Human an e io halamic nuclei a e in ol ed in emo ion–a en ion
in e ac ion
Lihua Sun
a,1
, Ja i Pe äkylä
a,1
, Ma kus Pol i aa a
a
, Juha Öhman
b
, Jukka Pel ola
b
,
Kai Leh imäki
b
, Heini Huh ala
c
, Kaisa M. Ha ikainen
a,b,
n
a
Beha io al Neu ology Resea ch Uni , Tampe e Uni e si y Hospi al, Finn-Medi 6-7, Pi kanmaa Hospi al Dis ic , P.O. Box 2000, FI-33520 Tampe e, Finland
b
Depa men o Neu osciences and Rehabili a ion, Tampe e Uni e si y Hospi al, Tampe e, Finland
c
School o Heal h Sciences, Uni e si y o Tampe e, Tampe e, Finland
a icle in o
A icle his o y:
Recei ed 3 June 2015
Recei ed in e ised o m
1 Oc obe 2015
Accep ed 2 Oc obe 2015
A ailable online 18 Oc obe 2015
Keywo ds:
Deep b ain s imula ion
An e io halamic nuclei
EEG
Emo ion
A en ion
Epilepsy
abs ac
Pa ien s ea ed wi h deep b ain s imula ion (DBS) p o ide an oppo uni y o s udy a ec i e p ocesses in
humans wi h “lesion on demand”a key nodes in he limbic ci cui ies, such as a he an e io halamic
nuclei (ANT). ANT has been sugges ed o play a ole in emo ional con ol wi h i s connec ion o he
o bi o on al co ex and he an e io cingula e co ex. Howe e , di ec e idence o i s ole in emo ional
unc ion in human subjec s is lacking. Repo ed side e ec s o ANT–DBS in he ea men o e ac o y
epilepsy include dep ession ela ed symp oms. In line wi h hese mood- ela ed clinical side e ec s, we
ha e p e iously epo ed ha s imula ing he an e io halamus inc eased emo ional in e e ence in a
isual a en ion ask as indica ed by p olonged eac ion imes due o h ea - ela ed emo ional dis ac o s.
We used e en - ela ed po en ials o in es iga e po en ial a en ional mechanism behind his beha iou al
obse a ion. We hypo hesized ha ANT–DBS leads o g ea e a en ion cap u e by h ea - ela ed dis-
ac o s. We es ed his hypo hesis using cen o-pa ie al N2–P3 peak- o-peak ampli ude as a measu e o
alloca ed a en ional esou ces. Six epilep ic pa ien s ea ed wi h deep b ain s imula ion a ANT pa i-
cipa ed in he s udy. Elec oencephalog aphy was eco ded while he pa ien s pe o med a compu e
based Execu i e-Reac ion Time es wi h h ea - ela ed emo ional dis ac o s. Du ing he ask, ei he ANT
o a halamic con ol loca ion was s imula ed, o he s imula ion was u ned o . S imula ion o ANT was
associa ed wi h inc eased cen o-pa ie al N2–P3 ampli ude and inc eased eac ion ime in he con ex o
h ea - ela ed emo ional dis ac o s. We conclude ha high equency elec ic s imula ion o ANT leads
o g ea e a en ional cap u e by emo ional s imuli. This is he fi s s udy o p o ide di ec e idence om
human subjec s wi h on-line elec ic manipula ion o ANT o i s ole in emo ion–a en ion in e ac ion.
&2015 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND
license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
1. In oduc ion
S imula ing deep b ain s uc u es is an eme ging he apeu ic
me hod hough o modula e dys unc ional neu al ci cui s un-
de lying many neu ological and psychia ic diso de s. Limbic and
associa i e ci cui s impo an o emo ional and cogni i e p o-
cesses play a key ole in many neu opsychia ic diso de s ea ed
wi h deep b ain s imula ion (DBS). Howe e , knowledge on he
e ec s o DBS on hese ci cui s is limi ed. Deepe unde s anding o
how DBS impac s a ec i e unc ions is clinically ele an o op-
imizing DBS pa ame e s, allowing o op imal ea men e ec
and minimal a ec i e side e ec s, such as dep ession ela ed
symp oms (Fishe e al., 2010). In addi ion, DBS s udies p o ide
no el insigh in o he neu al ci cui s behind emo ion, a en ion
and cogni ion in a conscious human b ain wi h elec ical s imu-
la ion o he key nodes in hese ci cui s. High- equency elec ic
s imula ion used in DBS ea men is hough o mimic a e e sible
lesion ha empo a ily dis up s he unc ion o he a ge nuclei.
Thus, in aluable in o ma ion on emo ion, a en ion and cogni ion
and hei in e ac ion in humans is ob ained by pe iodically dis-
up ing and eco e ing he unc ion o he key nodes in he limbic
and associa i e ci cui s while b ain's elec ical esponses a e e-
co ded in asks engaging emo ional, a en ional and cogni i e
unc ions.
S imula ion a ge s used o he ea men o he medically
e ac o y epilepsy include he an e io nuclei o halamus (ANT).
ANT is a sui able DBS a ge due o i s cen al connec i i y and
possible ole in he p opaga ion and main enance o seizu e ac-
i i y (Child and Bena och, 2013;Takebayashi e al., 2007). In
addi ion o i s he apeu ic e ec o educing seizu es, ad e se
Con en s lis s a ailable a ScienceDi ec
jou nal homepage: www.else ie .com/loca e/neu opsychologia
Neu opsychologia
h p://dx.doi.o g/10.1016/j.neu opsychologia.2015.10.001
0028-3932/&2015 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
n
Co esponding au ho a : Beha io al Neu ology Resea ch Uni , Tampe e Uni-
e si y Hospi al, Finn-Medi 6-7, Pi kanmaa Hospi al Dis ic , P.O. Box 2000, FI-
33520 Tampe e, Finland.
E-mail add ess: kaisa.ha ikainen@u a.fi(K.M. Ha ikainen).
1
These au ho s ha e con ibu ed equally o his s udy.
Neu opsychologia 78 (2015) 88–94
e ec s, such as dep essi e symp oms, ha e been epo ed ol-
lowing ANT–DBS (Fishe e al., 2010;Möddel e al., 2012). In line
wi h hese ad e se a ec i e e ec s we ha e p e iously shown ha
s imula ing he an e io halamus enhanced emo ional in e -
e ence o h ea - ela ed dis ac o s (Ha ikainen e al., 2014).
ANT's ole in emo ional p ocessing was fi s in oduced by
Papez (Papez, 1937) and i is pa o he MacLean's limbic sys em
(MacLean, 1949). Since he concep o he limbic sys em ou un-
de s anding o he neu al ci cui s unde lying emo ional p ocessing
has e ol ed significan ly (Dalgleish, 2004;LeDoux, 2012), espe-
cially in he a eas o emo ion–a en ion and emo ion–cogni ion
in e ac ion (Ha ikainen e al., 2000;Ochsne and G oss, 2005;
Okon-Singe e al., 2015;Pe e sen and Posne , 2012). Recen
findings a e acili a ed by he mode n neu oimaging me hods and
he ex ensi e esea ch especially abou he oles o he amygdala
and he PFC and he in e ac ion o he a ious pa s o he emo-
ional ci cui s. Howe e , e en i ANT is ou inely men ioned in he
adi ional emo ion li e a u e, mos ly based on i s ana omical
connec ions, i s ole in emo ional p ocessing has emained elusi e.
This s udy seeks o fill he gap by aking ad an age o he ANT–
DBS used o ea e ac o y epilepsy.
ANT has been sugges ed o play a ole in emo ional (Ma chand
e al., 2014) and execu i e unc ions mainly due o i s connec ions
wi h he amygdala ( an G oen e al., 1999), o bi o on al co ex
(OFC) and an e io cingula e co ex (ACC) (Child and Bena och,
2013), bu di ec e idence om humans o ANT's ole in hese
unc ions is limi ed (Bocko a e al., 2014;Ha ikainen e al., 2014).
ANT has majo e e en connec ions o ACC (Xiao and Ba bas,
2002) which in u n has ex ensi e co ico-co ical connec ions
wi h he la e al p e on al co ex (LPFC) (Paus, 2001). The ACC has
been implica ed in a wide a ie y o di e en mo i a ional, emo-
ional and cogni i e unc ions (Bush e al., 2000), wi h he do sal
ACC (dACC) iden ified as playing a key ole in cogni i e con ol
(Bo inick e al., 2001). A model o dACC unc ion has been sug-
ges ed desc ibing he ole o he dACC as being in ol ed in in-
eg a ing in o ma ion o de e mining and egula ing he amoun
o LPFC cogni i e con ol (Shenha e al., 2013). Su ficien amoun
o LPFC cogni i e con ol is equi ed o e ficien ly inhibi ing
emo ional dis ac ion. Missing o noisy inpu om ANT o dACC
due o high equency elec ic s imula ion o ANT could lead o
inadequa e alloca ion o cogni i e con ol a he LPFC he eby ac-
coun ing o inc eased emo ional dis ac ion o beha iou du ing
ANT–DBS (Ha ikainen e al., 2014).
The e ficacy o an in ac LPFC and he fideli y o i s cogni i e
con ol a e equi ed when selec ing ele an objec s o a en ion
while supp essing o fil e ing ou i ele an ones (Chao and
Knigh , 1998;Shimamu a, 2000). Objec s a e hough o compe e
o he b ain's limi ed p ocessing esou ces. Biased compe i ion
heo y o selec i e a en ion sugges s ha bo h ask- ela ed op-
down and s imulus- ela ed bo om-up biasing mechanisms influ-
ence he a en ional compe i ion (Desimone and Duncan, 1995). As
such, emo ional dis ac o s due o hei biological and beha iou al
ele ance cap u e a en ional esou ces (Ha ikainen e al., 2000;
Ohman e al., 2001;Vuilleumie and Schwa z, 2001). This in u n
leads o ask in e e ence (Ha ikainen e al., 2000;Ha ikainen
e al., 2010;Ha ikainen e al., 2007;Pessoa e al., 2012) and a -
en ion ne wo k ac i a ion (Ba celo, 2009;Jaege and Rugg, 2012;
Ma a os e al., 2000;Mäki-Ma unen e al., 2014). Thus, bo om-
up influence o emo ional s imuli is unde op-down on al con-
ol which limi s i s influence on a en ion and beha iou when
dis ac ing o he cu en goals. Any pe u ba ion o ac i ely e-
c ui p e on al con ol mechanisms can al e no mal emo ion–
a en ion in e ac ion. Co espondingly, dec eased on al unc ions
may lead o diminished op-down con ol and consequen ly en-
hance he bo om-up influence o nega i e emo ional in o ma ion.
This g ea e a en ion alloca ion o nega i e emo ional s imuli
hough o be ela ed o deficien p e on al con ol is seen in
anxie y (Bishop, 2008), dep ession (Leppänen, 2006;Ma hews
and Wells, 2000) and mild auma ic b ain inju y (Mäki-Ma u-
nen e al., 2015). And simila o dep ession (Leppänen, 2006;
Ma hews and Wells, 2000) g ea e emo ional in e e ence by
nega i e emo ional s imuli was seen du ing ANT–DBS as e i-
denced by p olonged eac ion imes (Ha ikainen e al., 2014).
To in es iga e whe he a en ional mechanisms pa icipa e in
inc eased emo ional in e e ence p e iously obse ed wi h ANT–
DBS (Ha ikainen e al., 2014) we compa ed he b ain's elec ical
esponses o e en s, i.e. e en - ela ed po en ials (ERPs), when his
s imula ion was on and o . ERPs a e well-sui ed o s udying he
neu al mechanism behind emo ion–a en ion in e ac ion and i s
al e a ions esul ing om DBS. On he o he hand, pa ien s ea ed
wi h ANT–DBS due o e ac o y epilepsy p o ide an oppo uni y
o s udy ANT's unc ion by pe iodically dis up ing and eco e ing
i s unc ion wi h high- equency elec ic s imula ion. Ta ge s in
a en ion asks e oke a posi i e pa ie al ERP wa e o m a abou
300–600 ms a e he a ge called P3 p eceded by a nega i e
deflec ion called N2 (Pa el and Azzam, 2005;Polich, 2007). In he
con ex o no el (Da ne e al., 1998) o emo ional s imuli (Ha -
ikainen e al., 2007)N2–P3 peak- o-peak ampli ude is hough o
eflec he amoun o a en ion alloca ion wi h g ea e N2–P3
peak- o-peak ampli ude eflec ing g ea e a en ion alloca ion.
Peak- o-peak ampli ude measu e accoun s o possible baseline
shi s o slow fluc ua ions ha migh con amina e single peak
measu emen s and hus makes i a mo e obus elec o-
physiological ma ke in s udies wi h small pa ien popula ions
ha possess g ea e a iabili y in ERP wa e o ms and noisie ERP
eco dings han heal hy subjec s. N2–P3 peak- o-peak ampli ude
has been p e iously used success ully o de ec al e a ions in
emo ion–a en ion in e ac ion in pa ien s wi h mild head inju y
(Mäki-Ma unen e al., 2015) and in pa ien s wi h lesion o he
o bi o on al co ex (Ha ikainen e al., 2012). emo ion–a en ion
in e ac ion and how i is eflec ed in N2–P3 ampli ude modula ion
is p edominan ly obse ed o e he pa ie al egion (Ha ikainen
e al., 2007;Kayse e al., 1997). In addi ion, he pa ie al egion is
impo an in P3 gene a ion and in a en ion in gene al (Beh mann
e al., 2004;Polich, 2007). To ha end we used cen o-pa ie al N2–
P3 ERP peak- o-peak ampli ude as a measu e o alloca ed a en-
ional esou ces o assess a en ional alloca ion in con ex o
emo ional dis ac o s and i s al e a ions due o DBS.
We hypo hesized ha ANT is in ol ed in emo ion–a en ion
in e ac ion and ha a en ional mechanisms play a ole in in-
c eased emo ional in e e ence p e iously obse ed wi h ANT–
DBS. Reflec ing g ea e alloca ion o a en ional esou ces o
h ea - ela ed emo ional dis ac o s we expec ed ANT–DBS o e-
sul in inc eased cen o-pa ie al N2–P3 ampli ude along wi h
g ea e beha iou al in e e ence in he con ex o emo ional
dis ac o s.
2. Ma e ial and me hods
2.1. Subjec s
Thi een pa ien s wi h bila e al ANT–DBS ea men o e ac o y epilepsy
pa icipa ed in he s udy. The s udy was app o ed by he Regional Re iew Boa d,
Tampe e, Finland. The deep-b ain-s imula o was implan ed in pa ien s by neu-
osu geons in Tampe e Uni e si y Hospi al.
Se en pa ien s we e excluded om he ERP analysis. Fi e ou o he se en
pa ien s we e excluded due o excessi e EEG a e ac s o epilep i o m ac i i y
leading o uniden ifiable ERPs. Two pa ien s we e excluded due o di e en ana-
omic loca ions o he s imula ing/ac i e con ac s. Six pa ien s (3 emales and
3 males) wi h he age o 37713 yea s old we e included in bo h beha iou al and
ERP analysis, Table 1. Ou o he six pa ien s, ou we e esponsi e o he ea men
wi h o e 50% educ ion o epilep ic ac i i y, while wo had less han 50% educ ion
o seizu es. None o he 13 pa ien s had p e ious expe ience in simila
L. Sun e al. / Neu opsychologia 78 (2015) 88–94 89
expe imen al es .
2.2. The Execu i e Reac ion Time Tes
Elec oencephalog aphy (EEG) was eco ded while pa icipan s pe o med he
Execu i e Reac ion Time (RT) - es (Ha ikainen e al., 2010). The Execu i e RT- es
is a compu e -based isual a en ion ask (Fig. 1) equi ing mul iple execu i e
unc ions o be engaged simul aneously. Pa ien s sa com o ably in a quie dimly
ligh oom in on o a compu e sc een and esponded wi h a keypad o isual
s imuli acco ding o ins uc ions. Subjec s we e ins uc ed o s ay elaxed, keep
hei eyes on he loca ion o he fixa ion c oss in he middle o he sc een, a oid any
unnecessa y eye mo emen s o blinks and espond as as and accu a ely as pos-
sible. The dis ance om he compu e sc een was fixed o one me e . Visual s imuli
we e p esen ed and beha iou al da a collec ed wi h P esen a ion so wa e (Neu-
obeha io al Sys em, Inc., Be keley, CA, USA).
The subjec 's ask was o espond as as and accu a ely as possible wi h a
bu on p ess o he o ien a ion o a iangle in case o a Go- ial and wi hhold om
esponding in case o a NoGo- ial. Each ial s a s wi h a iangle (150 ms)
poin ing up o down ollowed by a fixa ion c oss o 150 ms in he middle o he
compu e sc een. Then a Go- o a NoGo-signal is p esen ed o 150 ms indica ing
whe he o espond o he o ien a ion o he p e iously p esen ed iangle o no .
The Go/NoGo signal is ollowed by a fixa ion o 1550 ms allowing ime o he
pa ien o espond be o e he nex iangle. The Go/NoGo signal is a g een o a ed
a fic ligh wi h he ule o esponding changing e e y ew minu es. In he middle
o he a fic ligh he e is a dis ac o , which is ei he neu al (non- h ea ing) o
emo ional ( h ea ela ed). Th ea ela ed dis ac o is a line d awing making he
shape o a spide and neu al dis ac o is a line d awing wi h same elemen s as
con ol (Fig. 1). The significance o he g een and ed a fic ligh changes be ween
each block. In hal o he blocks g een ligh indica es a Go ial and ed a NoGo ial.
In he o he hal o he blocks his ule is e e sed. The di ec ion o he iangle and
he Go/NoGo signals a e andomized. Dominan hand was used o p essing bu -
ons (pa ien p10 used le hand; o he pa ien s used igh hand). A o al numbe o
32 blocks wi h 64 ials in each block leading o o al o 2048 ials pe subjec we e
included in he es .
Subjec pe o mance in he Execu i e-RT es is eflec ed in he speed and
accu acy o esponses. Di e en e o ypes eflec ailu es in di e en cogni i e
p ocesses. The e we e h ee di e en e o ypes, i.e. inco ec bu on p ess, misses
and commission e o s. Inco ec bu on p ess o he o ien a ion o he iangle
indica es lapse in wo king memo y pe o mance. A miss is a ailu e o espond
wi hin he gi en ime indica ing a lapse in a en ion pe o mance. A commission
e o is a ailu e in wi hholding a esponse du ing a NoGo ial indica ing ine ficien
esponse inhibi ion. In addi ion o es ing e ficiency o di e en cogni i e p ocesses,
he Execu i e-RT es wi h he h ea - ela ed dis ac o s allow o e alua ing he
au oma ic alloca ion o a en ion o h ea (Ha ikainen e al., 2010;Ha ikainen
e al., 2012;Ha ikainen e al., 2014;Mäki-Ma unen e al., 2015).
2.3. EEG eco ding and p ocessing
EEG was eco ded using a 64-channel ac iCAP elec odes (B ain P oduc s
GmbH, Ge many) wi h sampling a e o 500 Hz using a common e e ence. Elec-
ode impedance was kep below 5 kΩ o all elec odes. ERP analysis was con-
duc ed wi h B ain Vision Analyze 2 so wa e (B ain P oduc s GmbH, Ge many). A
he beginning o he p e-p ocessing EEG was e- e e enced o he linked mas oids
(Tp9 and Tp10). In o de o emo e low equency d i s and high equency a e-
ac s, such as DBS a e ac s, EEG signal was fil e ed wi h 0.1–30 Hz band pass fil e .
Ocula mo emen a e ac s we e emo ed using Independen Componen Analysis
(ICA), whe e he EEG was decomposed in o independen componen s using he
ex ended In omax algo i hm. Componen s co esponding o ocula mo emen a -
e ac s we e iden ified isually and emo ed, ypically one o wo componen s. The
EEG was segmen ed in o 2000 ms segmen s beginning 200 ms p e-s imulus ( i-
angle) and con inuing 1800 ms pos -s imulus. Segmen s we e baseline co ec ed
o each ial by se ing he a e age o 200 ms pe iod p e-s imulus o ze o. Seg-
men s con aining ac i i y g ea e han 770 mV we e conside ed a e ac s and e-
jec ed. Nex , ERPs we e calcula ed by a e aging he segmen s o each condi ion
sepa a ely.
Visual inspec ion o he ERP wa e o ms showed nega i e deflec ion wi hin
200–400 ms a e he onse o he a fic ligh s (Go/NoGo signal) ollowed by a
posi i e deflec ion wi hin 300–700 ms co esponding o N2 and P3 peaks. Thus, N2
was defined as he lowes nega i e peak wi hin 200–400 ms (500–700 ms om he
ial onse , i.e. he p esen a ion o he iangle) and P3 as he highes posi i e peak
wi hin 300–700 ms (600–1000 ms a e ial onse ). The N2 and P3 peaks we e
de ec ed au oma ically om each subjec 's ERP wa e o ms and isually inspec ed
o confi m co ec de ec ion. Final peak alue was an a e age o 20 ms a ound
de ec ed maximum/minimum. Finally, N2–P3 peak- o-peak ampli ude was ob-
ained by sub ac ing N2 peak ampli ude om P3 peak ampli ude. Regional N2–P3
peak- o-peak ampli ude, co e ing he cen al (C1, C2, C3, C4, and Cz) and cen o-
pa ie al (CP1, CP2, CP3, CP4, and CPz) b ain a ea, was used as a gene al index o
a en ional esou ces alloca ion. Regional N2–P3 ampli ude was analyzed using
s a is ical me hods as desc ibed below.
2.4. Deep b ain s imula ion
Bila e al DBS elec odes (Med onic 3389, Med onic, Inc.) we e implan ed
acco ding o indi idual 3T magne ic esonance imaging (MRI) images isualizing
he mamillo- halamic ac and ANT. The ini ial s e eo ac ic a ge o he elec odes
was a 5–6 mm la e al, 12 mm supe io and 0–2 mm an e io o he mid-
commisu al poin (MCP) and u he adjus ed acco ding o indi idual imaging da a.
Pos ope a i e loca ions o DBS con ac s we e de e mined ela i e o isible bo de s
o ANT in 3T MRI using pos ope a i e CT –p eope a i e MRI usion images. The
cen e be ween posi i e and nega i e con ac s used in bipola s imula ion was
defined wi h espec o e e ence lines a he pos e io , an e io , medial, la e al,
in e io and supe io bo de s o ANT in each pa ien 's le and igh side (Fig. 2).
Du ing he expe imen bila e al and bipola s imula ion wi h a equency o 140 Hz,
pulse wid h o 90 ms and cons an cu en o 5 mA was used. Ac i e con ac loca-
ions we e balanced be ween ANT and halamic con ol loca ion. When ANT was
s imula ed he ac i e con ac loca ion was chosen o be he bes loca ion a ailable
o s imula ing ANT, i.e. ei he inside o a immedia e p oximi y o ANT and when
con ol loca ion was s imula ed he mos dis an elec ode om ANT was chosen as
he ac i e con ac . The halamic con ol loca ions we e a he an e io o supe io
aspec o he do somedial nucleus, Fig. 2. Since bipola s imula ion was applied
du ing he es , we calcula ed he ma hema ical cen e be ween posi i e and ne-
ga i e con ac s o es ima e he ac ual s imula ion si e.
Du ing he Execu i e-RT es , s imula ion was u ned ON o OFF al e na i ely
Table 1
Demog aphy o he ANT–DBS pa ien s.
Pa ien numbe Age/gende Age a diagnosis (y ) Types o epilepsy Ae iology Imaging findings Medica ion
1 31/Male 11 Occipi al Co ical dysplasia MRI þGabapen in
2 27/Female 7 Tempo al Co ical dysplasia MRI þOxca bazepine, clobazam, zonisamide
4 32/Female 28 Mul i ocal Encephali is MRI - Clobazam, zonisamide, lacosamide,
5 24/Female 16 Mul i ocal Encephali is MRI þOxca bazepine, opi ama e, clobazam, le e i ace am,
10 49/Male 12 Tempo al Co ical dysplasia MRI þOxca bazepine, clobazam, lacosamide,
13 57/Male 15 Mul i ocal unknown MRI Oxca bazepine
MRI¼magne ic esonance imaging; ‘þ’¼imaging findings; ‘’¼no imaging findings.
Fig. 1. Schema ic p esen a ion o he Execu i e-RT es . Subjec s espond o he
o ien a ion o he iangle by a bu on p ess in case o a Go- ial indica ed by he
colou o he a fic ligh . In he middle o he a fic ligh he e is a ask-i ele an
emo ional (spide ) o emo ionally neu al dis ac o . The emo ional and emo ion-
ally neu al dis ac o consis o exac ly same line componen s bu in a di e en
configu a ion. This allows o con olling he physical a ibu es o he s imuli such
as colou , con as , complexi y, e c. Thus, any di e ences be ween emo ional and
emo ionally neu al s imuli can be a ibu ed o emo ional significance. (Fo in-
e p e a ion o he e e ences o colou in his figu e, he eade is e e ed o he
web e sion o his a icle.)
L. Sun e al. / Neu opsychologia 78 (2015) 88–9490
o 5–6 min o allow o wo blocks o es ing, wi h pa ien s blind o he s imula o
se ing. Du ing 16 blocks ei he ANT o halamic con ol loca ion adjacen o ANT
was s imula ed (512 ials each) and du ing 16 blocks s imula ion was u ned o
(1024 ials). Thus, al oge he 2048 ials we e collec ed pe subjec . The expe i-
men was di ided in o wo consecu i e sessions including 16 blocks each. In one
session ANT was s imula ed du ing wo blocks o es ing and hen he s imula o
was u ned o o ano he wo blocks and his was epea ed ou imes. Iden ical
es ing sessions o s imula ing he con ol loca ion was ca ied ou . The o de o
sessions was balanced be ween subjec s, ha ing h ee pa ien s (pa ien 1, 2 and 4)
wi h ANT fi s ly s imula ed and he o he h ee pa ien s wi h con ol loca ion as
he fi s s imula ed loca ion, Fig. 3.
2.5. S a is ical analysis
The impac o he emo ional and neu al dis ac o s o eac ion imes and ERPs
wi hin a S imula ion S a us we e analyzed using Wilcoxon signed ank es whe e
he e ec o Emo ion (neu al, emo ional) was compa ed when s imula ion was ON
a ANT, ON a he con ol loca ion and OFF. Symme y o di e ences o Wilcoxon
signed ank es was ensu ed wi h Miao, Gel, and Gas wi h symme y es . The
impac o he dis ac o s ac oss S imula ion S a uses was compa ed using asymp-
o ic K-Sample Fishe –Pi man pe mu a ion es .
E o s we e analyzed using bina y logis ic eg ession. Sepa a e models we e
c ea ed o he h ee e o ypes, i.e. inco ec bu on p esses, commission e o s
and missing esponses, wi h each model p edic ing pa ien s’p obabili y o make a
co esponding e o . Ou come a iable (e o ) was dicho omized o bina y logis ic
eg ession so ha o inco ec bu on p esses ou come was ei he “inco ec ”o
“o he ”(co ec bu on p ess o a miss), o missing bu on p esses ei he “miss”
( ailu e o espond wi hin a gi en ime) o “o he ”(any bu on p ess in a Go ial)
and o commission e o s ei he “commission e o ”(a ailu e in wi hholding om
esponding in a NoGo- ial) o “no esponse”(adequa ely wi hholding om e-
sponding in a NoGo ial). Subjec , S imula ion S a us, Emo ion and In e ac ion
be ween Emo ion and S imula ion S a us we e used as p edic o a iables, all co-
ded as dummy a iables. In case o in e ac ion da a was s a ified in o sub models
in o de o find ou specific pa ame e s d i ing he in e ac ion.
3. Resul s
3.1. Beha iou al da a
Wilcoxon signed ank es indica ed ha when ANT was s i-
mula ed he emo ional dis ac o s induced a s a is ically sig-
nifican inc ease in subjec ’s eac ion ime compa ed o neu al
dis ac o s (Z¼2.2014, p¼0.03; Fig. 4,Table 2). The e we e no
Fig. 2. The isualiza ion o ANT nucleus and loca ions o s imula ion si es in he halamus. Sagi ally o ien ed 3T MRI STIR image demons a es he ANT nuclea complex and
i s subdi isions Ap and AM (A, B). The a ea shown as a ec angle in he panel B is illus a ed in he panel C wi h highe magnifica ion oge he wi h delinea ions o ANT
bo de s and e e ence lines used in es ima ion o con ac loca ions. Pos e io , in e io and medial (no shown) e e ence lines we e defined as 0 and an e io , supe io and
la e al (no shown) e e ence lines as 1. In panel C, he ound shapes e e o he 25% and 75% qua ile a ea om he median s imula ion si e in le side and igh side. Red
colou e e s o s imula ion si e a ANT and blue colou o he s imula ion a he con ol loca ion. Ana omically, con ol loca ion may be defined as an a ea bo de ing he h ee
majo halamic nuclea g oups (ANT, do somedial nucleus (DM) and en al an e io nucleus (VA)). The a ea o VA is es ima ed acco ding o Schal enb and–Wah en a las
(Schal enb and and Wah en, 1998) (since i is no clea ly isible in sagi ally o ien ed images) and is shown in g ey in panel C. Abb e ia ions: Ap , an e io p incipal nucleus;
AM, an e omedial nucleus; DM, do somedial nucleus; m , mamillo- halamic ac ; VA, en al an e io nucleus. (Fo in e p e a ion o he e e ences o colou in his figu e
legend, he eade is e e ed o he web e sion o his a icle.)
Fig. 3. Illus a ion o he o de o blocks in expe imen al sessions. The o de
o he ac i e con ac was balanced be ween subjec s. ANT¼ac i e con ac a ANT,
Con ol¼ac i e con ac a con ol loca ion, ON¼S imula ion u ned on,
OFF¼S imula ion u ned o .
Fig. 4. Inc eased emo ional in e e ence due o ANT–DBS. (A) The RTs we e
modula ed by he alence o he dis ac o s wi h longe RTs in con ex o emo ional
dis ac o s in compa ison o neu al dis ac o s when ANT was s imula ed. The
eac ion imes did no di e due o emo ional alence o he dis ac o when DBS
was OFF (B) and when he con ol loca ion was s imula ed (C). The e we e no
di e ence in RTs be ween S imula ion S a uses o he same dis ac o . n.s.¼no
significance.
Table 2
Reac ion imes o indi idual pa ien s.
Pa ien numbe ANT Con ol OFF
Emo ional Neu al Emo ional Neu al Emo ional Neu al
1 734 719 703 684 657 665
2 387 340 413 410 367 366
4 615 590 505 503 525 537
5 460 435 639 626 542 552
10 599 557 573 583 620 617
13 359 348 393 409 351 356
Table lis s eac ion ime in milliseconds. ANT¼ac i e con ac a ANT, Con-
ol¼ac i e con ac a con ol loca ion, OFF¼S imula ion u ned o . Emo ional¼
h ea - ela ed dis ac o , Neu al¼non- h ea ening dis ac o
L. Sun e al. / Neu opsychologia 78 (2015) 88–94 91
di e ence when s imula ion was OFF (Z¼1.5724, p¼0.12§) o he
con ol loca ion was s imula ed (Z¼0.52414, p¼0.60). Sym-
me y es showed ha eac ion ime di e ences we e symme ic
(ANT: es s a is ic¼0.66, p¼0.49; con ol loca ion: 0.25,
p¼0.80; OFF: 0.93, p¼0.35). Pe mu a ion es indica ed no s a-
is ically significan di e ence in eac ion imes ac oss S imula ion
S a uses o nei he o he dis ac o s (neu al:
χ
2
¼1.68, p¼0.49;
emo ional:
χ
2
¼0.92, p¼0.69).
No s a is ically significan p edic o s we e ound o any e o
ypes (Table A.1 and A.2).
3.2. ERP da a
To in es iga e po en ial a en ional mechanism behind in-
c eased emo ional in e e ence ERPs we e analyzed. The cen o-
pa ie al N2–P3 peak- o-peak ampli ude (Fig. 5A) was used as an
index o a en ional alloca ion. Wilcoxon signed ank es indica ed
ha when ANT was s imula ed, he emo ional dis ac o s led o
s a is ically significan inc ease in cen o-pa ie al N2–P3 ampli-
ude (Z¼2.2014, p¼0.03; Fig. 5B, Table 3). The e we e no in-
c ease when s imula ion was OFF (Z¼0.7338, p¼0.4631) o he
con ol loca ion was s imula ed (Z¼0.10483, p¼0.92). Symme y
es showed ha ERP ampli ude di e ences we e symme ic (ANT:
es s a is ic¼1.48, p¼0.20; con ol loca ion: 2.15, p¼0.15; OFF:
0.42, p¼0.70). Pe mu a ion es indica ed no s a is ically sig-
nifican di e ence in N2–P3 ampli ude ac oss S imula ion S a uses
o nei he o he dis ac o s (neu al:
χ
2
¼1.01, p¼0.60; emo-
ional:
χ
2
¼3.16, p¼0.21).
4. Discussion
This is he fi s s udy o p o ide beha iou al and
elec ophysiological e idence o he ole o ANT in emo ion–a -
en ion in e ac ion in humans. Dis up ing and eco e ing ANT's
no mal unc ion in humans while hey pe o med a ask equi ing
op-down con ol o emo ional dis ac ion showed ha ANT–DBS
has immedia e e ec s on he human limbic ci cui ies c i ical o
emo ional p ocesses. ANT–DBS inc eased au oma ic alloca ion o
a en ional esou ces o h ea - ela ed emo ional dis ac o s.
ANT has been hough o be in ol ed in human execu i e and
emo ional unc ions mainly due o i s p ojec ions o he OFC and
he ACC (Child and Bena och, 2013). Fu he e idence o ANT’s
ole in a ec i e unc ion comes om clinical e idence o pa ien s
wi h an e io halamic lesion. Lesions o his a ea epo edly lead
o apa hy and agg essi eness (Lanna e al., 2012). Dep ession e-
la ed side e ec s epo ed by epilep ic pa ien s ea ed wi h ANT–
DBS u he poin o a possible ole o ANT and i s ci cui s in a -
ec i e unc ions (Fishe e al., 2010;Möddel e al., 2012). ANT's
co ical connec ions, i.e. OFC and ACC, a e also in ol ed in emo ion
and execu i e unc ions (Bush e al., 2000).
We ha e p o ided unique ERP e idence om humans ha
ANT–DBS inc eases a en ion alloca ion o h ea - ela ed dis-
ac o s. Howe e , he cu en s udy does no add ess wha aspec
o he ci cui y o he han ANT a e in ol ed and how. We can only
specula e on he ole o o he b ain egions connec ed o ANT such
as he OFC and ACC ha may be in ol ed. The OFC plays an im-
po an ole in modula ing b ain's esponses o a ec i e s imuli by
fil e ing ask-i ele an a ec i e s imuli (Rule e al., 2002;Shi-
mamu a, 2000) as well as alloca ing a en ion o emo ionally e-
le an s imuli (Ha ikainen e al., 2012). Thus, inc eased a en ion
alloca ion o emo ional dis ac o s due o ANT–DBS migh ei he
eflec he OFC's dis up ed unc ion in fil e ing h ea - ela ed
dis ac o s o enhanced unc ion in alloca ing a en ion o hem.
On he o he hand, he dACC is hough o in eg a e in o ma ion
om o he b ain egions o de e mining and egula ing he allo-
ca ion o app op ia e amoun o execu i e con ol esou ces o he
la e al p e on al co ex (Shenha e al., 2013). Thus, wi h ANT–
DBS dis up ing inpu om ANT o ACC inadequa e alloca ion o
con ol esou ces o he la e al p e on al co ex would esul in
ine ficien op-down con ol o emo ional dis ac o s.
Deficien p e on al op-down con ol is hough o be a po-
en ial cause o g ea e a en ion alloca ion o nega i e emo ional
in o ma ion in mild auma ic b ain inju y wi h suscep ibili y o
dep ession (Mäki-Ma unen e al., 2015). Inc eased a en ion al-
loca ion o nega i e in o ma ion is also obse ed in dep ession
(Leppänen, 2006;Ma hews and Wells, 2000). Simila o dep es-
sion, g ea e a en ion cap u e by nega i e emo ional s imuli was
seen du ing ANT–DBS as e idenced by p olonged eac ion imes
Fig. 5. Inc eased a en ion cap u e by emo ional s imuli due o ATN–DBS. (A) G and a e age ERP o he cen o-pa ie al egion demons a ing N2–P3 peak- o-peak ampli ude
du ing ANT s imula ion. When ANT was s imula ed, N2–P3 peak- o-peak ampli ude was inc eased in con ex o emo ional dis ac o s compa ed o neu al dis ac o s.
(B) S imula ing he an e io halamic nuclei inc eased a en ional alloca ion o emo ional dis ac o s, as indica ed by inc eased N2–P3 ampli ude. The e was no di e ence in
N2–P3 peak- o-peak ampli ude be ween S imula ion S a uses o he same dis ac o .
Table 3
Cen o-pa ie al N2–P3 ampli udes o indi idual pa ien s.
Pa ien numbe ANT Con ol OFF
Emo ional Neu al Emo ional Neu al Emo ional Neu al
1 5.47 4.89 4.68 3.81 4.51 4.92
2 7.81 7.23 6.79 8.32 5.98 7.25
4 5.97 4.01 3.61 3.11 4.50 3.90
5 25.07 21.78 15.48 18.87 19.34 20.02
10 4.96 3.77 6.83 6.15 5.31 5.21
13 12.68 12.22 11.61 11.09 13.53 13.31
Table lis s ERP ampli ude in mic o ol s.
L. Sun e al. / Neu opsychologia 78 (2015) 88–9492

and inc eased cen o-pa ie al N2–P3 ampli ude in he con ex o
emo ional dis ac o s. Thus, we con end ha g ea e a en ion
cap u e by nega i e emo ional s imuli due o deficien on al
con ol migh be he neu al mechanism unde lying subjec i e
dep ession ela ed symp oms in ANT–DBS (Fishe e al., 2010;
Möddel e al., 2012).
The inc ease in cen o-pa ie al N2–P3 peak- o-peak ampli ude
in esponse o emo ional dis ac o s, along wi h emo ional in e -
e ence o RTs, p o ide possible bioma ke s o DBS e ec s on
limbic ci cui y and al e ed emo ion–a en ion in e ac ion possibly
linked wi h a ec i e symp oms. N2–P3 peak- o-peak ampli ude
measu e cancelling ou any o e lapping posi i e o nega i e slow
wa es o shi s makes i a mo e obus measu e han single N2 o
P3 peak measu emen , especially when used in pa ien popula-
ions such as epilepsy pa ien s wi h high in e -indi idual a ia-
bili y in ERP wa e o ms. Such bioma ke s o DBS e ec s on a -
ec i e unc ions ha e clinical significance especially when DBS is
used o ea ing dep ession (Maybe g e al., 2005) as well as when
ying o minimize a ec i e symp oms epo ed as side e ec s o
ANT–DBS (Fishe e al., 2010;Möddel e al., 2012).
Any po en ial bioma ke s o guiding he selec ion o DBS
pa ame e s owa ds bes ea men e ec wi h minimal side e -
ec s would be o u mos clinical impo ance gi en he as
numbe o possible pa ame e combina ions and complexi y o
esponses ha make pa ame e op imiza ion challenging. In cu -
en clinical p ac ice he e a e no e ficien ools o assessing he
immedia e e ec s o chosen s imula ion pa ame e s on cogni ion
and emo ion ha would help guide pa ame e selec ion owa ds
ei he wan ed a ec i e and beha iou al e ec s o minimal side
e ec s in a ious clinical popula ions amenable o DBS. Con-
comi an ly, he e a e no objec i e measu es o assessing al e a-
ions in emo ional unc ions. Applying a compu e -based eac ion
ime es engaging mul iple execu i e unc ions while apping in o
emo ion–a en ion in e ac ion and by compa ing ERPs du ing
di e en s imula o se ings as was done in he cu en s udy
shows ini ial p omise as an app oach ha migh allow one o
minimize neu opsychia ic side e ec s in DBS pa ame e selec ion.
While he cu en s udy p o ides no el e idence o ANT's ole
in human emo ion–a en ion in e ac ion, he e a e limi a ions. The
pa ien popula ion in his s udy was small and he e ogeneous and
se e al ac o s o he han DBS could a ec emo ion–a en ion
in e ac ion and ERPs in hese pa ien s, including epilep ic ac i i y,
unde lying epilepsy ae iology and pa ien medica ions. These
ac o s we e con olled o in he cu en s udy by applying a
wi hin-subjec design. Fu he , he cu en finding migh no be
gene alizable o clinical si ua ions whe e he s imula ion pa a-
me e s a e somewha di e en (Fishe e al., 2010). Whe he ANT–
DBS is impai ing he no mal op-down con ol o emo ion owa d
inc eased a en ion alloca ion o h ea o enhancing possibly
blun ed bo om-up influence o emo ional s imuli owa d no -
malized emo ion–a en ion in e ac ion is no clea om his s udy.
Fu u e s udies wi h mo e pa ien s a e equi ed o shed mo e ligh
on hese issues.
In addi ion o ANT, he halamus includes o he s uc u es
implica ed in emo ional pa hways and emo ion–a en ion in e -
ac ion, e.g. mammillo halamic ac (MacLean, 1949;Papez, 1937)
and pul ina (A end e al., 2015;Wa d e al., 2007). I is possible
ha hese s uc u es also con ibu e o he e ec s obse ed in his
s udy. In o de o dis inguish he gene al e ec s o b ain s imu-
la ion om he egion specific e ec s o ANT s imula ion a ha-
lamic con ol loca ion in he icini y o ANT a ew millime es
away owa d he medial halamus was also s imula ed. Unlike ANT
s imula ion, s imula ing he con ol loca ion did no esul in in-
c eased a en ion alloca ion o h ea - ela ed dis ac o s. Also,
since he halamus is a physically a la ge s uc u e, app oxima ely
3.5 cm in leng h, 2–2.5 cm in ans e se and app oxima ely 6.5–
7 cc in olume (Sen e al., 2005;Spinks e al., 2002), and he DBS
Volume o Tissue A ec ed (VTA) ela i ely small (Mon gome y,
2010), in ou case ew millime es om he s imula ion ocus wi h
5mA bipola s imula ion, we can assume ha he e ec o elec ic
s imula ion is local o ANT. Taken oge he , he small VTA and no
s imula ion e ec in he halamic con ol loca ion suppo he
specific ole o ANT and i s ne wo ks in emo ion–a en ion
in e ac ion.
In conclusion, his s udy elucida es he impo an ole o ANT in
emo ion–a en ion in e ac ion. By s imula ing ANT, inc eased a -
en ional esou ces we e alloca ed o emo ional dis ac o s, pos-
sibly indica ing ine ficien op-down con ol. Al e ed emo ion–
a en ion in e ac ion as a unc ion o ANT–DBS poin s owa ds ANT
as an in e sec ion o a en ion and emo ion ci cui ies. In addi-
ion, ANT–DBS inc easing a en ional alloca ion o h ea high-
ligh s he need o conside a ec i e side-e ec s in addi ion o he
Table A.1
A e age e o a es unde di e en S imula ion S a uses and wi h di e en emo ional dis ac o s.
S imula ion s a us Inco ec (%) Miss (%) Commission e o s (%)
Emo ional Neu al Emo ional Neu al Emo ional Neu al
ON a ANT 5.1 5.0 1.4 1.2 3.5 3.3
ON a Con ol 6.8 6.4 2.0 1.7 2.9 2.9
OFF 4.8 4.4 1.6 1.6 2.7 3.3
Table A.2
Summa y o s a is ical esul s o all e o ypes.
P edic o s Inco ec Miss Commission e o s
In e cep 0.07 (0.05–0.10) 0.01 (0.00–0.02) 0.00 (0.00–0.01)
S imula ion s a us:
ON a con ol 1.38 (1.00–1.92) 1.50 (0.83–2.69) 0.78 (0.51–1.20)
OFF 0.90 (0.66–1.21) 1.19 (0.70–2.03) 0.72 (0.49–1.05)
Emo ion:
Neu al 0.97 (0.68–1.38) 0.85 (0.44–1.63) 0.93 (0.61–1.43)
Emo ions imula ion s a us:
ON a con ol emo ion flowe 0.95 (0.59–1.51) 0.97 (0.41–2.29) 1.07 (0.58–1.98)
OFFemo ion flowe 0.94 (0.61–1.45) 1.00 (0.46–2.20) 1.37 (0.81–2.32)
Resul s o logis ic eg ession analysis o all e o ypes wi h Odds Ra io ollowed by 95% Confidence In e al in pa en hesis.
L. Sun e al. / Neu opsychologia 78 (2015) 88–94 93
he apeu ic e ec when op imizing DBS s imula o se ings.
Conflic o in e es
The au ho s decla e no conflic o in e es .
Acknowledgemen s
We hank P o esso Kei h H. Ogawa o his e iew and aluable
commen s on he manusc ip .
This esea ch was suppo ed by he Academy o Finland and he
Compe i i e Resea ch Fund o Pi kanmaa Hospi al Dis ic .
Appendices
see Table A.1 and A.2
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