Pa ie o-mo o Co ical Dys unc ion in P ima y Ce ical Dys onia
Paolo Po cacchia
a
, F ancisco J. Paloma
a
,
b
, Ma ía T. Cáce es-Redondo
a
,
Ismael Hue as-Fe nández
a
, Juan F. Ma ín-Rod íguez
a
, Fá ima Ca illo
a
,
Giacomo Koch
c
,
d
, Pablo Mi
a
,
b
,
*
a
Unidad de T as o nos del Mo imien o, Se icio de Neu ología y Neu ofisiología, Ins i u o de Biomedicina de Se illa (IBiS), Hospi al Uni e si a io Vi gen del Rocío/CSIC/Uni e sidad de
Se illa, Se ille, Spain
b
Cen o de In es igación Biomédica en Red sob e En e medades Neu odegene a i as (CIBERNED), Spain
c
S oke Uni , Dipa imen o di Neu oscienze, Uni e si à di Roma To Ve ga a, Rome, I aly
d
Labo a o io di Neu ologia Clinica e Compo amen ale, Fondazione S. Lucia I.R.C.C.S., Rome, I aly
a icle in o
A icle his o y:
Recei ed 28 Janua y 2014
Recei ed in e ised o m
17 June 2014
Accep ed 17 June 2014
A ailable online 17 July 2014
Keywo ds:
Dys onia
Hypokinesia
Pa ie al lobe
T ansc anial magne ic s imula ion
abs ac
Backg ound: Dys onia is conside ed as a mo o ne wo k diso de in ol ing he dys unc ion o he pos-
e io pa ie al co ex, a egion in ol ed in p epa ing and execu ing eaching mo emen s.
Objec i e/hypo hesis: We used ansc anial magne ic s imula ion o es he hypo hesis ha ce ical
dys onic pa ien s may ha e a dis up ed pa ie o-mo o connec i i y.
Me hods: We en olled 14 pa ien s wi h p ima y ce ical dys onia and 14 con ols. A pai ed-pulse
ansc anial magne ic s imula ion p o ocol was applied o e he igh pos e io pa ie al co ex and he
igh p ima y mo o a ea. Changes in he ampli udes o mo o e oked po en ial we e analyzed as an
index o pa ie o-mo o e ec i e connec i i y. Pa ien s and heal hy subjec s we e also e alua ed wi h a
eaching ask. Reac ion and mo emen imes we e measu ed.
Resul s: In heal hy subjec s, bu no in dys onic pa ien s, he e was a acili a ion o mo o e oked po en ial
ampli udes when he condi ioning pa ie al s imulus p eceded he es s imulus applied o e he p ima y
mo o a ea by 4 ms. Reac ion and mo emen imes we e significan ly slowe in pa ien s han in con ols. In
dys onic pa ien s, he ela i e s eng h o pa ie o-mo o connec i i y co ela ed wi h mo emen imes.
Conclusions: Pa ie o-mo o co ical connec i i y is impai ed in ce ical dys onic pa ien s. This neu o-
physiological ai is associa ed wi h slowe eaching mo emen s.
Ó2014 Else ie Inc. All igh s ese ed.
In oduc ion
Dys onia is a mo emen diso de cha ac e ized by excessi e
in olun a y muscle con ac ion. P ima y ocal dys onias a e mo e
common han p ima y gene alized dys onias [1]. Ce ical dys onia
is he mos common o m o ocal dys onia [2].
The pa hophysiology o dys onia is no comple ely unde s ood.
Impai ed inhibi ion a mul iple le els o he cen al ne ous sys em
is p esen [3], wi h al e a ions o mo o ci cui s in ol ing he basal
ganglia [4], he ce ebellum [5,6] and he senso imo o co ex [7,8].
Recen e idences seem o sugges ha he dys unc ion o he mo o
ne wo k in ol es o he co ical a eas such as he pa ie al co ex
[9,10]. Neu opa hological and neu oimaging e idences e iewed in
a ecen pape [11], sugges ha he pa ie al egion is implica ed in
di e en o ms o dys onia, in e ms o changes o egional blood
flow o g ay ma e olume. A educ ion o he pa ie al co ex
ac i a ion was de ec ed du ing imaging o mo emen in pa ien s
wi h ce ical dys onia [12]. Mo eo e , a e epe i i e ansc anial
magne ic s imula ion (TMS) o e he pa ie al co ex, he ac i a ion
o he pa ie al co ex du ing mo o execu ion, measu ed by unc-
ional magne ic esonance imaging ( MRI), was educed in pa ien s
wi h ce ical dys onia [13].
In he cu en s udy we aim o explo e, wi h a TMS echnique,
he connec i i y among he pos e io pa ie al co ex (PPC) and he
ipsila e al p ima y mo o a ea (M1) [14] in ce ical dys onia. Wi h
his me hod a condi ioning s imulus (CS) is fi s used o ac i a e
pu a i e pa hways, while a second es s imulus (TS), deli e ed
o e M1 a ew milliseconds la e , is used o explo e changes in
Funding: This wo k was suppo ed by g an s om he Minis e io de Economía y
Compe i i idad de España (SAF2007-60700), he Ins i u o de Salud Ca los III (CP08/
00174, PI10/01674, PI13/01461), he Conseje ía de Economía, Inno ación, Ciencia y
Emp esa de la Jun a de Andalucía (CVI-02526, CTS-7685), he Conseje ía de Salud y
Bienes a Social de la Jun a de Andalucía (PI-0377/2007, PI-0741/2010, PI-0437-
2012, PI-0471/2013), he Sociedad Andaluza de Neu ología, he Fundación Alicia
Koplowi z, he Fundación Mu ua Mad ileña and he Jaques and Glo ia Gossweile
Founda ion.
The au ho s epo no conflic o in e es .
*Co esponding au ho . Unidad de T as o nos del Mo imien o, Se icio de
Neu ología y Neu ofisiología Clínica, Hospi al Uni e si a io Vi gen del Rocío. A .
Manuel Siu o s/n., 41013 Se illa, Spain. Tel.: þ34 955012593; ax: þ34 955012597.
E-mail add ess: [email p o ec ed] (P. Mi ).
Con en s lis s a ailable a ScienceDi ec
B ain S imula ion
jou nal homepage: www.b ains imj nl.com
1935-861X/$ esee on ma e Ó2014 Else ie Inc. All igh s ese ed.
h p://dx.doi.o g/10.1016/j.b s.2014.06.007
B ain S imula ion 7 (2014) 650e657
exci abili y p oduced by he inpu [14,15]. In heal hy subjec s, a
condi ioning TMS pulse applied o e he igh PPC is able o in-
c ease he exci abili y o he hand a ea o he igh M1 [16].
The PPC-M1 in e ac ion is c ucial in p epa a ion and planning o
eaching and g asping mo emen s owa d isual a ge s [17e19],as
well as in isuospa ial mechanisms ha a ec empo al pe o -
mance, accu acy and a iabili y [18,20]. Reaching mo emen s ha e
been p o ed as a eliable beha io al co ela e o he PPC-M1
in e ac ion, because he exci abili y o his pa hway a ies du ing
he ask [17]. Dys onic pa ien s may show beha io al mo o ask
abno mali ies; in ac eac ion ime ask s udies in pa ien s wi h
idiopa hic o sion dys onia showed ha ini ia ion and execu ion
esponses we e slowe han in con ol subjec s [21].
Hence ou aim was o s udy PPC-M1 connec i i y in ce ical
dys onic pa ien s, a es , using his pai ed-pulse TMS p o ocol.
Mo eo e we hypo hesize ha he e ficacy o PPC-M1 in e ac ion
could be di ec ly ela ed o he slowness in mo emen ime ha
cha ac e izes ce ical dys onic pa ien s.
Me hods and ma e ials
Subjec s
Fou een igh -handed pa ien s (5 men, 9 women, mean age
48 14 yea s, disease du a ion 8 5 yea s) a ec ed by p ima y
ce ical dys onia (Table 1) we e ec ui ed om he Mo emen
Diso de s Ou pa ien Clinic a he Hospi al Uni e si a io Vi gen del
Rocío in Se ille, Spain. Diagnosis o ce ical dys onia was made by
expe neu ologis s, based on clinical and anamnes ic findings.
The assessmen included a comple e To on o Wes e n Spasmodic
To icollis Ra ing Scale (TWSTRS) and he Bu keeFahneMa sden
Dys onia Ra ing Scale (BFMDRS). The TMS expe imen s we e pe -
o med a leas 3 mon hs a e he las bo ulinum oxin injec ion.
All o he o al d ugs we e s opped 48 h be o e he TMS expe imen s.
Fou een age-ma ched (6 men and 8 women, 48 15 yea s),
heal hy, igh -handed olun ee s se ed as con ol subjec s. They
we e ec ui ed om he hospi al and esea ch s a . The s udy was
app o ed by he local e hics commi ee and all he subjec s ga e
w i en in o med consen .
Expe imen al p ocedu e
PPC-M1 connec i i y
Subjec s we e sea ed com o ably and we ollowed he same
design, elec omyog aphy (EMG) eco dings and o -line peak- o-
peak ampli ude analysis ha we e used in a p e ious s udy [16,22].
The pai ed-pulse s imula ion echnique was used wi h wo di -
e en high-powe Mags im 200
2
machines (Mags im Co., Whi -
land, Dy ed, UK). The hand mo o a ea o he igh M1 was ound a
he poin whe e he la ges mo o e oked po en ial (MEP) om he
con ala e al FDI muscle was elici ed and he op imal posi ion was
ma ked on he scalp, o ensu e he minimum displacemen du ing
he expe imen . The in ensi y o he TS was adjus ed o elici 1 mV
MEP ampli ude in he elaxed FDI. The es s imula o was con-
nec ed o a figu e-o -eigh coil wi h a 55 mm ex e nal diame e . The
coil was posi ioned a a 45

angle om he midline o induce a
pos e io -an e io cu en flow. The condi ioning s imula o was
connec ed o a s anda d figu e-o -eigh shaped coil wi h a 70 mm
ex e nal diame e , posi ioned o e he P4 posi ion (10-20 EEG
sys em) (Fig. 1A). This si e is si ua ed in he in e io pa ie al lobule
[18,23e26], ha is pa o he pos e io pa ie al co ex, and i is
defined by he ollowing Taila ach coo dina es: 38.4 6.1,
67.2 4.4, and 46.3 5.8 mm [27]. The cen e o he coil was
posi ioned o e P4 angen ially o he skull and wi h he handle
poin ing downwa d and sligh ly medial (10

). MRI-guided ame-
less s e eo axy (B ainsigh F ameless; Rogue Resea ch, Mon eal,
Quebec, Canada) was used in all subjec s o ensu e he minimum
displacemen du ing PPC s imula ion (Fig. 1B). We pe o med h ee
blocks wi h di e en in ensi ies o he CS se a 70%, 90% and 110%
o he es ing mo o h eshold (RMT). RMT was es ed acco ding o
in e na ional s anda ds [28], wi h he figu e-o -eigh shaped coil
(70 mm diame e ). In e -s imulus in e als (ISI) be ween CS and TS
we e 2, 4, 6, 8, 10, 15, and 20 ms (Fig. 1A). Each block consis ed o 20
ials only wi h TS and 10 ials wi h CS þTS o each ISI ( o al 90
ials pe block). In each block he ials we e andomly in e -
mingled wi h an in e - ial ime o 5 s. The o de o p esen a ion o
he blocks o ials a ied andomly in con ol and pa ien s.
Reac ion ime ask
We used a choice eac ion ime ask simila o ha adop ed
p e iously [17,22]. All subjec s sa com o ably in a 45-cm-high
s aigh -back chai acing a able, 120 cm wide and 60 cm deep. On
he opposi e edge o he able an up igh , home-made fla wooden
panel was fixed,80 cmwide and 50 cm high, placed a 60 cm dis ance
om he subjec . Subjec s placed he index finge o hei le hand on
an up aised bump (2.5 cm-diame e coin), ha ac ed as s a ing
poin , on he able su ace. Pe iphe al a ge s comp ised 2 cm-
diame e up aised bumps, posi ioned 20 cm le o igh o a fixa ion
c oss a a iewing dis ance o 60 cm (Fig. 1C). The s a ing poin
Table 1
Clinical cha ac e is ics o pa ien s wi h p ima y ce ical dys onia.
No. Sex Age (yea s) Disease du a ion
(yea s)
TWSTRS BFMDRS Dominan hand/
head de ia ion
T ea men (mg/day)
1 M 39 3 26.7 13.5 R/L BT
2 F 34 15 16 12 R/R BT
3 M 34 9 40.75 17.5 R/R BT
4 M 32 15 32.25 8 R/R BT
5 M 32 5 55.75 22 R/R BT, clonazepam (2)
6 F 44 3 44 25 R/L BT, clonazepam (10)
7 F 48 8 22.5 7.5 R/L BT
8 F 68 10 32 6 R/L BT
9 M 64 16 36 26 R/R BT, ihexyphenidyl (6)
10 F 66 9 9.75 21 R/L T ihexyphenidyl (6)
11 F 55 2 12 1.5 R/R BT
12 F 68 4 30.75 23.5 R/L BT
13 F 40 2 31 38.2 R/R BT
14 F 48 8 25 39.5 R/L BT
M¼male; F ¼ emale; R ¼ igh ; L ¼le ; BT ¼bo ulinum oxin; TWSTRS ¼To on o Wes e n Spasmodic To icollis Ra ing Scale; BFMDRS ¼Bu keeFahneMa sden Dys onia
Ra ing Scale.
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657 651
and bo h pe iphe al a ge s we e wo n using h ee independen
p oximi y senso s o plas ic op ic fibe ( eflec i e fib e op ic senso ,
LL3-DT01, SICKOPTEX, Japan). This kind o plas ic op ic fibe senso
p oduces a posi i e squa e signal du ing senso ac i a ion (senso
swi ch on) o a nega i e squa e signal du ing senso deac i a ion
(senso swi ch o ). Senso esponses we e digi ally con e ed by a
Powe 1401 (Camb idge Elec onic De ices, UK) and eco ded wi h
SIGNAL so wa e (Camb idge Elec onic De ices, UK). Each ial
beganwi h an audi o y wa ning ollowed by he impe a i e audi o y
signal andomly gi en 1e3 s la e . Subjec s we e equi ed o each
owa d and ouch he pe iphe al le o igh a ge as soon as hey
hea d he impe a i e sound. The impe a i e signal consis ed o ei he
a high (800 Hz, 30 ms) o low (200 Hz, 30 ms) equency one pulse
ha indica ed which pe iphe al a ge subjec s had o each (high
meaning each igh , low meaning each le , o ice e sa). All
subjec s pe o med a block o 80 ials. A aining block o 35 ials
was pe o med be o e s a ing wi h he 80 ial block. The in e - ial
in e al was 6 s. A he s a o each block, he high and low ones
we e assigned andomly o indica e he side a ge o each (le o
igh ). These ins uc ions we e coun e balanced wi hin and ac oss
Figu e 1. (A) TMS p ocedu e. Sho e a ows ep esen he pos e io pa ie al co ex (PPC) condi ioning s imulus (CS), ha p eceded es s imulus (TS) (longe a ow). (B) PPC
s imula ion using neu ona iga ion sys em. (C) Reac ion ask. A e he impe a i e sound, he subjec s eached o he le o igh a ge . Modified om Re . [22].
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657652
subjec s. In consequence, each ial had a single eac ion ime (RT)
ha was defined as he ime be ween he impe a i e sound and he
swi ching o o he s a ing poin senso , co esponding o he fi s
mo emen o he le index finge . Mo emen ime (MT) was defined
as he ime be ween he RT and he swi ching on o he co e-
sponding eached pe iphe al a ge senso . TMS expe imen and
eac ion ime ask we e pe o med in wo sepa a e days a leas one
week apa . All he con ol subjec s and wel e o he ou een ce -
ical dys onic pa ien s pe o med he eac ion ime ask. Two pa-
ien s did no a end o he eac ion ime ask session and hey we e
los on ollow-up.
Da a analysis
Shapi oeWilk es was used o check he no mal dis ibu ion o
he da a. Pa ame ic o non-pa ame ic es s we e used o da a
wi h o wi hou no mal dis ibu ion espec i ely. Magne ic s imu-
la ion in ensi ies, clinical and demog aphic da a we e analyzed
using Wilcoxon and ManneWhi ney U es s, depending on da a
ype. In PPC-M1 connec i i y expe imen s, PPC-condi ioned MEP
ampli udes we e no malized o non-condi ioned one (TS alone).
No malized da a we e analyzed using epea ed measu es ANOVA,
wi h PPC CS “INTENSITY”(70%, 90% and 110% o RMT) and “ISI”(2, 4,
6, 8, 10, 15, and 20 ms) as he wi hin-subjec ac o s and “GROUP”
(pa ien s s. con ol) as he be ween-subjec ac o . A significan
in e ac ion in he ANOVA was ollowed by pos -hoc pai ed - es
analysis wi h Bon e oni co ec ion. The G eenhouseeGeisse co -
ec ion was used o non sphe ical da a and Mauchly’s es exam-
ined o sphe ici y.
In he eac ion ime expe imen , RT and MT we e calcula ed
sepa a ely o he le and igh a ge . Independen and epea ed
measu es - es s we e used o analyze RT and MT da a. Pea son’s
and Spea man’s co ela ions be ween condi ioned MEP ampli udes
a 4 ms ISI (CS 90% o RMT), RTand MT, TWSTRS and BFMDRS sco es
head de ia ion side and age was pe o med o explo e he clinical o
unc ional ela ionship. A P alue o <0.05 was conside ed o be
s a is ically significan in all analyses. All s a is ical analyses we e
ca ied ou using IBM SPSS S a is ics 20 so wa e.
Resul s
Demog aphic da a and magne ic s imula ion in ensi ies
No significan di e ences we e ound in demog aphic da a be-
ween pa ien s and con ol subjec s. RMT and TS in ensi ies we e
no di e en among g oups (P¼0.92 and P¼0.98 espec i ely).
Mean RMT alues we e 41.2% 6.4 o maximum s imula o ou pu
in con ol subjec s and 41.0% 6.9 in pa ien s. Mean TS in ensi y
alues we e 51.2% 8.6 o maximum s imula o ou pu in con ol
subjec s and 51.1% 7.8 in pa ien s.
PPC-M1 connec i i y
Fac o ial epea ed measu es ANOVA showed a significan
GROUP ISI (F¼2.890; P¼0.011) and GROUP ISI INTENSITY
(F¼2.184; P¼0.012) in e ac ions. Pai ed - es analyses e ealed a
significan di e ence be ween con ol and dys onic g oups a 4 ms
ISI o a CS in ensi y o 90% RMT (P<0.001) (Fig. 2A and B). Con ols
showed an e ec o double pulse in e en ion (P¼0.011 a 4 ms)
Figu e 2. (A) A single condi ioning s imulus (CS), applied o e he pos e io pa ie al co ex (PPC), changed mo o e oked po en ial (MEP) ampli ude in con ols bu no in dys onic
pa ien s, when in e -s imulus in e al was 4 ms and CS in ensi y was 90% o es ing mo o h eshold (RMT). MEP ampli ude alues a e exp essed ela i e o uncondi ioned MEP.
E o ba s ep esen s anda d e o . *P<0.05. ISI: in e -s imulus in e al. (B) MEP ampli ude (4 ms ISI) in con ols and pa ien s. Ho izon al ba s ep esen mean and 95% o
confidence in e al.
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657 653
while no e ec was p esen in pa ien s, showing ha he e was an
MEP acili a ion when he PPC CS p eceded he TS o e M1 by 4 ms
a a CS in ensi y o 90% o he RMT in con ol subjec s and ha his
e ec was no obse ed in he g oup o dys onic pa ien s. No di -
e ences we e obse ed be ween con ol and dys onic pa ien s
g oups a any o he ISI o CS in ensi y (Supplemen a y Fig. 1).
Reac ion ime ask
RT as well as MT bo h owa d he le and igh sides we e
significan ly lowe in con ol subjec s han in pa ien s (P
s
less han
0.007, Figs. 3 and 4). When es ed o igh -le di e ence, bo h
g oups showed mino le mo emen ime alues espec o he
igh ones (P<0.0001 in pa ien s and P¼0.002 in con ols)
wi hou di e ences in eac ion ime alues. No co ela ion was
ound be ween RT and MT in bo h g oups.
We hen co ela ed he indi idual alues ob ained in he TMS
expe imen s o he PPC-M1 connec i i y (wi h he in ensi y o CS
a 90% RMT, 4 ms ISI) wi h he indi idual RTs and MTs. In con ol
subjec s MEP ampli ude did no co ela e wi h ei he RT o MT.
Howe e , in ce ical dys onic pa ien s MEP ampli ude significan ly
co ela ed wi h MT owa d bo h he le side (P¼0.016, ¼0.674)
and he igh side (P¼0.032, ¼0.619) bu no wi h RT (Figs. 3
and 4).
No di e ences be ween he wo g oups we e ound in decision
e o s. The e we e no an icipa ion e o s (RT <150 ms), no omis-
sion e o s ( he subjec do no mo e a e he impe a i e sound)
and no abno mal long esponses (RT þMT >2 s).
In pa ien g oup, no significan co ela ion was ound be-
ween TWSTRS, BFMDRS sco es, head de ia ion side, and age
wi h MEP ampli ude (CS a 90% RMT, 4 ms ISI) o wi h RT and MT
alues.
Figu e 3. Le wa d mo emen s. Reac ion ime and mo emen ime (A) and i s ela ionship wi h MEP ampli ude (in e -s imulus in e al 4 ms, condi ioning s imulus a 90% o es ing
mo o h eshold) (B, C). A significan co ela ion was obse ed only in pa ien s, be ween MEPs and mo emen imes (P¼0.016, ¼0.674; con inuous line (C)).
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657654

Discussion
This s udy shows ha pa ie o-mo o co ical connec i i y is
impai ed in ce ical dys onic pa ien s a es and ha pa ie al
dys unc ion co ela es wi h slowe mo emen ime in a choice e-
ac ion ask.
Explo ing pa ie o-mo o co ical connec i i y wi h TMS is a
well-es ablished pa adigm bo h in heal hy subjec s [16e18] and in
neu ological pa ien s [22,29,30]. The ac i a ion o co ico-co ical
p ojec ions a ising om he in e io pa ie al lobe and/o in a-
pa ie al sulcus and e mina ing in M1 is p obably esponsible o
he ea ly peak (4e8 ms) ha is obse ed wi h his p o ocol [16]. The
ans e o his in o ma ion p obably occu s h ough fibe s o he
supe io longi udinal asciculus [31], ei he h ough di ec p ojec-
ion o an indi ec pa hway in ol ing he ipsila e al en al p e-
mo o co ex [18]. In ou s udy, when CS o e PPC was se a 90% o
RMT and p eceding TS by 4 ms, MEPs a ising om M1 we e
inc eased in con ol subjec s bu no in pa ien s, sugges ing he
exis ence o a dys unc ion o pa ie o- on al co ico-co ical con-
nec i i y in ce ical dys onic pa ien s.
Pa ie o-mo o impai men canno be easily asc ibed o a di -
e en h eshold o ac i a ion o he co ico-co ical ou pu o igi-
na ing om PPC (bo h CS a 70% and 110% o RMT ailed o modula e
M1 esponse) bu p obably eflec s some in insic changes o some
loss o unc ionali y o he PPC neu onal popula ion and/o
abno mal influences o PPC on ipsila e al M1 ci cui s. A p e ious
s udy using MRI showed dec eased pa ie al ac i a ion du ing
mo emen in ce ical dys onic pa ien s [13], and ask-independen
(a es ) al e a ions o p emo o -pa ie al ci cui s in w i e ’s c amp
pa ien s [32]. Ou s udy ollows his p eceden , e ealing, wi h a
TMS pa adigm, an a es impai men o he pa ie o-mo o ci cui
in ce ical dys onic pa ien s. I can be a gued ha he same M1
Figu e 4. Righ wa d mo emen s. Reac ion ime and mo emen ime (A) and i s ela ionship wi h MEP ampli ude (in e -s imulus in e al 4 ms, condi ioning s imulus a 90% o
es ing mo o h eshold) (B, C). A significan co ela ion was obse ed only in pa ien s, be ween MEPs and mo emen imes (P¼0.032, ¼0.619; con inuous line (C)).
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657 655
ci cui s can be implica ed in his al e ed esponse, and he p esen
s udy did no es i specifically. Anyway M1 exci abili y should no
g ossly di e be ween pa ien s and con ols gi en ha RMTand he
in ensi y needed o es s imuli a e e y simila in he wo g oups.
Slowe ini ia ion and execu ion esponses we e obse ed in
pa ien s wi h idiopa hic o sion dys onia [21] and, simila ly,
olun a y head mo emen s ha e been epo ed o be slow in ce -
ical dys onic pa ien s [33e36]. In e es ingly, a ecen s udy in
ce ical dys onia p o ed an impai men o he coo dina ion o la ge
gaze eo ien a ions as well as a educ ion o body segmen al
eloci y (in pa icula , unk b adykinesia), leading o g oss p o-
longa ions in a ge acquisi ion ime [37], and suppo ing he ex-
is ence o “b adykinesia”in ce ical dys onic pa ien s. As expec ed,
in ou g oup o ce ical dys onic pa ien s we ound slowe eac ion
and mo emen imes. We also ound a nega i e ela ionship be-
ween MEP ampli ude (a 4 ms ISI, wi h PPC-CS a 90% o RMT) and
mo emen ime, poin ing owa d he ole o pa ie al dys unc ion in
mo emen s’slowness. Anyway, he design o ou s udy does no
pe mi o es ablish a causal ela ionship be ween he pa ie al
impai men and mo emen s’slowness in ce ical dys onic pa-
ien s. Fu u e s udies, applying TMS du ing he eac ion ime ask o
manipula ing PPC unc ion by inhibi o y epe i i e TMS be o e he
mo o ask, could cla i y he e ec i e causal ela ionship be ween
PPC unc ion and “b adykinesia.”The ole o his pa ie o-mo o
unc ional connec ion in he pa hophysiology o b adykinesia has
been ecen ly sugges ed in Pa kinson’s disease, wi h he same
expe imen al p ocedu e [22]. This analogy should be ca e ully
e alua ed o a leas wo easons. Fi s he na u e o b adykinesia
may be di e en in he wo condi ions. In ce ical dys onic pa ien s,
he close associa ion be ween head-on- unk eloci y and unk
eloci y [37] suppo s he iew ha he “b adykinesia”is a leas in
pa “seconda y” o he slow head mo emen , as opposed o “p i-
ma y”b adykinesia in Pa kinsonism. Second, his analogy migh
sugges ha impai ed PPC-M1 connec i i y and i s ela ion o e-
ac ion ime is an unspecific ai . I i is p esen in di e en ype o
mo emen diso de s, i may ep esen an epiphenomenon o an
abno mal ou pu o o he ne ous s uc u es and one can hypo h-
esize ha basal ganglia could be implica ed. Fu he s udies a e
needed o p o e i hese esul s can be ex ended o o he dys onia
ypes o o he mo emen diso de s.
In ou pa ien s we canno exclude impai men in he p og am-
ming (i le o igh ) and planning o eaching mo emen s, he
abili y o ini ia e mo emen p omp ly and isual mo o -in eg a ion
du ing mo emen . Pa ie o-mo o dys unc ion may a ec all hese
di e en componen s [19,20], leading o a p og essi e summa ion
o ime delays, beginning om he fi s p oposal o he mo emen
and pe sis ing un il he end o he eaching ask. Indeed ou ce ical
dys onic pa ien s showed no only p olonged MT bu also slowe
RTs, while, in Pa kinson’s disease pa ien s, RTs we e no slowe [22].
In addi ion, mo o co ical exci abili y ha p ecedes a olun a y
mo emen is abno mally modula ed in pa ien s wi h uppe limb
dys onia [38]. They canno p ope ly ec ui he neu ons o ci cui s
equi ed o pe o m he mo emen and his could also con ibu e in
making eac ion ime slowe .
When analyzing igh ele di e ences, we obse ed ha le -
side MT alues we e smalle han igh side ones in bo h g oups.
The explica ion can be ound in he expe imen se ing, o he
eason ha , when eaching he igh a ge , he le a m unde goes
a bigge displacemen han owa d he le a ge . The ac ha
longe igh side MTs we e obse ed i in bo h con ol and dys onic
g oup suppo his hypo hesis.
In e es ingly we ound a ela ion o pa ie o-mo o ac i i y wi h
MT owa d bo h he ipsila e al and he con ala e al space, while a
unc ional in e play was demons a ed in heal hy subjec s only
owa d con ala e al di ec ions [17]. Pa ie al dys unc ion could be
bila e al and compa able in he wo hemisphe es and i could be
associa ed o a bila e al inc ease o MT o , as an unspecific and non
causal ai , o he mechanisms and s uc u es a e implica ed, as
men ioned be o e.
The lack o co ela ion o hese pa ame e s wi h TWSTRS and
BFMDRS may indica e a educed sensibili y o clinical scales in
de ec ing sub le neu ophysiological and mo o ask changes in ou
g oup o pa ien s o ha pa ie o-mo o dys unc ion is an adap i e
phenomenon, no necessa ily co ela ed wi h clinical scale.
We chose o explo e igh PPC-M1 connec i i y because, e en i
pa ie o-mo o acili a ion is p esen bila e ally, in he le hemi-
sphe e he ime cou se is qui e di e en [16] and he e ec s a e
somewha milde in e m o ela i e acili a ion [17].
Finally, bo h in con ols and in pa ien s, we did no obse e a la e
(15 ms) pa ie o-mo o in e ac ion [16,18,39]. As obse ed in a
p e ious s udy [22], a dec eased unc ion o non-p ima y mo o
a eas ac i i y in olde subjec s [40] may explain hese di e ences.
A limi a ion o he s udy is how we se pa ie al spo . As in a
p e ious s udy [22], we used de 10-20 elec ode sys em o place he
TMS coil and hen wi h he B ainsigh we ensu ed he minimum
displacemen du ing he s udy. So i is possible ha we did no
localize he op imal acili a o y spo in all subjec s. Anyway we used
he same p ocedu e in con ols and pa ien s and he di e ences we
ound be ween hese wo g oups canno be asc ibed o a be e
pa ie al spo loca ion in one g oup espec o he o he .
In conclusion we p o ed ha ce ical dys onic pa ien s show
a pa ie o-mo o co ical dys unc ion ha is e iden a es as a
ask-independen neu ophysiological abno mali y. The slowe
mo emen ime du ing a choice eac ion ime ask could be an
epiphenomenon o his pa ie o-mo o impai men . The s udy
suppo s he hypo hesis ha pa ie al co ex is one o he s uc u es
in ol ed in he pa hophysiology o dys onia, as a ne wo k diso de
ha in ol es di e en b ain egions [41]. A ne wo k in which i may
be di ficul o dis inguish al e a ions ha a e causa i e, adap i e o
maladap i e. Finally iden i ying a neu ophysiologicalebeha io al
ela ionship may pe mi , in he u u e, o imp o e clinical symp-
oms by p oducing plas ic changes in he co esponding a ea o he
b ain.
Acknowledgmen s
We would like o hank Juan Manuel P aena Fe nández o his
help wi h he s a is ical analysis, Félix Jesús Pé ez Simón o his
echnical suppo in he eac ion ime ask and all he pa ien s o
hei kind pa icipa ion in his s udy.
Supplemen a y da a
Supplemen a y da a ela ed o his a icle can be ound a h p://
dx.doi.o g/10.1016/j.b s.2014.06.007.
Re e ences
[1] G eene P, Kang UJ, Fahn S. Sp ead o symp oms in idiopa hic o sion dys onia.
Mo Diso d 1995;10:143e52.
[2] Ta sy D, Simon DK. Dys onia. N Engl J Med 2006;355:818e29.
[3] Halle M. The neu ophysiology o dys onia. A ch Neu ol 1998;55:601e3.
[4] Ge ne M, Bennay M, Fed owi z M, Rehde s JH, Rich e A. Al e ed discha ge
pa e n o basal ganglia ou pu neu ons in an animal model o idiopa hic
dys onia. J Neu osci 2002;22:7244e53.
[5] Jinnah HA, Hess EJ. A new wis on he ana omy o dys onia: he basal ganglia
and he ce ebellum. Neu ology 2006;67:1740e1.
[6] Teo JT, Van De Wa enbu g BP, Schneide SA, Ro hwell JC, Bha ia KP. Neu o-
physiological e idence o ce ebella dys unc ion in p ima y ocal dys onia.
J Neu ol Neu osu g Psychia y 2009;80:80e3.
[7] Abb uzzese G, Ma chese R, Buccolie i A, Gaspa e o B, T ompe o C. Abno -
mali ies o senso imo o in eg a ion in ocal dys onia: a ansc anial magne ic
s imula ion s udy. B ain 2001;124:537e45.
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657656
[8] Bäume T, Demi alay C, Hidding U, e al. Abno mal plas ici y o he senso i-
mo o co ex o slow epe i i e ansc anial magne ic s imula ion in pa ien s
wi h w i e ’s c amp. Mo Diso d 2007;22:81e90.
[9] Egge K, Muelle J, Schocke M, e al. Voxel based mo phome y e eals specific
g ey ma e changes in p ima y dys onia. Mo Diso d 2007;22:1538e42.
[10] Ga aux G, Baue A, Hanakawa T, e al. Changes in b ain ana omy in ocal hand
dys onia. Ann Neu ol 2004;55:736e9.
[11] Neyche VK, G oss R, Lehé icy S, Hess EJ, Jinnah HA. The unc ional neu o-
ana omy o dys onia. Neu obiol Dis 2011;42:185e201.
[12] De V ies PM, Johnson KA, de Jong BM, e al. Changed pa e ns o ce eb al
ac i a ion ela ed o clinically no mal hand mo emen in ce ical dys onia.
Clin Neu ol Neu osu g 2008;110:120e8.
[13] De V ies PM, de Jong BM, Bohning DE, e al. Reduced pa ie al ac i a ion in
ce ical dys onia a e pa ie al TMS in e lea ed wi h MRI. Clin Neu ol Neu-
osu g 2012;114:914e21.
[14] Koch G, Ro hwell JC. TMS in es iga ions in o he ask-dependen unc ional
in e play be ween human pos e io pa ie al and mo o co ex. Beha B ain
Res 2009;202:147e52.
[15] Ci a di C, Can ello R, Asselman P, Ro hwell JC. T ansc anial magne ic s imu-
la ion can be used o es connec ions o p ima y mo o a eas om on al and
medial co ex in humans. Neu oimage 2001;14:1444e53.
[16] Koch G, Fe nandez Del Olmo M, Chee an B, e al. Focal s imula ion o he
pos e io pa ie al co ex inc eases he exci abili y o he ipsila e al mo o
co ex. J Neu osci 2007;27:6815e22.
[17] Koch G, Fe nandez Del Olmo M, Chee an B, e al. Func ional in e play be ween
pos e io pa ie al and ipsila e almo o co ex e ealed by win-coil ans-
c anial magne ic s imula ion du ing each planning owa d con ala e al
space. J Neu osci 2008;28:5944e53.
[18] Koch G, Ce cignani M, Pecchioli C, e al. In i o defini ion o pa ie o-mo o
connec ions in ol ed in planning o g asping mo emen s. Neu oimage 2010;
51:300e12.
[19] Van De We J, Jensen O, F ies P, Medendo p WP. Neu onal synch oniza ion in
human pos e io pa ie al co ex du ing each planning. J Neu osci 2010;30:
1402e12.
[20] Vica io CM, Ma ino D, Koch G. Tempo al accu acy and a iabili y in he le
and igh pos e io pa ie al co ex. Neu oscience 2013;245:121e8.
[21] Jahanshahi M, Rowe J, Fulle R. Impai men o mo emen ini ia ion and execu-
ion bu no p epa a ion in idiopa hic dys onia. Exp B ain Res 2001;140:460e8.
[22] Paloma FJ, Conde V, Ca illo F, e al. Pa ie o-mo o unc ional connec i i y is
impai ed in Pa kinson’s disease. B ain S imul 2013;6:147e54.
[23] He wing U, Sa api P, Schön eld -Lecuona C. Using he in e na ional 10-20
EEG sys em o posi ioning o ansc anial magne ic s imula ion. B ain Topog
2003;16:95e9.
[24] Rushwo h MF, Taylo PC. TMS in he pa ie al co ex: upda ing ep esen a-
ions o a en ion and ac ion. Neu opsychologia 2006;44:2700e16.
[25] Koch G, Ce cignani M, Bonnì S, e al. Asymme y o pa ie al in e hemisphe ic
connec ions in humans. J Neu osci 2011;31:8967e75.
[26] Koch G, Bonnì S, Giacobbe V, e al.
q
-bu s s imula ion o he le hemi-
sphe e accele a es eco e y o hemispa ial neglec . Neu ology 2012;78:
24e30.
[27] Caspe s S, Eickho SB, Geye S, e al. The human in e io pa ie al lobule in
s e eo axic space. B ain S uc Func 2008;212:481e95.
[28] Rossini PM, Ba ke AT, Be a delli A, e al. Non-in asi e elec ical and magne ic
s imula ion o he b ain, spinal co d and oo s: basic p inciples and p o-
cedu es o ou ine clinical applica ion. Repo o an IFCN commi ee. Elec-
oencephalog Clin Neu ophysiol 1994;91:79e92.
[29] Koch G, Oli e i M, Chee an B, e al. Hype exci abili y o pa ie al-mo o unc-
ional connec ions in he in ac le -hemisphe e o pa ien s wi h neglec . B ain
2008;131:3147e55.
[30] Koch G, Ribolsi M, Mo i F, e al. Connec i i y be ween pos e io pa ie al co ex
and ipsila e al mo o co ex is al e ed in schizoph enia. Biol Psychia y
2008;64:815e9.
[31] Mak is N, Kennedy DN, McIne ney S, e al. Segmen a ion o subcomponen s
wi hin he supe io longi udinal ascicle in humans: a quan i a i e, in i o,
DT-MRI s udy. Ce eb Co ex 2005;15:854e69.
[32] Delnooz CC, Helmich RC, Toni I, an de Wa enbu g BP. Reduced pa ie al
connec i i y wi h a p emo o w i ing a ea in w i e ’s c amp. Mo Diso d
2012;27:1425e31.
[33] Ca boncini MC, Manzoni D, S ambi S, e al. Impai ed agonis s ec ui men
du ing olun a y a m mo emen s in pa ien s a ec ed by spasmodic o icollis.
A ch I al Biol 2004;142:113e24.
[34] Boccagni C, Ca pane o J, Mice a S, Bagna o S, Gala di G. Mo ion analysis in
ce ical dys onia. Neu ol Sci 2008;29:375e81.
[35] G ego i B, Agos ino R, Bologna M, e al. Fas olun a y neck mo emen s in
pa ien s wi h ce ical dys onia: a kinema ic s udy be o e and a e he apy
wi h bo ulinum oxin ype A. Clin Neu ophysiol 2008;119:273e80.
[36] De Beyl DZ, Sal ia P. Neck mo emen speed in ce ical dys onia. Mo Diso d
2009;26:2267e71.
[37] Anas asopoulos D, Zia a N, Pea ce R, B ons ein AM. T unk b adykinesia and
o ea ion delays du ing whole-body u ns in spasmodic o icollis. J Neu ol
2013;260:2057e65.
[38] Gilio F, Cu à A, Inghille i M, e al. Abno mali ies o mo o co ex exci abili y
p eceding mo emen in pa ien s wi h dys onia. B ain 2003;126:1745e54.
[39] Da a e M, Ro hwell JC, Lemon RN. Causal connec i i y be ween he human
an e io in apa ie al a ea and p emo o co ex du ing g asp. Cu Biol 2010;
20:176e81.
[40] Talelli P, Ewas A, Waddingham W, e al. Neu al co ela es o age- ela ed
changes in co ical neu ophysiology. Neu oimage 2008;40:1772e81.
[41] P uden e CN, Hess EJ, Jinnah HA. Dys onia as a ne wo k diso de : wha is he
ole o he ce ebellum? Neu oscience 2014;260:23e35.
P. Po cacchia e al. / B ain S imula ion 7 (2014) 650e657 657