w n i n Fi g. 
6 .  
 
D at a b ase a n d P atie nt  I nf or m ati o n 
Data  will  be  e ntere d i n t he HI P A A - c o m plia nt N Y U  R E D Ca p  data base  desi g ne d  s pe cific all y f or t his st u d y. A n  
a n o n y m o us data base  n u m ber  will  be  assi g ne d  t o e ac h partici pa nt  a n d will  be  use d  f or b ot h  t he Data  E ntr y  S he et  a n d t he 
Patie nt  F oll o w -u p  S heets.  T he  ori gi nal  fr o nt s heet, w hic h  i ncl u des t he patie nt  na me  a n d I D n u m ber,  will  be  st ore d 
se paratel y i n a  l oc ke d fili n g c a bi net i n a  l oc ke d offic e.  Acc ess  t o t his data  will  be  restricte d t o st u d y pers o n nel  o nl y.  
Researc h  data  will  be  e ntere d  o nli ne  t hr o u g h t he sec ure N Y U  data base  s oft ware R E D Ca p  a n d s o urc e d oc u me nts  will  be  
ke pt  i n a  l oc ke d fili n g c a bi net i n a  l oc ke d office.  Patie nt  cli nic al data  will  be  e ntere d  dire ctl y  i nt o t he Patie nt  Re gistr y  ( o n-
li ne e ntr y). Partici pa nt  data  will  be  c o de d b y  t he assi g ne d  I D a n d i de ntif yi n g i nf or mati o n will  n ot  be  prese nte d  or  
p u blis he d  t o mai ntai n partici pa nt  pri va c y  a n d c o nfi de ntialit y.  
 
A d diti o n al  Q u alit y  Ass ur a nce  Me as ures  
•  
De vel o p me nt  of  sta n dar d pr ot oc ols  t o perf or m  all data  c olle cti o n  a n d f oll o w-u p  a cti vities. 
•  
Use of sta n dar dize d f or ms. 
•  
U nif or m criteria f or patie nt  recr uit me nt. 
•  
Sta n dar dize d data  pr ocessi n g.  
•  
Re g ular  c o m m u nic ati o ns  bet we e n  st u d y staff a n d st u d y i n vesti gat ors t o res ol ve q uesti o ns.  
•  
Perf or ma nc e  m o nit ori n g  of  data  c ollecti o n a n d data  pr ocessi n g  a cti vities, as well  as pre parati o n  of  peri o dic  
re p orts a n d a nal yses o n  perf or ma nce  m o nit ori n g.  
•  M o nt hl y m o nit ori n g of recr uit m e nt  statistics. 
 
D at a S afet y M o nit ori n g  Pl a n  
A n a d verse e ve nt is defi ne d as a n y rati n g (at a n y ti me) of pai n of greater t ha n “ m o derate ” or si de  effects or se nsati o ns t hat 
arise pre ce di n g, d uri n g, or f oll o wi n g sti m ulati o n. Pai n a n d t olera bilit y will be assesse d b y t D C S tec h nicia n at e ver y sessi o n ; 
me as ure d bef ore, d uri n g a n d after e a c h sessi o n.  Tr eati n g p h ysicia ns will m o nit or a n d assess t he rele va nt A Es a n d seri o us 
A Es i n t he st u d y c hart a n d will tre at partici pa nts wit h A Es a p pr o priatel y, per us ual c are.  A Es will be c olle cte d fr o m t he st art 
of t he st u d y u ntil a partici pa nt ter mi nates fr o m t he st u d y; t h ose t hat are u nres ol ve d at  t he ti me of ter mi nati o n will be 
f oll o we d u ntil t he y res ol ve or u p t o 3 0 da ys.  As n ote d, t here is a n e xte nsi ve b o d y of literat ure de m o nstrati n g t he safet y a n d 
 
 
 
 
 
 
 
 
 
 
 
Fi g ure 6 . Ass ess me nt o f grasp e x ec uti on a n d  learni n g wit h  the i n str u me nte d gri p d e vice 
a n d a p p 

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t olera bilit y of t D C S b ot h i n M S a n d i n a ra n ge of cli nical dis or ders. O ur la b at St o n y Br o o k Me dici ne a d mi nistere d > 2 0 0 
a cti ve t D C S sessi o ns t o M S partici pa nts wit h n o pai n  rati n gs of se vere or gre ater a n d n o disc o nti n ue d sessi o n (f or a n y 
re as o n, safet y or t olera bilit y) 1 0 9.  All a d verse e ve nts will be re p orte d t o I R B per N Y U p olic y a n d t o D o D via Q ua rterl y 
Te c h nical Pr o gress Re p ort . 
 
W e will s u b mit st u d y data safet y m o nit ori n g re p orts t o t he I R B after 1 0 partici pa nts are e nr olle d i n t he a cti ve  c o n diti o n 
(a p pr o xi matel y 2 0 t otal partici pa nts bet we e n a cti ve a n d s ha m c o n diti o n), a n d f oll o w wit h re p orts  a fter t he e nr oll me nt of t he 
4 0 t h, 6 0t h, a n d 8 0t h partici pa nt . 
 
W e  will  utilize  o perati n g  pr oc e d ures  f or re vie wi n g patie nt  safet y data  a n d s o urce data  ge nerate d  fr o m t his st u d y. T his  will  
i ncl u de we e kl y  me eti n gs  bet we e n  t he PI,  C o -i n vesti gat ors, a n d st u d y c o or di nat or.  At t hese  me eti n gs,  t he e ntire  researc h 
te a m will  re vie w t he cli nic al rati n gs, assess me nts,  cli nic al c o urse, a d verse a n d/or serio us e ve nts a n d me dic al  rec or ds f or e a c h 
s u bje ct. C o nsi derati o n  of  dr o p pi n g  a n y patie nt  fr o m t he st u d y f or a n y reas o n will  be  disc usse d.  If after  t he c o m pleti o n  of  
t he first 1 0  s u bje cts t he c o m plia nce  is si g nific a ntl y less i n o ne  or  m ore  ar m of  t he st u d y relati ve t o o ur  pre vi o usl y  o bser ve d  
c o m plia nc e  rates, t he st u d y will  be  p ut  o n  h ol d  a n d re vie we d. Base d  o n  t he e xte nsi ve  b o d y  of  literat ure usi n g  t D C S acr oss 
a  ra n ge of  c o n diti o ns, a n d o ur  i nitial partici pa nts  st u die d t o date  (c o m plete d at St o n y  Br o o k  Me dici ne,  we  ha ve  ha d  > 9 4 %  
c o m plia nc e  i n t he a cti ve c o n diti o n. T heref ore, t his discre pa nc y i n c o m plia nce is n ot e x pecte d. We w o ul d defi ne 
discre pa nc y i n  c o m plia nc e as > 5 0 %  differe nce  i n mea n  n u m ber  of  visits  c o m plete d  a n d/ or  5 0 %  differe nc e  i n n u m ber  of  
“ c o m pleters”  i n e ac h  c o n diti o n ( defi ne d b y  c o m pleti n g  at le ast 5 0 %  of  n = 5/ 1 0  sessi o ns). If t here is si g nific a ntl y p o or  
c o m plia nc e  i n t he acti ve  sessi o n, we  will  be  a ble  t o i de ntif y re as o ns i ncl u di n g t olera bilit y as well  as s y m pt o m e x perie nc es.  
T olera bilit y is me as ure d bef ore, d uri n g a n d after ea c h sessi o n a n d all partici pa nts will be m o nit ore d f or  all sessi o ns. 
S afet y  is caref ull y  a d dresse d  i n o ur  pr ot oc ol  wit h  a  series of  st o p criteria  a n d clearl y defi ne d  acti o n ite ms. 
 
I n de pe n de nt Rese arc h M o nit or  
La na Z h o vtis R yers o n, M D will ser ve as  t he i n de pe n de nt researc h m o nit or a p p oi nte d t o t he st u d y.  T he i n de pe n de nt 
researc h m o nit or, is a n i n de pe n de nt e x pert c o m missi o ne d a n d c har ge d wit h t he res p o nsi bilit y of e val uati n g c u m ulati ve 
safet y a n d ot her cli nical trial data at re g ular i nter vals. As s uc h, t he pri mar y o bje cti ve of t he i n de pe n de nt rese arc h m o nit or is 
t o m o nit or t he safet y of t he s u bjects e nr olle d a n d t o be e nr olle d i n t he St u d y b y re vie wi n g t he a vaila ble cli nic al data at 
sc he d ule d ti me p oi nts, as well as o n a n a d h oc basis, as nee de d.  
 
A fter t he re vie w of e a c h Data S afet y M o nit ori n g Re p ort, w hic h will be ge nerate d after e nr oll me nt of t he first te n acti ve 
c o n diti o n partici pa nts a n d after t he 4 0 t h, 6 0t h a n d 8 0 t h partici pa nt, t he i n de pe n de nt researc h m o nit or will pr o vi de t he official 
re c o m men dati o n t o t he PI re gar di n g t he a p pr o priate ness of c o nti n ui n g t he st u d y, fr o m a safet y pers pecti ve, as well as a n y 
ot her rec o m me n dati o ns rele va nt t o st u d y c o n d uct a n d/ or patie nt safet y . 
 
T he i n de pe n de nt rese arc h m o nit or is a ut h orize d a n d c har ge d t o perf or m  t he f oll o wi n g f u ncti o ns:  
 Pr o vi de ti mel y re vie w a n d a p pr o val of, a n d o perate i n ac c or da nce wit h t he s pecific ati o ns o utli ne d i n t he pr ot oc ol.  
 Re vie w t he pr o vi de d st u d y d oc u me nts t hat are a p pr o ve d b y t he PI f or re vie w s uc h as t he pr ot oc ol.  
 T he i n de pe n de nt researc h m o nit or will re vie w st u d y data t o e ns ure t he safet y of s u bje cts e nr olle d i n t he st u d y a n d 
ma ke re c o m me n dati o ns c o nc er ni n g st u d y c o n d u ct. 
 T he i n de pe n de nt researc h m o nit or ma y, c o nta ct a n d i n v ol ve o utsi de e x pert c o ns ulta nts w h o ma y pr o vi de a d diti o n al, 
rele va nt i nsi g ht or e x pertise, re gar di n g a n y s pecific iss ues t hat ma y arise ( o nc e t he y ha ve e ntere d i nt o c o nfi de ntialit y 
discl os ure a gre e me nts).  O utsi de e x pert c o ns ulta nts s h o ul d n ot be e x p ose d t o c o nfi de ntial, u n bli n de d data u nless 
a bs ol utel y ne cessar y f or t he c o ns ulta nt’s i n p ut t o be me a ni n gf ul.  
 Pr o vi de ti mel y res p o nse t o re q ueste d re vie w of d oc u me ntati o n a n d me eti n g a vaila bilit y re q uests ma de t o i n de pe n de nt 
researc h m o nit or. 
 Atte n d t he Kic k -Off meeti n g t o rec ei ve trai ni n g, pr ot oc ol orie ntati o n a n d researc h m o nit or o perati o nal trai ni n g.  
 M o nit or t he safet y of patie nts e nr olle d a n d t o be e nr olle d i n t he St u d y t hr o u g h sc he d ule d re vie w of a cc u m ulati n g 
cli nic al data fr o m t he o n g oi n g cli nic al trial.  
 Re vie w a n d e val uate t he c o nte nt of all Data Safet y M o nit ori n g Re p orts rec ei ve d.  
 E ns ure t hat bli n de d re prese ntati ves (s pecific all y i ncl u di n g t he i n de pe n de nt researc h 
m o nit or), a n d St u d y 
re prese ntati ves are n ot e x p ose d t o t he c o nfi de ntial, u n bli n de d data ma de a vaila ble t o t he i n de pe n de nt rese arc h m o nit or. 
T he U n bli n de d pers o n nel has t he sa me a cc ess t o t he data t hat is re vie we d b y t he i n de pe n de nt rese arc h m o nit or; 
t heref ore, it is n ot ne c essar y f or t he i n de pe n de nt rese arc h m o nit or t o ta ke ste ps t o mai ntai n t his i n di vi d ual i n a bli n d e d 
p ositi o n.  
 Mai ntai n ulti mate res p o nsi bilit y f or safe st u d y c o n d uct, ac c or di n g t o I C H G o o d Cli nic al Pra ctic es ( G C P) G ui deli n e .  

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T he Researc h M o nit or is res p o nsi ble t o o versee t he safet y of t he rese arc h s u bjects a n d re p ort o bser vati o ns/fi n di n gs t o 
t he I R B or a desi g nate d i nstit uti o nal official. T he Researc h M o nit or will re vie w all u na ntici pate d pr o ble ms i n v ol vi n g 
ris ks t o s u bje cts or ot hers ass ociate d wit h t he pr ot oc ol a n d pr o vi de a n i n de pe n de nt re p ort of t he e ve nt t o t he I R B. T he 
Researc h M o nit or ma y disc uss t he researc h pr ot oc ol wit h t he i n vesti gat ors; s hall ha ve a ut h orit y t o st o p a researc h 
pr ot oc ol i n pr o gress, re m o ve i n di vi d ual h u ma n s u bjects fr o m a researc h pr ot oc ol, a n d ta ke w hate ver ste ps are 
ne c essar y t o pr otect t he safet y a n d well -bei n g of h u ma n s u bje cts u ntil t he I R B c a n assess t he m o nit or's re p ort; a n d s hall 
ha ve t he res p o nsi bilit y t o pr o m ptl y re p ort t heir o bser vati o ns a n d  fi n di n gs t o t he I R B or ot her desi g nate d official a n d 
t he H R P O. 
 
P ot e nti al Ris ks & Be n efits:  
t D C S: 
T o  o ur  k n o wle d ge,  h u n dre ds  of  t D C S st u dies i n t he U S  ha ve  all bee n  desi g nate d  N o n -Si g nific a nt -Ris k  ( N S R) t he l o west 
ris k le vel ( de vic es t hat are  n ot:  i nte n de d as a n i m pla nt wit h  p ote ntial  f or seri o us ris k t o he alt h,  safet y, or  welfare  of  
s u bje ct; p ur p orte d  or  re prese nte d t o be  f or use  i n s u p p orti n g or  s ustai ni n g h u ma n  life wit h  a  p ote ntial  f or seri o us ris ks; f or 
use  of  s u bsta ntial i m p orta nc e i n dia g n osi n g  c uri n g, miti gati n g,  tre ati n g disease  or  ot her wise  pre ve nti n g  i m pair me nt of  
h u ma n  he alt h  wit h  p ote ntial  f or si g nific a nt ris k; ot her wise  prese nts  si g nific a nt ris k t o t he he alt h,  safet y, or  welfare  of  a  
s u bje ct). F or  t hese reas o ns, t he S oteri x  Mi ni  C T,  as use d  i n t his st u d y, als o q ualifies  as a  N S R  de vice .  W hile  t D C S 
re mai ns a n i n v esti g ati o n al te c h ni q ue (si m pl y bec a use  n o  c o m pa n y  has  a p plie d t o t he F D A  f or a p pr o val t o mar ket  
t D C S f or a n y gi ve n  i n dic ati o n), t D C S is a  br oa dl y  re pr o d uc e d a n d teste d tec h ni q ue t hat is c o nsi dere d effecti ve  i n 
m o d ulati n g  brai n  e xcita bilit y i n  a  ma n ner  t hat ma y  s u p p ort le ar ni n g a n d wit h  a d verse e ve nts ( differe nt t ha n s ha m) li mite d 
t o ti n gli n g, itc hi n g, a n d re d ness  t hat dis pel  after  sti m ulati o n st o ps. I n a p ri o r  st u d y of  use  i n a  v ul nera ble  p o p ulati o n  
( de vel o p me ntall y disa ble d  c hil dre n), t he F D A  iss ue d a  N S R  f or t D C S de vice  (see attac he d letter). T he  letter pr o vi de d  as 
a n e xa m ple  of  t he F D A’s  desi g nati o n  of  t D C S de vic es  as ha vi n g a b bre viate d -I D E. Bec a use  of  its pri or  desi g nati o n of  
t D C S de vices  as a b bre viate d-I D E, trials d o  n ot  t y picall y see k f urt her declarati o n.  I n t he letter pr o vi de d,  Dr.  Wasser ma n  
s pecific all y s o u g ht F D A  re vie w of  t he trial d ue  t o t he use  of  t D C S i n a  v ul nera ble  p o p ulati o n  ( de vel o p me ntall y disa ble d  
c hil dre n).  T o  date,  h u n dre ds  of trials  ha ve  be e n  desi g nate d  as n o n -si g nifica nt-ris k b y  I R B re vie w w hic h  pr o vi des  its 
a b bre viate d I D E stat us. Res ults  of  c o m plete d  trials, i ncl u di n g o ur  o w n  w or k  i n M S  usi n g  t his pr ot oc ol,  ha ve s u p p orte d  
t he ris k desi g nati o n  pr o vi de d  b y  I R Bs. T he  St o n y  Br o o k  Me dici ne  I R B c o nfir me d  t he N S R  a n d a b bre viate d I D E stat us 
of  t D C S f or o ur  st u d y. 
 
T he  safet y of  t his te c h ni q ue has  bee n  a d dresse d  a n d teste d b y  m ulti ple  rese arc hers ( Fre g ni, et. al. [5 9 ];  Nitsc he,  et al. 
[6 0 ]; Pri ori,  et al. [1 5 ]) w h o  ha ve  c o ncl u de d t hat t D C S, as a p plie d i n a ma n ner  si milar t o o ur  pr o p ose d  pr ot oc ol,  i n d uc es 
o nl y  te m p orar y m o o d,  c o g niti ve  / m ot or  effects, a n d n o  ne gati ve  si de effects.  F or  e xa m ple, rese arc hers at t he Nati o nal  
I nstit ute of  Ne ur ol o gic al  Dis or d er s  a n d Str o ke  ( NI N D S), I yer et al. [1 7 ] c o n d ucte d  a  safet y st u d y o n  t D C S, 
i n vesti gati n g 2 0 -mi n ute  sessi o ns of  1  m A  a n d 2  m A  c urre nt sti m ulati o n wit h  he alt h y  c o ntr ols ( n = 1 0 3). N o  ne gati ve  
effects were  i de ntifie d. Nitsc he  a n d c olle a g ues  f o u n d n o  me as ura ble  str uct ural c ha n ges i n brai n  tiss ue d ue  t o t D C S [6 1 ]. 
I n a  meta -a nal ysis of  o ver  2 0 0  t D C S st u dies c o n d ucte d  fr o m 1 9 9 8  t o 2 0 1 0,  5 6 %  of  st u dies me nti o ne d  a d verse  e ve nts, 
w hic h  were  ge nerall y  mi n or.  T he  m ost  c o m m o nl y re p orte d si de effects i ncl u de d itc hi n g, ti n gli n g, hea dac he,  b ur ni n g  
se nsati o n a n d disc o mf ort  li mite d t o t he scal p site w here  t he t D C S electr o des were  a p plie d. T o  date,  t here ha ve  bee n  n o  
re p orts of  seiz ures i n d uce d b y  t D C S1 4 . I m p orta ntl y t his is t he case  i n n or mal  v ol u nte ers,  b ut  als o i n differe nt  p o p ulati o ns  
of  patie nts,  i ncl u di n g patie nts wit h  dis or ders  w here  t here mi g ht  be  a n i ncre ase d ris k of  seiz ures (e. g. Alz hei mer’s  disease,  
rece nt str o ke, e pile ps y). A  st u d y fr o m N Y U  o n  t he use  of  t D C S i n patie nts  wit h  e pile ps y [6 2 ] e nc o u ntere d  n o  i ncrease i n 
c o m plic ati o ns  of  t D C S i n t he patie nts  as c o m pare d  wit h  c o ntr ols. S pecific all y,  t here were n o  i nsta nces of  seiz ures 
i n d uce d b y  t D C S. 
 
H a n d hel d gri p de vice : 
T he gras pi n g a n d lifti n g tas ks c arr y n o ris ks be y o n d t h ose of or di nar y a cti vities. Patie nts will be all o we d t o ta ke fre q ue nt 
rest brea ks d uri n g t he sessi o ns.  T here ma y be ot her ris ks or disc o mf orts i n t he st u d y t hat we d o n’t k n o w  a b o ut.   
T he c u p c o ntr oller, n o vel p h ysical o bje ct ga me c o ntr oller c o nsisti n g of a plastic c u p e xteri or 5 i nc hes tall a n d 2. 7 5 i nc hes i n 
dia meter.  T he c u p is i nstr u me nte d wit h a n A D X L - 3 4 5, 3 -a xis acc eler o meter ( A nal o g De vic e I nc. N or w o o d, M A) t o dete ct 
o bje ct orie ntati o n a n d F S R 4 0 6 (I nterli n k Electr o nics Ca marill o, C A) f orce se ns ors t o dete ct user gri p f orc e. A n Ar d ui n o 
U n o R 3 usi n g a n A T me ga 3 2 8 Micr oc o ntr oller ( At mel Sa n J ose, C A) is use d t o rec or d a n d i nte grate se ns or data. T he c u p 
ga me c o ntr oller will  be c o m pare d wit h a sta n dar d L o gite c h o ptic al m o use a n d wit h a Ni nte n d o Wii c o ntr oller.   
 

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L oss of C o nfi de nti alit y:  
Partici pa nts  i n all gr o u ps  ma y  fi n d t he q uesti o n naires  ti me c o ns u mi n g  a n d p ote ntiall y  b ot hers o me.  Ne ur o ps yc h ol o gical  
testi n g a n d t he c o m p uter  trai ni n g sessi o ns ma y,  i n s o me i n di vi d uals, be  stressf ul or  a n xiet y pr o d uci n g.  T here  is a  s mall ris k of  
l oss of  c o nfi de ntialit y.  Partici pa nts  will  be  assi g ne d a  st u d y I D a n d t heir na me  will  n ot  be  use d  o n  a n y of  t he i nf or mati o n 
c olle cte d. T he  pr o gra m  use d  f or a d mi nisteri n g t he gri p lifts  will  n ot  c olle ct a n y pers o nall y  i de ntifia ble i nf or mati o n. T he  
res ults of  t hese data  c olle cte d  ma y  be  use d  f or p u blicati o n  b ut  will  n ot  i ncl u de t he partici pa nts’  na mes.  Har dc o pies  of  t he data  
files will  be  ke pt  i n sec ure, l oc ke d files a n d data  will  be  e ntere d i n a  sec ure, N Y U  a p pr o ve d  data base . 
 
Be n efits t o P artici p a nts:  
Partici pa nts ma y n ot rec ei ve a n y direct be nefits fr o m partici pati n g i n t his researc h st u d y.  W e h o pe t he k n o wle d ge 
gai ne d fr o m t his st u d y will hel p ot hers wit h M S i n t he f ut ure.  
 
P a y m e nt f or p artici p ati o n:  
Partici pa nts will re cei ve u p t o $ 1 0 0 i n t otal c o m pe nsati o n.  T he y will be c o m pe nsate d $ 5 0 f or t he i nitial scree ni n g a n d 
baseli ne visit, a n d $ 5 0 f or t he e n d of st u d y visit.  Atte m pte d  c o m pleti o n  of  a  st u d y sessi o n will  be  defi ne d  b y  si g ni n g i n 
t o t he sec ure i nter net-base d  vi de o  f or c o ntact wit h  st u d y te c h nicia n wit hi n  1 5  mi n utes  of  sc he d ule d ti me f or all da ys  of  
re m ote c o nta ct.  If t he partici pa nt  is u na ble  t o esta blis h vi de o  c o nta ct wit h  t he st u d y te c h nicia n d ue  t o te c h nic al 
diffic ulties,  t he y m ust  c o nta ct t he st u d y te c h nicia n b y  p h o ne  b y  t he sc he d ule d ti me t o rec ei ve cre dit f or eff ort. 
 
I n or der f or partici pa nts t o re c ei ve a pa y me nt c he c k or gift c ar d , t he y will ne e d t o pr o vi de t he st u d y staff eit her t heir S ocial 
S e c urit y n u m ber or Alie n Re gistrati o n n u m ber.  If partici pa nt d oes n ot ha ve eit her of t hese n u m bers, partici pa nt ma y be 
e nr olle d i n t he st u d y b ut will n ot re c ei ve a n y pa y me nt .  
 
P o we r A n al ysis a n d D at a A n al ysis  Pl a n  
S a m ple Size Deter mi n ati o n: W e c alc ulate o ur sa m ple size f or t he p ri mar y o utc o mes, 
prel oa d  p hase d urati o n 
a n d 
pe a k l oa d f orc e rate a cr oss li g ht a n d hea v y wei g hts fr o m pre - t o p ost-tre at me nt. Base d o n o ur preli mi nar y data, 
t hese varia bles are a p pr o xi matel y n or mall y distri b ute d wit h s mall varia nc e. E x pecti n g a me di u m eff ect size ( 0. 5) f or t he 
differe nce i n 
prel oa d p hase d urati o n bet wee n t he a cti ve t D C S a n d t he  s ha m t D C S gr o u ps, gr o u p size of 3 0 i n e ac h ar m 
(t otal 6 0) will a c hie ve 8 0 % p o wer t o dete ct t he effe ct size of 0. 5  wit h a si g nific a nce le vel of 0. 0 5 usi n g a t w o -si de d t-test. 
A si milar effe ct size is e x pecte d f or t he  
pe a k  l oa d f orc e rate. Ac c o u nti n g f or 2 5 % attritio n of t he sa m ple, t he act ual 
sa m ple size will be 4 0 i n e a c h ar m (t otal 8 0).  
D at a  A n alysis  Pl a n:  F or  S pe cific  Ai m  1 , t o deter mi ne  t he e xte nt t o w hic h  t D C S paire d  wit h  ma n ual de xterit y  
trai ni n g i m pr o ves fi ne m ot or  e xec uti o n  o n  a  gras p  a n d lift tas k, t he pri mar y  o utc o me  will  be  t he te m p oral c o or di nati o n 
bet we e n gras pi n g a n d lifti n g f orc es, as assesse d b y t he prel oa d p hase d urati o n wit h  a cti ve t D C S  c o m pare d  t o s ha m t D C S. 
T o  test o ur  h y p ot hesis  t hat a cti ve  vs.  s ha m t D C S will  si g nific a ntl y re d uc e t he prel oa d p hase d urati o n pre - t o p ost-
i nter ve nti o n wit h a cti ve c o m pare d wit h s ha m-t D C S paire d wit h trai ni n g, we will perf or m a re peate d meas ure A N O V A f or 
t he t w o gr o u ps fr o m pre-t o-p ost -i nter ve nti o n o n t he prel oa d p hase d urati o n  w hic h  is t he pri mar y  o utc o me  me as ure  f or 
gras p  e xec uti o n.  F or  e a c h gr o u p,  t he effect size will  be esti mate d  a n d re p orte d wit h  mea n  a n d 9 5 %  c o nfi de nce  
i nter vals. W e  ex pect t h at t he i m p air me nt i n gr as p e xe c uti o n will be si g nific a ntly re d uc e d wit h activ e t D C S v ers us s h a m 
t D C S fr o m pre- t o p ost -tre at me nt. Se c o n daril y, t he  c ha n ge i n pre -l oa d p hase d urati o n will be c orrelate d wit h t he c ha n ge i n 
ti mi n g o n t he 9 H P T as well as i n ma n ual de xterit y sc ores i n t he t w o  gr o u ps.  
F or S pe cific Ai m 2 , t o assess t he a da ptati o n or le ar ni n g of fi n gerti p f orc es t o o bje ct wei g ht w he n t D C S is paire d 
wit h ma n ual de xterit y trai ni n g. T he pri mar y o utc o me will be t he differe nce i n t he pea k l oa d f orce  rate bet we e n trials wit h 
the li g ht vers us he a v y o bjects. T o test o ur h y p ot hesis t hat a cti ve vs. s ha m t D C S paire d  wit h trai ni n g  will  o pti mize  t he 
differe nce  i n t he pea k  l oa d f orc e rates bet wee n  t he li g ht a n d he a v y  o bje cts  pre - t o p ost-i nter ve nti o n, we  will  first 
c o m pare  partici pa nts’  perf or ma nc es  t o t hat of  healt h y  c o ntr ols. A  n or mati ve  data base f or t he o pti mal pe a k l oa d f orce 
rate f or healt h y c o ntr ols i n a p o p ulati o n alrea d y e xists [ 8 5]. Usi n g t he e xisti n g data base as a be nc h mar k we will perf or m a 
re peate d me as ure A N O V A f or t he t w o gr o u ps fr o m pre -t o- p ost -i nter ve nti o n. F or ea c h gr o u p, t he effe ct size will be 
esti mate d a n d re p orte d wit h me a n a n d 9 5 %  c o nfi de nce i nter vals.  We  e x pe ct t h at t he i m p air me nt i n gr as p  a d a pt ati o n  or  
le ar ni n g will  be  cl oser t o t he be nc h m ark  wit h activ e t D C S v ers us s h a m t D C S fr o m pre - t o p ost-tre at me nt. O ne of t he 
si g nific a nt c o ntri b uti o ns of t his pr o p ose d st u d y  is t hat w e  will  be  a ble  t o tra c k detaile d  rec o ver y pr o gressi o n  f or b ot h  
tre at me nt gr o u ps  o ver  t he 2 0  sessi o ns. We will use l o n git u di nal gr o wt h c ur ve m o deli n g [ 8 6] t o deli ne ate t y pic al t y pes of 
re c o ver y traje ct ories i n e ac h gr o u p. We will assess t he relati o ns hi p bet we e n wit hi n-sessi o n a n d bet wee n-sessi o n le ar ni n g 

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traje ct ories t o de e pe n o ur u n dersta n di n g o n h o w s h ort-ter m le ar nin g affects t he l o n ger -ter m tre at me nt res p o nse. 
 
Tr a nsiti o n Pl a n  
W e belie ve t hat st u dies of t D C S i n M S ha ve bee n li mite d b y sa m ple size a n d n u m ber of  treat me nt sessi o ns d ue t o t he barrier 
of a cc ess f or m ost M S patie nts t o partici pate i n st u dies re q uiri n g m u lti ple c o nsec uti ve cli nic visits f or tre at me nt. E ve n 
relati vel y mi n or re d ucti o ns i n ma n ual de xterit y c a n le a d t o maj or pr o ble ms i n dail y life, a n d t his is a  lea di n g ca use  of  M S -
relate d disa bilit y.  C o m bi ni n g  t D C S wit h  ma n ual  de xterit y  trai ni n g a c c esse d fr o m h o me re prese nts a maj or a d va nc e t hat is 
i m me diatel y a p plic a ble t o re al-w orl d cli nic use. I n  s u m, t his st u d y re prese nts a ti mel y a n d m uc h-ne e de d a d va nc e f or b ot h 
t he st u d y of t D C S i n ge neral, a n d f or t he re ha bilitati o n of ma n ual de xterit y i m pair me nts i n M S s pecificall y, t hr o u g h t he use 
of a  telere ha bilitati o n a p pr oac h. 
 
T he re m otel y -s u per vise d met h o ds t o be pil ote d c a n tra nsf or m t D C S i nt o a via ble tre at me nt m o dalit y.  T he  st u d y’s pr ot oc ol  
is hi g hl y  ge n eraliza ble  f or use  i n cli nic al  tri als t o e v al uat e ot her  are as  of  p ote ntial  effi cac y  f or t D C S (i ncl u di n g 
c o g niti v e i m pair me nt, m o o d dist ur ba nce, pai n a n d slee p pr o ble ms) i n M S as well as  i n ma n y ot her c o n diti o ns. 
T o dat e, t he use of t D C S has l ar gel y re m ai ne d wit hi n t he researc h re al m wit h  fe w treat me nt sessi o ns st u die d i n 
s mall sa m pl e sizes. H o we ver, tec h n ol o g y is ra pi dl y a d va nci n g wit h t he  e mer gi n g de vel o p m e nt of de vices 
mar ket e d dir ectl y t o t he c o ns u mer wit h o ut a n y cli ni c al st u d y. I n t his c o nte xt, it  is p arti c ularl y criti cal t o f a cilitat e 
research t hat will d eter mi ne t h e use of t he t ec h n ol o g y t hat will saf el y l ea d t o  t he gre atest b e nefit. O ur i n n o vati v e 
pr ot oc ol will facilitat e st u d y e nr oll me nt a n d m uc h m ore e xte nsi v e st u d y of  t he c u m ulati ve treat me nt effe cts.  
 
T his trial will be a defi niti ve ste p t o war ds deter mi ni n g t he tre at me nt be nefit of t D C S f or  e n ha nci n g m ot or re ha bilitati o n. 
A p pl yi n g preli mi nar y fi n di n gs f or use i n M S, we will directl y me as ure t he  c u m ulati ve tre at me nt effe ct of pairi n g t D C S wit h 
a pr o gra m of re ha bilitati o n. I n a d diti o n, o ur n o vel me as ure me nt  de vice will all o w f or a better u n dersta n di n g of t he relati o n 
of gras p a n d gri p lear ni n g t o ot her meas ures a n d i n  res p o nse t o trai ni n g e xercises. T he dire ct ne xt ste p fr o m t his pil ot st u d y 
will be a defi niti ve trial utilizi n g o ur  re m otel y- s u per vise d pr ot oc ol t o i m pr o ve ma n ual de xterit y.  
 
D at a S h ari n g Pl a n  
 
T he data deri ve d fr o m t his pr oje ct will be p u blis he d i n peer -re vie we d scie ntific p u blic ati o ns a n d prese ntati o ns. I n or der t o 
c ater t o t he i nterests of a br oa d s pectr u m of a u die nc e, differe nt as pects of t he pr o p osal will be p u blis he d i n c orres p o n di n g 
s pecialize d j o ur nals a n d s y m p osia. S pecial atte nti o n will be ta ke n i n pre pari n g t he ma n uscri pts t o i ncl u de details of materia ls 
a n d met h o ds i ncl u di n g pr ot oc ols, a nal ytical t o ols, a n d s u p p orti n g data f or t he c haracterizati o n of c o m p o u n ds. T he data will 
be als o prese nte d t hr o u g h lect ures a n d researc h se mi nars.  
 
As s o o n as t he fi nal data is acc e pte d f or p u blicati o n, t he data will be s hare d wit h i nter este d rese arc hers  t hr o u g h pers o nal 
c o m m u nic ati o ns. W he ne ver p ossi ble, we will als o de p osit data i n p u blic arc hi ves, we b sites, a n d data ce nters after ac hie vi n g 
t he milest o nes of t his gra nt a p plic ati o n. T h us, data will be ma de a vaila ble t o t he p u blic a n d rese arc h c o m m u nities i n a ti mel y 
f or mat, a me na ble t o f urt her researc h a n d de vel o p me nt. T his will e ns ure ot h er scie ntists p urs ui n g t he t o pics i n f urt her 
directi o ns a n d s u p p ort testi n g of ne w or alt er nati ve h y p ot heses a n d met h o ds of a nal ysis. F or researc h ers i ntereste d 
i n a d diti o nal met h o d ol o gic al details of o ur w or k or i n c o m pari n g t heir o w n data t o o ur fi n di n gs, we will pr o vi de a 
data base f or a n o n y miz e d dat a/i ma ge d o w nl o a d. A n y cli ni cal d ata will be a n o n y miz e d a n d o nl y r elate d t hr o u g h 
partici pa nt c o des s o t ha t data c a n be s hare d i n a HI P A A-c o m plia nt ma n ner.  
 
Et hic al C o nsi der ati o ns  
T he g oal t o alle vi ate de bilitati n g fati g ue is t h e maj or et hic al dri v er f or t his st u d y. A first c o nc er n  is w het her t he 
t D C S ma y ca use a n y effect t hat w o ul d b e c o nsi der e d har mf ul. As descri be d, acr oss h u n dre ds  of cli nic al trials, 
i ncl udi n g i n M S a n d o ur pil ot st u dies, t D C S has bee n f o u n d t o be safe a n d well -t olerat e d [ 3 0, 8 7, 8 8]. A rece nt 
a n d c o m pre h e nsi ve safet y r e vie w f o u n d n o ris k of a d verse e ve nts wit h t D C S as pla n ne d f or use  i n t his st u d y [ 2 5]. 
All p ote ntial p arti ci pa nts will be war ne d of a n y p ossi ble si de eff ect. Pri or t o  e nr oll m e nt, partici pa nts will u n der g o 
me dic al cleara n ce wit h a c o nfir mati o n of e nr oll me nt criteria i n cl u di n g  c o g niti ve scre e ni n g m eas ures t o e ns ure 
t hat t h e y ha ve s uffi cie nt c o g niti ve c a pacit y t o u n d ersta n d t he f u n d a me ntal pri nci pl es of cli nical resear c h, t he 
s pecifics of t his st u d y, a n d t o c o m pl y wit h st u d y pr o ce d ures.  
 

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Dr. C har vet’s  f oc us of her care er has bee n t o me as ure a n d a m eli or ate t h e s y m pt o ms of M ulti ple Scler osis 
i ncl u di n g c o g niti ve i m pair me nt a n d fati g u e. S he is a w orl d lea der i n re m ote-s u per vise d tr a nscra ni al dir ect c urre nt 
sti m uli ati o n ( R S-t D C S) i ncl u di n g se ver al p u blicati ons o n safet y a n d feasi bilit y. S he bri n gs o ver 2 0 years of 
cli ni cal r esearc h e x p erie n ce t o t his pr oje ct, i n cl u di n g ke y i n vesti g at or r ol es i n past NI H -s u p p orte d pr ojects. S he is 
a lic e nse d cli nical ne ur o ps yc h ol o gist a n d tr ai ni n g h as i ncl u de d t h e c o m pleti o n o f a n A B P P-A B C N certifi e d 
i nter ns hi p a n d p ost d o ct oral fell o ws hi p pr o gra ms i n cli nic al ne ur o ps yc h ol o g y wit h b ot h a d ult a n d pe diatri c 
trai ni n g. 
 
Dr. Kr u p p’s q ualificati o ns i ncl u d e o ver a 2 5 ye ar rec or d of cli ni cal a n d researc h e x peri e nce o n m ulti ple s cler osis  
( M S), a p u blicati o n hist or y c o v eri n g c o g niti ve f u n cti o n a n d relate d as pects of t he dise ase, le a ders hi p e x p erie nce 
directi n g o bser vati o nal st u dies o n c o g niti o n i n M S, NI H s u p p orte d m ultic e nter trials o n fati g ue a n d c o g niti o n, a n d 
access t o a lar ge gr o u p of  patie nts wit h M S.  
 
Dr. Preeti Ra g ha v a n  is a n e x pert i n m ot or le ar ni n g after ne ur ol o gical i nj ur y, partic ularl y r e-le ar ni n g of m a n ual 
de xterit y. S he de vel o pe d t he i nstr u me nte d gri p d e vic e i n c o nj u n cti o n wit h t he c o m p ut er i nterf ace a n d trai ni n g 
al g orit h ms f o r i n-h o me use.  
 
Dr. Mar o m Bi ks o n  (c olla b or at or) is a n i nter nati o nal l ea der i n t he fi el d of t D C S f or cli nical tri als, a n d will pr o vi de 
his e x pertise i n tri al desi g n a n d e xec uti o n, as well as ser ve as a li ais o n f or t he me dic al de vice c o m pa n y S oteri x. 
He will  g ui de t he rese arc h re gar di n g t he mec h a nis ms of acti o n of t D C S i nc or p orati n g ne ur oi ma gi n g  data a n d 
electr o de pl ace m e nt 2 3.  
 
Dr. Yi n g L u , is a n e x pert i n statistic al met h o d ol o g y f or m o del sel ecti o n a n d h y p ot h esis testi n g f or hi g h 
di me nsi o nal bi o m ec ha nic al data fr o m t he C e nter f or t he  Pr o m oti o n of R esearc h I n v ol vi n g Statisti cal Met h o d o l o g y 
( P RI S M), at N Y U Stei n har dt. 
 
N o a d diti o nal D o D trai ni n gs ar e re q uire d.  
 
O nce  e nr oll e d, all partici p a nts (i ncl u di n g t h eir c are gi ver or ot her pr o x y as warra nt e d) will b e trai ne d t o o p erate  
st u d y e q ui p me nt b y use of esta blis he d tr ai ni n g pr ot o c ols t hat i ncl u d e scree ns f or a ptit u de a n d e xt e ns i ve s afet y 
c hec ks at eac h ste p. All sessi o ns will be a d mi nist ere d wit h real -ti m e s u per visi o n t o m o nit or t he partici p a nt’s 
stat us (relate d t o saf et y or t ol era bilit y) or wis h t o disc o nti n ue d uri n g offic e h o urs a n d staff a vaila bilit y. T hese 
meas ures pre ve nt a n y partici p a nt fr o m  c o nti n ui n g if t here are a n y a d verse eff ects, i m pr o per use of t h e de vice or 
st u d y e q ui p me nt, or iss ue rel ate d t o c o m pli a nce.  Pr o ce d ures are i n plac e t o i m me diat el y alert t he st u d y 
ne ur ol o gist if a n y p ote ntiall y a d v erse e ve nts ar e  re p orte d.  
W hile t he o ver w hel mi n g maj orit y of t D C S trials t o d ate ha v e f o u n d o nl y be nefici al res ults, t w o  rece nt 
st u dies ha ve re p orte d p ossi ble s u p pressi o n of c o g niti ve perf or ma n ce aft er t he a d mi nistrati o n of o ne  t D C S 
sessi o n [ 8 9, 9 0]. T hese fi n di n gs are q uesti o na bl e gi v e n t he e xte nsi ve a n d well -d oc u me nt e d i m pr o v e me nts  i n 
c o g niti o n a n d le ar ni n g wit h t D C S a p plic ati o n [ 6 6, 6 8], a n d o ne sessi o n is n ot li k el y t o h a ve a s ustai ne d  eff ect 
( p ositi ve or ne g ati v e) [ 3 0]. F urt her, t her e is n o i n di cati o n of a n y p ost-sessi o n decli ne or c o g niti ve c ha n g es  i n 
o ur feasi bilit y st u d y. W hile we di d n ot i n cl u de c o g niti ve m eas ure m e nt at eac h sessi o n, partici pa nts’  m o o d 
i m pr o ve d after ea c h tre at m e nt (i n crease d p ositi ve aff ect, p = 0. 0 7; d ecre ase d ne gati ve aff ect, p = 0. 0 4).  
A d diti o nall y, part ici p a nts ha d n o i n dicati o n of c o g niti ve decli ne f oll o wi n g t h e treat me nts, wit h sc ores o n t he 
S D M T (a re prese ntati ve me as ure of c o g niti ve f u n cti o ni n g i n M S[ 9 1],[ 9 2]) sli g htl y i m pr o vi n g after t e n  sessi o ns 
( 4 4. 9 ± 1 3. 5 vs. 4 6. 6 ± 1 5. 4, p = 0. 2 8).  
A sec o n d p ossi ble c o ncer n is t hat partici pa nts m a y n ot recei ve e x pe cte d b e nefit. I n t his c ase, t he  st u d y 
desi g n a n d ra n d o mizati o n pr oce d ur es will be e x plai n e d i n det ail t o all partici pa nts. T h ose i n t h e s ha m  c o n diti o n 
will be offer e d t o c o nti n ue wit h 1 0 o p e n -la b el sessi o ns at st u d y e n d w hic h m a y pr o vi de t he m wit h treat m e nt 
be nefit.  At st u d y c o m pl eti o n, all p artici pa nts will re cei ve f ee d bac k o n t heir st u d y o utc o m es a n d t h ose t h at  d o 
n ot e x peri e nce a n y b e nefit wit h a cti v e tre at m e nt m a y gai n dire cti o n f or f ut ure tri als of t D C S t hat ma y  b e  

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a da pte d t o t heir i n di vi d ual n ee ds base d o n t he r es ults of t his  st u d y. 
 
S U B J E C T  R E C R UI T M E N T  A N D  C O N S E N T/ A S S E N T:  
Met h o d of S u bject I de ntific ati o n a n d Recr uit me nt   
Researc h c a n di dat es will be r ecr uite d fr o m t he N Y U M S C o m pre he nsi ve Care C e nter p atie nt dat a base  as well as 
fr o m n o n-N Y U referri n g faciliti es a n d/ or p h ysicia ns.  Patie nts w h o are se e n b y me dical st aff at N Y U La n g o ne 
Me dical C e nter, w h o fit t he eli gi bilit y criteri a, will b e referre d f or t h e st u d y b y t he st u d y PI a n d s u b -
i n vesti gat ors. All p h ysici a ns a n d me dical staff at t he M S Care Ce nter will be prese nte d wit h t h e st u d y 
descri pti o n. A patie nt w h o is seei n g o ne of t h ese me dical st aff me m bers as t heir treati n g p h ysicia n will b e 
i ntr o d uce d t o t he st u d y b y t hat me di cal staff me m b er. If t he patie nt is i nter este d a n d a gr ees, t he n a me m ber of 
t he st u d y staff will c o nt act t he m. O nce a patie nt is i d e ntifi e d, st u d y staff will me et wit h t he patie nt or call t he m 
t o pr o vi de a d diti o n al i nf or mati o n re gar di n g st u d y p artici p ati o n. Aft er t he patie nt has re vi e we d t he c o nse nt f or m 
a n d as ke d all q uesti o ns, a n d pr o vi des c o nse nt t o p arti ci pat e, t he p ati e nt will be e nr olle d i n t he st u d y.  
 
Partici p a nt pers o nal i nf or mati o n will be ke pt i n Ri p ple ™, a sec ur e we b a p plicati o n desi g ne d  f or t he st ori n g a n d 
ma na ge me nt of p ers o nall y i d e ntif yi n g i nf or m ati o n of researc h  partici p a nts. Ri p pl e was i nitiall y de vel o pe d at t he 
U ni versit y of Mic hi g a n t o pr o vi d e a user  frie n dl y, we b -base d sec ure i nterfa ce w here r esearc h t ea ms c a n 
ce ntraliz e t he st ora g e a n d  m a na ge me nt of r esearc h p artici pa nts’ pers o nal i nf or mati o n, i n cl u di n g n a me, 
partici pa nt I D,  de m o gra p hics, a n d st u d y w or kfl o w (e. g., a p p oi nt m e nts). Parti ci pa nt i nf or m ati o n ma na ge d  
wit h Ri p ple ™ is pri vat e a n d sec ur e. T his i nf or mati o n is ke pt i n f ull y e ncr y pte d  f or mat i nsi de d e dic ate d 
data bases t h at are se gr e gat e d fr o m ot h er Ri p pl e ™ ac c o u nts a n d t h us o nl y  a ut h oriz e d st u d y staff will ha ve access 
t o t he st u d y data. Li ke wise, Ri p ple i nfrastr uct ure c o m plies wit h t he pri v ac y a n d sec urit y g ui d eli n es of t h e Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), i ncl u di n g 2 0 4 8 -bit dat a e ncr y pti o n i n tra nsit a n d at rest,  
a ut o matic l o g off, a u dit trail, dail y bac k u ps i n tri plicate de di cat e d ser vers, fire wall, c ust o m  acc ess per missi o n f or 
la b me m bers, z xc v b n p ass w or d stre n gt h esti mati o n, a n d e nter prise a d mi nistrati ve safe g u ar ds t o pre ve nt 
u na ut h oriz e d staff fr o m a ccessi n g partici pa nt  i nf or m ati o n. F urt her m ore, Ri p ple ™ is use d o nl y f or st ori n g 
pers o nall y i d e ntifia bl e i nf or mati o n  of partici pa nts a n d is n ot use d t o ca pt ure ot h er researc h d ata ( e. g., 
q uesti o n nair es, healt h  rec or ds, et c.). T his e ns ures t h at t he pers o nall y i d e ntifia bl e i nf or mati o n a n d r esearc h data 
are se gre gate d. Ri p ple ™ is alrea d y bei n g use d at N Y U La n g o ne Healt h . 
 
I nf or me d C o nse nt Pr ocess 
All  p ote ntial  parti ci p a nts  will  c o m plete a scree ni n g i nter vie w t o e ns ure ge neral  eli gi bilit y.  T he  st u d y staff 
me m ber  s pe a ki n g t o t h e s u bject will  pr o vi de  t he s u bj ect wit h  a n o ver vi e w  of  t he st u d y a n d ver b all y  re cei v e 
t heir p er missi o n,  u n der  a  wai ver  of  d oc u m e ntati o n  of  c o nse nt,  t o c o m pl ete t he ge neral  eli gi bilit y scre e ni n g. 
T his  p h o ne  scree n is mi ni mal  ris k t o t he partici pa nt  a n d c olle cte d  i nf or mati o n will  be  mai ntai ne d  i n sec ur e d, 
l oc ke d files. De -i d e ntifie d i nf or mati o n (assi g ne d a st u d y scree ni n g c o d e) will  be  e nter e d  i nt o a  sec ure, N Y U  
a p pr o ve d  o nli ne  scr ee ni n g dat a base.  If a partici pa nt  is n ot  eli gi ble,  t he y will  be  c o nsi d ere d  a scr ee n f ail. N o  
a d diti o n al i nf or mati o n will  be  c ollecte d.  P HI  will  be  destr o ye d  i m me diat el y if a p artici pa nt  is n ot  eli gi bl e or  
d oes  n ot  ret ur n t o si g n writte n  c o nse nt/ a ut h ori zati o n  t o partici p ate.  O nl y  st u d y staff will  ha ve  a ccess  t o t h ese 
rec or ds. 
O nce  t he parti ci pa nt  is ge n erall y  eli gi bl e,  t h e PI,  or  o ne  of  t he tr ai ne d st u d y t ea m me m bers  will  r e vie w t h e 
c o nse nt f or m wit h  t he s u bject a n d e x plai n  t he p ur p ose  of  t he st u d y, t he pr oce d ur es,  as  well  as  ris ks a n d  
be nefits.  All  q uesti o ns  will  be  a d dresse d  bef ore  ac q uiri n g  t he partici pa nt’s  si g n e d c o nse nt.  
Partici p a nts  will  b e  i nf or me d of  t he assess me nt a n d c o nse q ue nces  of  t he assess me nt  –  t h ose w h o  ref use t he 
ca pacit y  assess me nt  will  n ot  be  e nr oll e d.  T he  assess me nt  i n v ol v es a M S  Ne ur ol o gical  E xa mi nati o n  i ncl u di n g 
E D S S,  P h ysical  E xa mi nati o n  s u m m ar y t o a d dress  Ge neral,  H E E N T,  L u n gs,  C O R,  A b d o me n, E xtre mities,  
a n d S ki n.  A d diti o n all y,  Dr.  Kr u p p, Dr. C har vet or Dr. Ra g ha va n  will  assess  ca pacit y t o c o nse nt o n  t he 
partici pa nts  u n dersta n di n g  of  t he f oll o wi n g 4  ite ms a)  t hat t h e acti vit y descri be d  i n t his c o nse nt d o c u me nt  
c o nstit ut es  researc h, n ot  sta n dar d tr eat me nt, b)  t he ris ks a n d be nefits  of  t his st u d y c) t he alter nati ves  t h at ar e  
a vail a ble  if s/ he c h o oses  n ot  t o parti ci pate,  a n d d)  t hat t he decisi o n  t o n ot  p artici pat e  will  be  a cce pte d  wit h o ut  
pe nalt y,  i.e., wit h o ut  je o par di zi n g his/ her  cli ni cal care. 
 

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Pr ocess  t o D oc u me nt  C o nse nt  i n Writi n g  
 
After  re vie w of  t he c o nse nt f or m a n d pri or  t o t h e start of  t he first sessi o n, t he PI  or  a n I R B st u d y 
re prese ntati ve will  o btai n  writte n  c o nse nt wit h  a si g n at ure of  t h e patie nt  o n  t he c o nse nt f or m. All  ori gi n al  
si g ne d c o nse nt  f or ms will  be  m ai nt ai ne d  i n t h e st u d y file, se par ate fr o m t h e partici pa nt  dat a.  
 
I nf or me d c o nse nt ca n be o bt ai ne d o n p a per d oc u me nts or electr o nic all y via R E D Ca p. T h ere is n o diff ere n ce 
bet wee n t h e pa per a n d ele ctr o ni c versi o ns. Parti ci pa nts w h o are o n -site a n d pr efer a n e-I C F (electr o nic 
i nf or me d c o nse nt f or m) will be prese nt e d wit h th e e -I C F b y a st u d y t ea m me m b er o n a t a blet or ot her de vice 
t o c o m pl ete via R E D Ca p. Partici pa nts will si g n ele ctr o nicall y usi n g a m o use, fi n ger, or st yl us a n d ha v e t h e 
o pti o n t o re cei v e a c o p y vi a e -m ail.  
 
Re m ote p arti ci pa nts will be e -maile d a se c ure R E D C a p li n k t o acc ess, re vie w, a n d si g n t he I C F a n d 
partici pa nt a gree m e nt. A st u d y te a m m e m ber will c o ntact t he partici pa nt o n t he p h o ne t o r e vie w t h e c o ns e nt 
f or m t o get h er, a ns wer a n y q uesti o ns, a n d pr o vi de t ec h nical assista nce if necessar y. T h e st u d y te a m m e m b er 
will c o nfir m t hat t he p arti ci pa nt is i n a pri v ate r o o m t o e ns ure c o nfi de ntialit y. Partici p a nts will h a ve t h e 
o pti o n t o na vi gat e f or war d a n d bac k war d a n d ca n st o p t he c o nse nt a n d res u me at a l ater ti m e. Parti ci pa nts 
will be a ble t o c o nta ct a st u d y tea m me m b er s h o ul d t he y ha ve a d diti o n al q uesti o ns bef ore si g ni n g.  
 
T he e -I C F ca n b e si g ne d el ectr o nicall y usi n g a m o use, st yl us or fi n ger. O nce c o m plete d, t h e e -I C F will b e 
sa ve d t o R E D Ca p a n d t he partici p a nt c a n d o w nl oa d a si g ne d c o p y or ha v e it e -maile d . 
 
S u bject  C a p acit y  
All  partici pa nts  will  b e  c o nfir me d  t o ha v e  t he c a pacit y  t o pr o vi de  c o nse nt b y  Dr.  C har vet  as  descri be d  a b o ve. 
F urt her,  t h ose p arti ci pa nts  wit h  esti mate d  pre m or bi d  i ntell ect u al f u ncti o ni n g a n d/ or  i m pair e d rea di n g a bilit y 
(as deter mi ne d  b y  t he W R A T -4  Re a di n g  S u bt est),  a n d t h ose wit h  se ver el y  i m p aire d i nf or mati o n pr ocessi n g  
s pee d (as deter mi ne d  b y  t he S D M T)  will  be  e xcl u de d.  
 
De briefi n g  P r oce d ures  
N o i nf or mati o n will be p ur p osel y wit h hel d fr o m t h e s u bjects. A cli nic al n e ur o ps yc h ol o gist ( PI) a n d  t he 
treat me nt te a m will  b e  a v ail a ble  t o a ns wer  a n y  q uesti o ns  c o ncer ni n g  t he tests a n d  res ults, a n d pr o vi de  i niti al 
fee d bac k as  warra nte d,  i n cl u di n g referr al f or cli nical ne ur o ps yc h ol o gic al  assess me nt.  
 
C o nse nt  F or ms  
Partici p a nts  will  rec ei ve a N Y U  c o nse nt  f or m t o re vie w a n d si g n pri or  t o parti ci pati n g  i n t h e st u d y.  Pati e nts 
will be all o we d a m ple ti m e t o re vi e w t he c o nse nt f or m a n d as k q uesti o ns i n a pri vate r o o m.  
 
D oc u me nt ati o n of  C o nse nt  
T he  PI  is res p o nsi ble f or e ns uri n g t hat v ali d  c o nse nt  is o btai ne d  a n d d oc u me nt e d  f or all s u bje cts. A n 
e nr oll m e nt l o g will  be  mai ntai ne d  a n d c o nse nt f or ms will  be  ke pt  i n sec ure l ocati o n se par ate fr o m t he 
partici pa nt’s  data.  A n e nr oll m e nt n ot e will b e ke pt wit h t he ori gi nal I C F as d oc u me ntati o n c o nfir mi n g t he 
I C F pr ocess. 
 
C osts t o t he  S u bject  
T here  will  be  n o  c ost t o t he partici pa nts.  
 
Refere nces  
1. Fr o h ma n, E. M., M. K. Rac ke, a n d C. S. Rai n e, M ulti ple scler osis --t he pl a q u e a n d its p at h o g e nesis. N E n gl J 
Me d,  2 0 0 6. 3 5 4 ( 9): p. 9 4 2 -5 5.  
2. Siffri n, V., et al., M ulti ple scl er osis - c a n di d ate m ec h a nis ms u n derlyi n g C N S atr o p hy. Tre n ds Ne ur osci, 2 0 1 0.  
3 3 ( 4): p. 2 0 2-1 0.  
3. P oser, C. M. a n d V. V. Bri nar, T he acc ur acy of pre v ale nc e r ates of m ulti ple scler osis: a critic al revi e w.  
Ne ur oe pi de mi ol o g y, 2 0 0 7. 2 9 ( 3-4): p. 1 5 0 -5.  

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4. A del ma n, G., S. G. Ra n e, a n d K. F. Villa, T he c ost b ur de n of m ulti pl e scler osis i n t h e U nite d St ates: a s yste m atic  
revie w of t he liter at ure. J Me d E c o n, 2 0 1 3. 1 6 ( 5): p. 6 3 9-4 7.  
5. C o nfa vre u x, C. a n d S. V u k usic, N at ur al hist ory of m ulti ple scler osis: a u nifyi n g c o nc e pt. Brai n, 2 0 0 6. 1 2 9 ( Pt 
3):  p. 6 0 6 -1 6.  
6. Kier ke gaar d, M., et al., T he rel ati o ns hi p bet wee n w alki n g, m a n u al de xterity, c o g ni ti o n a n d 
activity/ p artici p ati o n  i n pers o ns wit h m ulti ple scl er osis. M ult Scle r, 2 0 1 2. 1 8 ( 5): p. 6 3 9-4 6.  
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