Depósi o de In es igación de la Uni e sidad de Se illa
h ps://idus.us.es/
This is he pee e iewed e sion o he ollowing a icle: Ruiz-Veguilla, M., Ma ín-
Rod íguez, J. F., Paloma , F. J., Po cacchia, P., Ál a ez de Toledo, P., Pe ona-Ga celán, S.,
Rod íguez-Tes al, J. F., Hue as-Fe nández, I., & Mi , P. (2016). T ai - and s a e-
dependen co ical inhibi o y de ici s in bipola diso de . Bipola Diso de s, 18(3), 261–
271, which has been published in inal o m a h ps://doi.o g/10.1111/bdi.12382 . This
a icle may be used o non-comme cial pu poses in acco dance wi h Wiley Te ms and
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O iginal A icle
T ai - and s a e-dependen co ical inhibi o y
de ici s in bipola diso de
Ruiz-Veguilla M, Ma 
ın-Rod 
ıguez JF, Paloma FJ, Po cacchia P,

Al a ez de Toledo P, Pe ona-Ga cel
an S, Rod 
ıguez-Tes al JF,
Hue as-Fe n
andez I, Mi P. T ai - and s a e-dependen co ical
inhibi o y de ici s in bipola diso de .
Bipola Diso d 2016: 00: 000–000. ©2016 John Wiley & Sons A/S.
Published by John Wiley & Sons L d.
Objec i es: Eu hymic pa ien s wi h bipola diso de (BD) ha e de ici s in
co ical inhibi ion. Howe e , whe he co ical inhibi o y de ici s a e
ai - o s a e-dependen impai men s is no ye known and hei
ela ionship wi h psychia ic symp oms is no ye unde s ood. In he
p esen s udy, we examined ai - and s a e-dependen co ical inhibi o y
de ici s and e alua ed he po en ial clinical signi icance o hese de ici s.
Me hods: Nine een pa ien s wi h bipola I diso de we e e alua ed using
he pai ed-pulse ansc anial s imula ion p o ocol, which assessed
co ical inhibi ion du ing an acu e manic episode. Co ical inhibi ion
measu es we e compa ed wi h hose ob ained in 28 demog aphically
ma ched heal hy con ols. A ollow-up assessmen was pe o med in 15
o hese pa ien s h ee mon hs la e , when he e was emission om hei
mood and psycho ic symp oms. The associa ion be ween co ical
inhibi o y measu es and se e i y o psychia ic symp oms was also
s udied.
Resul s: Du ing mania, pa ien s showed dec eased sho -in e al
in aco ical and anscallosal inhibi ion, as well as a no mal co ical
silen pe iod and long-in e al co ical inhibi ion. These indings we e
he same du ing eu hymia. Symp oms associa ed wi h mo o
hype ac i i y we e co ela ed nega i ely wi h he deg ee o co ical
inhibi ion. These co ela ions we e no signi ican when a Bon e oni
co ec ion was applied.
Conclusions: The p esen longi udinal s udy showed co ical inhibi o y
de ici s in pa ien s wi h BD, and suppo s he hypo hesis ha co ical
inhibi o y de ici s in BD a e ai dependen . Fu he esea ch is
necessa y o con i m he clinical signi icance o hese de ici s.
Miguel Ruiz-Veguilla
a,†
,Juan
F ancisco Ma 
ın-Rod 
ıguez
b, †
,
F ancisco J Paloma
b
,Paolo
Po cacchia
b
,Paloma 
Al a ez de
Toledo
b
,Sal ado Pe ona-
Ga cel
an
a
,Juan F ancisco
Rod 
ıguez-Tes al
a,c
,Ismael
Hue as-Fe n
andez
b
and Pablo Mi
b,d
1
a
G upo Neu odesa ollo y Psicosis, Ins i u o de
Biomedicina de Se illa (IBIS), Hospi al
Uni e si a io Vi gen del Rocio/CSIC/Uni e sidad
de Se illa/UGC Salud Men al HVR,
b
Unidad de
T as o nos del Mo imien o, Se icio de
Neu olog
ıa y Neu o isiolog
ıa Cl
ınica, Ins i u o de
Biomedicina de Se illa, Hospi al Uni e si a io
Vi gen del Roc
ıo/CSIC/Uni e sidad de Se illa,
c
Depa amen o de Pe sonalidad, E aluaci
on y
T a amien os Psicol
ogicos, Facul ad de
Psicolog
ıa, Uni e sidad de Se illa, Se ille,
d
en o de In es igaci
on Biom
edica en Red sob e
En e medades Neu odegene a i as
(CIBERNED), Spain
2
doi: 10.1111/bdi.12382
Key wo ds: co ical inhibi ion – GABA
ecep o s – longi udinal s udy – mo o co ex –
sho -in e al in aco ical inhibi ion –
anscallosal inhibi ion
Recei ed 30 June 2015, e ised and accep ed
o publica ion 8 Feb ua y 2016
Co esponding au ho :
Pablo Mi , M.D., Ph.D.
Unidad de T as o nos del Mo imien o
Se icio de Neu olog
ıa y Neu o isiolog
ıa Cl
ınica
Hospi al Uni e si a io Vi gen del Roc
ıo
A da. Manuel Siu o s/n
Se illa 41013
Spain
Fax: +34-955923101
E-mail: [email p o ec ed]
†
These au ho s con ibu ed equally o his wo k.
Bipola diso de (BD) is a p e alen neu opsychi-
a ic diso de cha ac e ized by pe iods o ele a ed
mood (mania o hypomania) and dep ession. BD
is associa ed wi h signi ican impai men in bo h
he physical and men al quali y o li e, e en du ing
eu hymic pe iods (1). One o he main symp oms
o his diso de is an impai men in he inhibi ion
o inapp op ia e ac ions 3and hough s, esul ing in
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1
Bipola Diso de s 2016 ©2016 John Wiley & Sons A/S
Published by John Wiley & Sons L d.
BIPOLAR DISORDERS
B D I 12382
Dispa ch: 8.3.16 CE: Sa a anan
Jou nal Code Manusc ip No.
No. o pages: 11 PE: Thanga aj
o e amilia i y, impulsi i y, disinhibi ion, and de i-
ci s in o e bea ing esponse supp ession (2). These
beha io s a e pa icula ly d ama ic du ing mania.
Howe e , indi iduals wi h BD also display inhibi-
o y de ici s in dep ession and eu hymia (3–5), sug-
ges ing ha inhibi o y de ici s could be pa o he
co e symp oms o BD. I has been sugges ed ha
inhibi o y de ici s in BD a e ela ed o impai men
in co ical inhibi ion in which co ical c-aminobu-
y ic acid (GABA) inhibi o y in e neu ons play a
c ucial ole in inhibi ing he ac i i y o o he co i-
cal neu ons (6). In his ega d, expe imen al e i-
dence suppo s an in ol emen o he GABA
sys em in he pa hophysiology o BD. Mo eo e ,
gene ic associa ion s udies ha e ound dis inc
polymo phisms o GABA ecep o genes associ-
a ed wi h BD (7, 8), and abno mali ies in he
exp ession o mul iple GABA- ela ed p o eins
ha e been epo ed in pos mo em s udies in
pa ien s wi h BD (9, 10).
In o ma ion abou he unc ionali y o he co i-
cal GABAe gic sys em can be indi ec ly ob ained
using ansc anial magne ic s imula ion (TMS). By
using single- and pai ed-pulse TMS, i is possible
o assess he ac i i y o he GABAA and GABAB
ecep o s in he mo o co ex, as well as he physi-
ological in e ac ions be ween exci a o y and inhi-
bi o y ci cui s in human subjec s (11, 12). The
sho -in e al co ical inhibi ion (SICI) pa adigm
assesses he inhibi ion o he mo o ac i i y
induced by a condi ioned magne ic s imulus ha is
p esen ed sho ly (2–5 msec) be o e ano he s imu-
lus ha is able o p o oke a measu able mo o
e oked po en ial (MEP). This ype o inhibi ion
has been ela ed o he ac i i y o GABAA ecep-
o s (13). Addi ional measu es o co ical inhibi-
ion include he co ical silen pe iod (CSP) and
long-in e al in aco ical inhibi ion (LICI), which
a e bo h measu es o long-las ing in aco ical
inhibi ion and hough o be dependen on
GABAB ecep o ac i i y (14, 15). Ano he co i-
cal inhibi o y phenomenon, anscallosal inhibi-
ion (TCI), can be assessed wi h TMS using ei he
pai ed-pulse pa adigms o ia he ipsila e al silen
pe iod. Al hough in e hemisphe ic co icoco ical
inhibi o y mechanisms a e no ully unde s ood,
hey equi e he in ac in eg i y o callosal ibe
bundles, and p esumably also equi e a p ese ed
in aco ical GABAe gic inhibi o y in e neu on
sys em (16, 17).
Few TMS pape s ha e s udied co ical inhibi-
o y mechanisms in BD. Le inson e al. (18)
demons a ed se e al co ical inhibi o y de ici s
consis ing o dec eased SICI, TCI, and CSP,
which sugges s impai ed co ical GABAe gic
ecep o ac i i y in pa ien s wi h BD. By con as ,
LICI seems o be main ained in pa ien s wi h BD,
as obse ed in a combined TMS–elec oen-
cephalog aphy s udy (19). These p e ious s udies
ha e in es iga ed he ai and s a e ma ke s o
BD by compa ing co ical inhibi ion in eu hymic
pa ien s wi h BD wi h con ol subjec s in a c oss-
sec ional case-con ol design. The e is he e o e
he possibili y o in e subjec di e ences a ec ing
he a iabili y in co ical exci abili y, and i is di i-
cul o in es iga e he unde lying co ical inhibi-
o y de ici s o ai and s a e abno mali ies and
mood swi ching using such a design. Subs ance
abuse is a majo como bidi y in pa ien s wi h BD,
which may ha e p o ound clinical implica ions
(20, 21). Subs ances such as cannabis, cocaine, o
nico ine ha e been shown o al e co ical inhibi-
ion bo h in he non-psychia ic (22) and psychi-
a ic popula ion (23). Likewise, co ical
exci abili y and inhibi ion is also modula ed by
commonly used d ugs o ea BD, including
mood s abilize s, benzodiazepines, and an ipsy-
cho ic agen s. The e o e, como bid subs ance
abuse o cu en pha macological ea men
should be aken in o accoun when assessing co i-
cal exci abili y and inhibi ion in BD. To add ess
hese issues, we conduc ed a longi udinal s udy
wi h a TMS design o assess pa ien s du ing he
acu e manic phase (BD manic) and emission
om his acu e phase. We also assessed he associ-
a ion be ween co ical inhibi o y measu es, se e -
i y o psychia ic symp oms, and li e ime and
cu en d ug use.
Me hods
Pa icipan s
A o al o 19 igh -handed pa ien s wi h BD pa ic-
ipa ed in he s udy ( en pa ien s had i s -episode
BD; 12 males; mean age: 35.5 yea s; mean age a
onse : 30.4 yea s). Pa ien s we e ec ui ed o e a
wo-yea a pe iod om he Inpa ien Psychia ic
Uni o he Hospi al Uni e si a io Vi gen del
Roc
ıo Men al Heal h Depa men . Eligible
pa ien s me he diagnos ic c i e ia o bipola I
diso de , acco ding o DSM-IV classi ica ion s an-
da ds. The pa icipan s we e equi ed o ha e a
Young Mania Ra ing Scale (YMRS) (24) sco e
≥18. We excluded pa ien s: (i) <18 o >65 yea s o
age; (ii) wi h a his o y o b ain auma o neu o-
logical disease; and (iii) i hey had unde gone elec-
ocon ulsi e he apy in he p e ious 12 mon hs.
All pa ien s displayed acu e mania wi h a YMRS
>21 and none displayed majo dep essi e symp-
oms. In i s -episode BD, diagnosis was con i med
a e one yea o ollow-up.
2
Ruiz-Veguilla e al.
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A heal hy con ol g oup consis ing o 28 heal hy
subjec s was ec ui ed by ad e isemen , in addi-
ion o wo d-o -mou h eques s om s a in he
esea ch uni . Pa ien and con ol g oups we e
ma ched ia ec ui men by age, gende , and
social/occupa ional class. The heal hy con ols
exhibi ed no pas o p esen psychia ic o neu o-
logical diso de s and had no posi i e amily his o y
o psychia ic diso de s. O he exclusion c i e ia
o his g oup we e li e ime subs ance dependence,
subs ance abuse du ing he p e ious mon h, can-
nabis abuse du ing he p e ious mon h, in ellec ual
disabili y, demen ia, and neu ological illnesses.
Six een pa ien s ag eed o pa icipa e in he ol-
low-up assessmen and h ee wi hd ew du ing he
cou se o he s udy ( wo o hem mo ed o o he
ci ies a e discha ge and one no longe wished o
pa icipa e u he in he s udy). All pa ien s we e
eu hymic a he ollow-up assessmen , as de ined
by a YMRS sco e <7 and a Hamil on Dep ession
Ra ing Scale (HDRS) (25) sco e <10. Du ing he
one-yea ollow-up, one pa ien displayed symp-
oms consis en wi h schizoa ec i e diso de , so
was excluded om he analysis.
S udy design
This was a longi udinal and na u alis ic s udy ha
consis ed o comp ehensi e psychopa hological and
TMS assessmen s a wo poin s: baseline and a
h ee-mon h ollow-up. Baseline assessmen s we e
comple ed in he second week o hospi al admission.
Th ee mon hs a e hospi al discha ge, pa ien s we e
in i ed o pa icipa e in a second assessmen .
Heal hy subjec s unde wen a unique TMS assess-
men . The s udy p o ocol was app o ed by he local
e hics commi ee, and all p ocedu es ollowed we e
in acco dance wi h ins i u ional guidelines. W i en
in o med consen was ob ained om all subjec s.
Following sc eening o exclusion c i e ia, all
pa icipan s unde wen a de ailed examina ion by
expe ienced psychia is s o assess cu en mood
s a e. BD was diagnosed using he S uc u ed Clin-
ical In e iew o DSM-IV Diso de s, esea che
e sion wi h psycho ic sc een (26). Mood was also
a ed using he YMRS and he HDRS. Psycho ic
symp oms we e assessed using he Posi i e and
Nega i e Symp oms Scale (PANSS) (27). T ained
in e iewe s adminis e ed he PANSS as pa o a
s uc u ed clinical in e iew and sco ed i ems on a
scale om 1 (asymp oma ic) o 7 (ex emely symp-
oma ic). I ems o he PANSS we e g ouped using
Wallwo k e al.’s i e- ac o (posi i e, nega i e,
diso ganized/conc e e, exci ed, and dep essed)
model (28). Highe sco es in hese ac o s imply a
highe se e i y o psycho ic symp oms.
TMS assessmen s we e pe o med be ween 3:00
p.m. and 5:00 p.m. Doses o he a ypical an ipsy-
cho ic agen s we e ans o med o chlo p omazine
equi alen s (29). Du ing bo h assessmen s, benzo-
diazepines we e wi hd awn a leas 15 hou s p io
o he TMS s udy. Blood samples we e d awn o
de e mina ion o se um li hium and alp oic acid
le els du ing clinical examina ions. E ec i e
se um li hium le els we e de ined as concen a-
ions be ween 0.6 mEq/L and 1.0 mEq/L, while
e ec i e alp oic acid le els we e de ined as
be ween 50 mg/L and 100 mg/L. Pa e ns o can-
nabis and cocaine abuse we e assessed using he
L-sec ion o he Composi e In e na ional Diag-
nos ic In e iew (CIDI) (30). We in e iewed sub-
jec s on li e ime d ug use his o y and pa e ns o
d ug use du ing he p e ious 12 mon hs. U ine
oxicology sc eening (TOX/See; Bio-Rad 4, USA)
was pe o med in all pa ien s o con i m o ule
ou cu en exposu e o ha m ul d ugs. Nico ine
dependence was assessed in bo h g oups using he
Fage s €
om es o nico ine dependence (31). A
sco e ≥4 by combining i ems 1 and 4 o his es
was used o iden i y subjec s wi h high nico ine
dependence (32).
Elec omyog aphy (EMG) eco dings
Subjec s we e sea ed in a com o able chai and
su ace EMG eco dings we e aken a he i s
do sal in e osseous (FDI) muscles on he side
con ala e al o he s imula ed co ex wi h
Ag–AgCl su ace elec odes using a belly– endon
mon age. EMG signals we e ampli ied (1,0009)
and band-pass il e ed (bandwid h 20 Hz o
2 kHz) using a Digi ime D360 ampli ie (Dig-
i ime 5, UK), acqui ed a a sampling a e o
5 kHz h ough a CED 1401 labo a o y in e ace
(Camb idge Elec onic Design, Camb idge, UK)
and s o ed on a compu e . The EMG aces we e
analyzed using cus omized SIGNAL so wa e
e sion 4 6.
S imula ion p o ocols
Single- and pai ed-pulse TMS o he p ima y
mo o co ex we e applied using Mags im 200
magne ic s imula o s (Mags im Company Limi ed,
Whi land, UK). The s imula o s we e igge ed
h ough he SIGNAL so wa e and CED 1401
boa d. Pa ien s and heal hy subjec s we e es ed on
he le hemisphe e in a TMS session ha included
SICI, in aco ical acili a ion (ICF), LICI, and
CSP. Fo hese s udies, he magne ic s imula o s
we e connec ed o a s anda d igu e-o -eigh coil
wi h an ex e nal diame e o 70 mm (peak mag-
3
Mo o co ical disinhibi ion in BD
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ne ic ield 2.2T). The coil was held angen ially o
he skull wi h he handle poin ing backwa ds and
la e ally a an angle o ~45 deg ees o he sagi al
plane in o de o gene a e a pos e io –an e io cu -
en in he b ain. A BiS im module (Mags im
Company Limi ed) was used o in e connec s imu-
la o s when pai ed-pulse TMS p o ocols we e pe -
o med. SICI and ICF we e assessed o e he
con ala e al FDI muscle in a simila way o a p e-
iously desc ibed pai ed-pulse pa adigm (33),
whe eby a sub h eshold s imulus is used o condi-
ion he mo o ou pu o a sup a h eshold s imu-
lus, depending on he ime in e al be ween hem.
The in ensi y o he condi ioning s imulus (CS)
was 80% o he ac i e mo o h eshold (AMT),
de ined as he minimum in ensi y ha elici ed a
ep oducible MEP o a leas 200 lV in he oni-
cally con ac ing FDI muscle in a leas i e ou o
en consecu i e ials, while subjec s we e con ac -
ing a app oxima ely 20% o hei maximum ol-
un a y con ac ion. A cons an le el o muscle
con ac ion was achie ed by he use o isual eed-
back. The in ensi y o he es s imulus (TEST) was
adjus ed o elici an MEP o app oxima ely 1 mV.
SICI and ICF we e assessed in he same expe i-
men al block. SICI was assessed a es a in e -
s imulus in e als (ISIs) be ween he CS and a
TEST o 2 msec and 3 msec, and ICF a ISIs o
10 msec and 12 msec. The p esen a ion o TEST
and CS we e andomly in e mingled
7wi hin he
SICI–ICF expe imen al block. Fo assessmen o
LICI, he in ensi y o he CS was 120% o he es -
ing mo o h eshold (RMT) o he con ala e al
FDI muscle. RMT was de ined as he minimum
in ensi y ha e oked a peak- o-peak MEP o
50 lV in a leas i e ou o en consecu i e ials in
he elaxed eco ded muscle (34). LICI was
assessed a es a ISIs o 100 msec, 150 msec, and
250 msec. Ten MEPs we e collec ed o each ISI
and o he TEST. The p esen a ion o TEST and
CS s imuli we e andomly
8in e mingled wi hin he
LICI expe imen al blocks. Fo assessmen o CSP,
15 single TMS pulses we e applied a an in ensi y
o 120% RMT, while pa ien s p o ided a cons an
con ac ion o he FDI muscle a 20% o hei
maximum olun a y con ac ion, assis ed by isual
eedback. TCI was demons a ed using he dual-
pulse pa adigm desc ibed by Fe be e al. (17).
B ie ly, wo igu e-o -eigh coils (wi h an ou e
diame e o each hal -wing o 40 mm) we e used
wi h a TEST applied o he le mo o co ex and a
CS applied o he igh mo o co ex. Wi h hese
coils, RMT was again ob ained a bo h hemi-
sphe es
9. The TEST s imulus was se a an in ensi y
ha , when gi en alone, would e oke an EMG
esponse o 1 mV peak- o-peak ampli ude. The CS
was applied a 120% o he RMT. TCI was es ed
a ou condi ioning es in e als (7, 10, 45, and
75 msec), gi en in a andom o de , wi h a o al o
en sweeps o 10each condi ion.
S a is ical analysis
S uden ’s - es s o independen measu es and
Fishe ’s exac es we e used o in es iga e di e -
ences be ween pa ien s and heal hy con ols on
demog aphic a iables (i.e., age, gende , smoking
a iables, and d ug abuse his o y a iables). Fish-
e ’s exac es and pai ed-sample - es s we e used
o assess changes in clinical a iables a he ol-
low-up assessmen . The independen and
epea ed-measu es - es s we e used o de e mine
di e ences in mo o h esholds and CSP. Two sep-
a a e wo-way ixed-e ec s analyses o a iance
(ANOVAs) we e conduc ed o he e alua ion o
pai ed-pulse TMS p o ocols. To de ec co ical
inhibi o y de ici s du ing mania, TMS da a col-
lec ed om pa ien s in his episode we e compa ed
wi h hose ob ained om heal hy subjec s. This
analysis was ca ied ou wi h ISI as wi hin-subjec
ac o and G oup (heal hy e sus manic g oups) as
be ween-subjec ac o . Po en ial con ounde s (use
o cannabis, cocaine, obacco, and benzodi-
azepines) we e included in a seconda y model
analysis i a signi ican g oup di e ence was seen
in he p ima y analysis. To assess he longi udinal
e ec s o mood episodes on co ical inhibi ion, a
epea ed-measu e ANOVA wi h wo wi hin-sub-
jec ac o s, episode (manic and eu hymia) and
ISI, was used. Mauchly’s es assessed sphe ici y
and he G eenhouse–Geisse co ec ion was used
o non-sphe ical da a. Signi ican main e ec s
and in e ac ions in ANOVA we e ollowed by
pos -hoc independen o pai ed - es s wi h Bon-
e oni co ec ion. The ela ionship be ween clini-
cal symp om se e i y and TMS measu es in he
BD g oup was examined using he Pea son p o-
duc -momen co ela ion coe icien . A Bon e oni
co ec ion was applied o he co ela ion analysis,
se ing he signi icance cu -o a p <0.001. A
powe analysis using he Gpowe compu e p o-
g am 11(35) indica ed ha , gi en ou sample size, we
would expec o de ec mode a e e ec sizes
( =0.25), powe ed, 86%, a a signi ican le el o
p<0.05.
Resul s
Demog aphic da a and a his o y o subs ance use
bo h in pa ien s wi h BD and heal hy subjec s a e
displayed in Table 1. Mos pa ien s wi h BD we e
cu en ciga e e smoke s, al hough nico ine depen-
4
Ruiz-Veguilla e al.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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17
18
19
20
21
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56

dence measu es did no di e s a is ically be ween
pa ien s and con ols. Ten pa ien s epo ed a his-
o y o cannabis use, while daily cannabis use was
asce ained in six o hem. A posi i e u ine es o
cannabis was ound in nine o hem. In all o hese
cases, ime since he las cannabis exposu e
exceeded one week. Fou pa ien s epo ed a his o y
o cocaine use. All o hem, excep one, epo ed no
cocaine use in he p e ious yea . A posi i e u ine
es o cocaine was p esen in one pa ien , who
epo ed hei las cocaine consump ion o ha e
aken place in he p e ious mon h.
Table 2 shows changes in clinical and pha ma-
cological a iables in pa ien s du ing mania and
eu hymia. O e all, a signi ican imp o emen in
manic, posi i e, and gene al psycho ic symp oms
was obse ed (all p <0.001) in he ollow-up
assessmen . Ten ou o he 15 pa ien s sco ed
ze o in he YMRS. We also de ec ed a signi ican
inc ease in he se e i y o dep essi e symp oms in
he ollow-up assessmen . Fu he mo e, a signi i-
can dec ease in cannabis consump ion (i.e.,
es s posi i e o cannabis) was obse ed du ing
ollow-up.
Mo o h esholds
The da a on mo o h esholds a e shown in
Table 3. No signi ican di e ences could be
demons a ed in RMT in pa ien s wi h BD
(p =0.75 o pa ien s in he manic phase and
p=0.12 o eu hymic pa ien s). The e we e no s a-
is ically signi ican di e ences be ween heal hy
con ols and pa ien s wi h BD in he o he mo o
h esholds ob ained o igh FDI muscle (all
p>0.37). Likewise, no signi ican di e ences in
he mo o h esholds we e ound be ween pa ien s
du ing he manic episode and du ing eu hymia (all
p>0.86).
Co ical inhibi ion du ing he manic episode
SICI and ICF. A signi ican main e ec o
ISI (F
3,132
=49.6, p <0.001) and ISI 9g oup
in e ac ion (F
3,44
=6.6, p <0.001) we e ob ained.
Table 1. Pa icipan demog aphics and subs ance use da a
Bipola
diso de
(n =19)
Heal hy
con ols
(n =28) p- alue
Gende , male/ emale 12/7 18/10 0.937
Age, yea s,
mean SD
35.5 11.4 33.1 7.0 0.434
Cu en ciga e e
smoke , n
13 5 <0.001
FTND sco e, mean SD 3.19 0.9 2.92 0.4 0.168
High nico ine
dependence, n
6 2 0.065
Cannabis use his o y, n 10 0 <0.001
Posi i e u ine es , n 9 0 N/A
Daily smoke , n 6 –N/A
Weekly smoke , n 4 –
Time since las join ,
days, mean SD
17.3 27.6 –N/A
Age a onse , yea s,
mean SD
19.4 4.1 –N/A
Du a ion o use, yea s,
mean SD
9.5 5.1 –N/A
Cocaine use his o y, n 4 0 0.022
Posi i e u ine es , n 1 0 N/A
Daily cocaine use , n 2 –N/A
3–4 days a week, n 1 –N/A
1–2 days a week, n 1 –N/A
Age a onse , yea s,
mean SD
24.2 6.7 –N/A
Du a ion o use, yea s,
mean SD
7.4 5.5 –N/A
O he d ugs, n 0 0 N/A
FTND =Fage s €
om es o nico ine dependence; N/A =no
applicable; SD =s anda d de ia ion.
Table 2. Clinical cha ac e is ics o pa ien s who comple ed he ollow-
up s udy
Manic
episode
(n =15)
Eu hymic
episode
(n =15) p- alue
a
Mood s abilize , n
Li hium 7 3 0.428
Sodium alp oa e 8 8
Se um li hium le els,
mmol/L, mean (SD)
0.61 (0.08) 0.72 (0.21) 0.336
Se um alp oa e
le els, mg/L,
mean (SD)
59.6 (23.4) 49.2 (11.2) 0.346
An ipsycho ic
agen s, n
15 13 0.483
An ipsycho ic
agen doses,
chlo p omazine
equi alen s, mean
(SD)
649.8 (339.3) 595.8 (380.1) 0.392
Benzodiazepines, n 6 3 0.427
Cu en ciga e e
smoke , n
9 9 1.000
Cannabis use, n 8 2 0.020
YMRS sco e,
mean (SD)
35.1 (7.1) 1.5 (2.8) <0.001
HDRS sco e,
mean (SD)
1.2 (1.6) 2.9 (2.5) 0.039
PANSS sco e,
mean (SD)
Posi i e ac o 3 (1.1) 1.1 (0.3) <0.001
Nega i e ac o 1.3 (0.9) 1.4 (0.7) 0.309
Diso ganized/
Conc e e ac o
3.4 (0.8) 1.3 (0.5) <0.001
Exci ed ac o 4.1 (0.9) 1.2 (0.3) <0.001
Dep essed ac o 1.6 (0.1) 1.6 (0.7) 0.770
HDRS =Hamil on Dep ession Ra ing Scale; PANSS =Posi i e
and Nega i e Synd ome Scale; SD =s anda d de ia ion;
YMRS =Young Mania Ra ing Scale.
a
Fishe ’s exac es o pai ed-samples - es s.
5
Mo o co ical disinhibi ion in BD
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Pos -hoc analysis e ealed ha pa ien s wi h BD
du ing mania showed less SICI a ISIs 2 msec
(p <0.001) and 3 msec (p <0.05), while no di e -
ences we e ound in ICF (p >0.2) (Fig. 1A). A e -
aged ac oss bo h inhibi o y ISIs (2 msec and
3 msec), pa ien s du ing mania demons a ed
33.2% less inhibi ion compa ed wi h heal hy sub-
jec s (
44
=3.3, p =0.002). The e we e no di e -
ences be ween g oups when ICF measu es we e
pooled (p =0.203). Di e ences in SICI measu es
emained s a is ically signi ican a e con olling
o cu en obacco smoking (es ima ed ma ginal
means o SICI in he BD g oup =0.78, heal hy
g oup =0.36, p =0.01). We also assessed he e ec
o cu en o pas cannabis use on SICI measu es
in pa ien s wi h BD. In he mul i a ia e model,
he e was a signi ican e ec o ISI (p <0.001),
while nei he he ISI 9cu en cannabis use
(p =0.571) no cu en cannabis use main ac o
(p =0.947) eached signi ican le els. Simila
esul s we e ob ained a e including he a iables
equency o cu en cannabis smoking (in e ac ion
wi h ISI, p =0.287; main e ec , p =0.655), ime
since las join (p =0.166), age a cannabis use onse
(p =0.639), o du a ion o cannabis use (p =0.734)
on SICI 12. His o y o cocaine use did no show a sig-
ni ican main e ec (p =0.482) o in e ac ion wi h
ISI (p =0.117). Pa ien s on benzodiazepine ea -
men showed enhanced SICI a bo h 2 msec and
3 msec (bo h p <0.05, as compa ed wi h pa ien s
wi hou benzodiazepines).
Long-in e al co ical 14inhibi ion. A main e ec o
ISI (F
3,135
=17.28, p <0.001) was ound, indica -
ing a signi ican MEP educ ion when a condi-
ioned s imulus was applied bo h o con ols and
pa ien s (p <0.001). Howe e , no signi ican main
e ec o g oup (F
1,47
=0.022, p =0.883) o he
in e ac ion ISI 9g oup (F
3,141
=0.449, p =0.718)
was ound o his p o ocol.
CSP. The du a ion o CSP did no di e be ween
pa ien s wi h mania and heal hy con ols (mean
CSP du a ion manic pa ien s =110.3 msec; con-
ols =116.09 msec;
45
=0.708, p =0.483).
TCI. One pa ien could no comple e his p o o-
col. Signi ican main e ec s o ISI (F
3,129
=22.1,
p<0.001) and g oup (F
1,43
=7.8, p =0.008) we e
ob ained, while he g oup 9ISI in e ac ion was
no signi ican (F
4,43
=1.05, p =0.359) (Fig. 1B).
Planned - es s showed dec eased TCI in manic
pa ien s a ISIs 7 msec (p =0.021) and 10 msec
(p =0.018). A e a e aging ac oss all sho -in e -
al in e hemisphe ic inhibi o y ISIs (i.e., 7 msec
and 10 msec), pa ien s wi h BD displayed less inhi-
bi ion han heal hy con ols (17.5%, p =0.033).
An in e ac ion be ween cu en obacco smoking
and g oup was also de ec ed (F
1,44
=4.33,
p=0.044). Pos -hoc analysis e ealed ha smoke
Table 3. TMS in ensi y (% o maximum s imula o ou pu ) used in he
TMS assessmen s o pa ien s wi h bipola diso de and heal hy sub-
jec s
Heal hy
con ols
Manic
episode
Eu hymic
episode
Ac i e mo o h eshold
( igh FDI muscle)
31.8 1.3 32.1 1.7 32.2 1.8
Res ing mo o h eshold
( igh FDI muscle)
40.8 1.3 42.5 2.1 41.2 2.5
In ensi y MEP 1 mV
( igh FDI muscle)
49.4 1.9 51.4 2.5 51.2 2.6
Res ing mo o h eshold
( igh FDI muscle)
a
43.0 1.8 42.7 2.2 44.9 2.3
Res ing mo o h eshold
(le FDI muscle)
a
41.7 1.4 43.9 3.2 43.3 2.6
Values epo ed as mean s anda d de ia ion. FDI = i s do -
sal in e osseous; MEP =mo o e oked po en ial; TMS = an-
sc anial magne ic s imula ion.
a
Th esholds ob ained using 40-mm coils di ec ly connec ed o
he s imula o s.
AB
TEST
2 msec
3 msec
10 msec
12 msec
0.0
0.5
1.0
1.5
MEP ampli ude
No malized by TEST ampli ude
*** *
TEST
7 msec
10 msec
45 msec
75 msec
0.0
0.5
1.0
MEP ampli ude
No malized by TEST ampli ude
*
*
Fig. 1. (A) Sho -in e al in aco ical inhibi ion and in aco ical acili a ion in pa ien s wi h bipola diso de and heal hy subjec s.
(B) T anscallosal inhibi ion in pa ien s wi h bipola diso de and heal hy subjec s as a unc ion o he in e s imulus in e al be ween
he condi ioning and he es s imuli. Mean s anda d e o om pa ien s du ing he manic episode (black ba s, n =19) and
heal hy con ols (g ay ba s, n =28). Values <1 indica e inhibi ion. *p<0.05, ***p13
<0.001: independen - es s wi h Bon e oni co -
ec ion o mul iple compa isons. MEP =mo o e oked po en ial.
6
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1
2
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9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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26
27
28
29
30
31
32
33
34
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36
37
38
39
40
41
42
43
44
45
46
47
48
49
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51
52
53
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55
56
pa ien s wi h BD displayed TCI le els ha we e
compa able wi h hose ob ained in he heal hy
g oup (p =0.441), while TCI le els in non-smoke
pa ien s wi h BD we e signi ican ly educed
(p =0.018, as compa ed wi h heal hy subjec s).
Cu en obacco smoking did no a ec TCI le els
in heal hy subjec s (p =0.690). A cu en o pas
his o y o cannabis use did no show he main
e ec (p =0.221) o in e ac ion wi h ISI
(p =0.368). Likewise, equency o cu en cannabis
smoking did no show an e ec on TCI esul s (in-
e ac ion wi h ISI, p =0.637; main e ec ,
p=0.257). O he a iables ha did no in luence
TCI le els in pa ien s wi h BD included ime since
las join (p =0.993), age a cannabis use onse
(p =0.999), and du a ion o cannabis use
(p =0.837). A his o y o cocaine use did no show
a signi ican main e ec (p =0.419) o in e ac ion
wi h ISI (p =0.611). Nei he he main e ec o
benzodiazepine (p =0.287) no in e ac ion o ben-
zodiazepine wi h TCI ISIs we e signi ican
(p =0.596).
Co ical inhibi ion du ing eu hymia
SICI and ICF. A signi ican main e ec o ISI
(F
3,36
=10.06, p <0.001), bu no episode
(F
1,12
=0.007, p =0.935) o in e ac ion episode 9
ISI (F
3,36
=0.056, p =0.784), was ound in he ol-
low-up s udy, indica ing no di e ences be ween
pa ien s du ing manic and eu hymic phases a any
e alua ed condi ion
15 (Fig. 2A). Cu en obacco
smoking in he model did no s a is ically al e
hese esul s (p =0.575). Cannabis, cocaine, and
benzodiazepine e ec s we e no analyzed a he ol-
low-up assessmen owing o he small numbe o
pa ien s unde hese condi ions.
Long-in e al co ical inhibi ion
17 .No signi ican
main e ec o episode (F
1,13
=0.196, p =0.665)
o in e ac ion episode 9ISI (F
2,26
=1.764,
p=0.191) was ound in he ollow-up s udy.
Silen pe iod. No signi ican di e ences we e
ound be ween pa ien s in manic and eu hymic
phases (
14
=1.009, p =0.331).
TCI. Analysis o di e ences be ween he manic
episode and he ollow-up assessmen e ealed a
signi ican main ac o ISI (F
3,39
=7.94,
p<0.001), whe eas nei he main ac o episode
(F
1,13
=1.132, p =0.307) no he in e ac ion
be ween episode and ISI (F
3,36
=0.623, p =0.604)
we e signi ican (Fig. 2B). A signi ican main e ec
o obacco was also ound in he mul i a ia e anal-
ysis (F
1,13
=4.86, p =0.046). Cu en obacco
smoke s showed an inc eased mean TCI compa ed
wi h non-smoke s.
Rela ionship be ween se e i y o psychia ic symp oms
and measu es o co ical inhibi ion
SICI and TCI le els (a e aged ac oss all inhibi o y
ISIs) co ela ed posi i ely bo h in manic episode
and eu hymia. Pa ien s wi h a high sco e in he
PANSS exci ed ac o du ing he manic episode
displayed less SICI and TCI du ing bo h he manic
episode and eu hymia. PANSS diso ganized ac o
co ela ed posi i ely wi h he posi i e and nega i e
ac o s o he same scale. Mo eo e , he PANSS
dep essed ac o showed a nega i e co ela ion
wi h he HDS 18du ing mania. These co ela ions
did no each signi icance a e he Bon e oni co -
ec ion. The ull co ela ion ma ix is p esen ed in
Supplemen a y Table 1.
We also conduc ed a co ela ion analysis wi h
YMRS i em 2, which assesses inc eased mo o
ac i i y and ene gy. The sco e in his i em co e-
la ed nega i ely wi h he deg ee o co ical inhibi-
ion in bo h manic and eu hymic episodes bu
TEST
2 msec
3 msec
10 msec
12 msec
0.0
0.5
1.0
1.5
A
MEP ampli ude
No malized by TEST ampli ude
Tes
7 msec
10 msec
45 msec
75 msec
0.0
0.5
1.0
B
MEP ampli ude
No malized by TEST ampli ude
Fig. 2. (A) Sho -in e al in aco ical inhibi ion and in aco ical acili a ion in pa ien s wi h bipola diso de du ing he manic epi-
sode (g ay ba s) and eu hymia (whi e ba s 16
). (B) T anscallosal inhibi ion in pa ien s du ing he manic episode and eu hymia. Fi een
pa ien s we e included in his ollow-up s udy. Values <1 indica e inhibi ion. No signi ican di e ence in co ical inhibi ion be ween
manic episode and eu hymia was ound. Pai ed sample - es s wi h Bon e oni co ec ion o mul iple compa ison. MEP =mo o
e oked po en ial.
7
Mo o co ical disinhibi ion in BD
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
hese did no each signi icance a e he Bon e -
oni co ec ion (SICI mania: ho =0.632,
p=0.006; SICI eu hymia: ho =0.562,
p=0.046; TCI mania: ho =0.526, p =0.065;
TCI eu hymia: ho =0.409, p =0.103).
Discussion
We ound ha pa ien s wi h BD du ing mania dis-
play speci ic co ical inhibi o y de ici s –namely,
al e ed SICI and TCI. The deg ee o co ical inhibi-
ion was simila du ing mania and eu hymia, sug-
ges ing ha co ical inhibi o y de ici s cons i u e a
ai ma ke o BD. In an explo a o y co ela ion
analysis, se e al associa ions be ween psychopa ho-
logical symp om se e i y and co ical inhibi o y
measu es we e de ec ed. I should be highligh ed
ha pa ien s who sco ed high on i ems assessing
mo o hype ac i i y and goal-di ec ed beha io
(i.e., PANSS exci ed ac o i ems
19 , YMRS i em 2)
du ing mania displayed highe co ical SICI and
TCI de ici s bo h in manic episodes and eu hymia.
Se e al e o s ha e been made o dis inguish
which cogni i e, emo ional, and mo i a ional
al e a ions o BD a e mood-s a e dependen o
ai ma ke s by examining pa ien s ac oss a ious
mood s a es, including eu hymia (36, 37). How-
e e , ai - and s a e-dependen co ical inhibi o y
de ici s ha e no been ex ensi ely s udied, despi e
he ac ha hese de ici s ha e been linked o
impulsi eness, a co e symp om o BD (21, 38, 39).
Indeed, clinical scales o assess BD usually include
mo o ac i i y i ems. Thus, i may seem easonable
o e alua e ai - and s a e-dependen co ical
exci abili y/inhibi ion as an indica o o he neu-
opa hophysiology unde lying mo o de ici s in
mood diso de s. Ou esul s, which con i m and
u he ex end p e ious obse a ions in eu hymic
pa ien s (18, 19), include se e al new obse a ions
on mania ha p o ide a mo e comple e unde -
s anding o mo o inhibi ion de ici s in BD. In pa -
icula , he longi udinal design used in ou s udy
empowe ed he gene alizabili y o ou da a o he
comple e cou se o BD, no limi ed o a speci ic
ype o episode.
Al e ed co ical inhibi ion has been obse ed in
se e e psycho ic and mood diso de s, in spi e o
he concomi an
20 ele a ed pe iphe al and b ain
GABA le els (40, 41). The e o e, a plausible
hypo hesis o he mechanism in ol ed in co ical
inhibi o y de ici s seen in BD would in ol e al e -
a ions in he GABA ecep o sys em. Pha maco-
logical s udies sugges he in ol emen o GABAA
ecep o s in SICI assessed in he p ima y mo o
co ex. The e o e, and in ag eemen wi h Le inson
e al. (18), de ici s in SICI could e idence an
impai men in as inhibi o y co ical p ocesses
likely o in ol e GABAA ecep o s (42). We also
ound ha benzodiazepines modula ed he SICI
le el in pa ien s wi h BD du ing mania – ha is,
pa ien s aking benzodiazepines du ing he manic
episode displayed simila SICI le els o heal hy
con ols, while pa ien s wi hou his ea men dis-
played signi ican ly educed SICI le els. The e ec
o benzodiazepines on SICI could no be es ed
du ing eu hymia as only h ee pa ien s we e aking
benzodiazepines a ollow-up. The enhancing e ec
o benzodiazepines on SICI is consis en ly epo ed
in he pha maco-TMS li e a u e (43) and could
unde lie he indings in BD epo ed he e. The e-
o e, i is possible ha he SICI educ ion obse ed
in he manic phase could ha e been e en highe
han ha ob ained in he cu en s udy i pa ien s
had no been on benzodiazepine ea men . This
possibili y does no make ou main indings oid
as manic pa ien s s ill show de ici s in SICI, and
his does no change du ing eu hymia.
In addi ion o de ici s ound in SICI, in e hemi-
sphe ic inhibi ion a sho ISIs (7 msec and
10 msec) was also ound o be abno mal bo h in
manic and eu hymic episodes. Al hough he exac
mechanisms media ing TCI emain unde in es i-
ga ion, he e is a en a i e consensus on he
in ol emen o anscallosal glu ama e gic pa h-
ways linking wi h py amidal ac neu ons h ough
GABAe gic in e neu ons (44). In humans, TCI is a
obus phenomenon and occu s o e a wide ange
o ISIs (6–50 msec). Howe e , eme ging e idence
sugges s ha TCI elici ed a sho ISIs is media ed
by di e en mechanisms han ha elici ed a longe
in e als (45). Animal s udies ha e sugges ed ha
he ea ly las ing o m o TCI is media ed by
GABAA ecep o s (46). Ne e heless, da a in
humans a e inconclusi e (47, 48). Ano he po en-
ial ac o ha may unde lie TCI de ici s in BD
ega ds ana omical al e a ions in he co pus callo-
sum, such as he educed callosal wid h docu-
men ed in his popula ion (49, 50).
Subs ance use was no con olled in ou s udy.
The e o e, he e ec o hese a iables on co ical
inhibi o y measu es was analyzed sepa a ely in
mul i a ia e analyses. Consis en wi h o he s ud-
ies, pa ien s wi h BD displayed high a es o cu -
en and li e ime cannabis, cocaine, and obacco
use (20, 51). The analysis o cannabis and cocaine
use showed no e ec o hese subs ances on TMS
measu es in BD du ing mania. We also obse ed a
signi ican dec ease in he numbe o pa ien s wi h-
ou cannabis and cocaine use du ing ollow-up
(e.g., eigh pa ien s epo ed ha hey had s opped
smoking cannabis in ecen mon hs, which was u -
he con i med by he u ine d ug es , and no
8
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