Re e sible psychia ic ad e se e ec s ela ed o deep b ain s imula ion o
he an e io halamus in pa ien s wi h e ac o y epilepsy
Soila Jä enpää
a,b,
⁎, Jukka Pel ola
a,b
, Si pa Rainesalo
b
,EsaLeinonen
a,c
, Kai Leh imäki
a,b
, Kaija Jä en aus a
a,c
a
Uni e si y o Tampe e, Facul y o Medicine and Biosciences, Tampe e, Finland
b
Tampe e Uni e si y Hospi al, Depa men o Neu osciences, Neu ology and Rehabili a ion, Tampe e, Finland
c
Tampe e Uni e si y Hospi al, Depa men o Psychia y, Tampe e, Finland
abs ac a icle in o
A icle his o y:
Recei ed 2 Augus 2018
Re ised 7 Sep embe 2018
Accep ed 9 Sep embe 2018
A ailable online 2 Oc obe 2018
Objec i e: An e io nucleus o halamus (ANT) deep b ain s imula ion (DBS) is becoming a mo e common ea -
men o d ug- esis an epilepsy. Epilepsy and dep ession display a bidi ec ional associa ion. An e io nucleus o
halamus has connec ions o an e io cingula e co ex and o bi omedial p e on al co ex, hence, a possible ole
in emo ional and execu i e unc ions, and hus, ANT DBS migh exe psychia ic ad e se e ec s. Ou aim was o
e alua e p e ious and cu en psychia ic symp oms in pa ien s wi h epilepsy unde going ANT DBS su ge y and
assess he p edic abili y o psychia ic ad e se e ec s. P og amming- ela ed psychia ic ad e se e ec s a e also
epo ed.
Me hod: Twen y- wopa ien s wi h ANT DBS o e ac able epilepsy we e examined, and a psychia ic e alua ion
o dep essi e and o he psychia ic symp oms was pe o med wi h Mon gome y and Åsbe g Dep ession Ra ing
Scale (MADRS), Beck Dep ession In en o y (BDI), and Symp om Checklis p io o su ge y, concen a ing on o -
me and cu en psychia ic symp oms and medica ions. The ollow-up isi was one yea a e su ge y.
Resul s: A heg oup le el, no changes on mood we e obse ed du ing ANTDBS ea men . Two pa ien s wi h o -
me his o ies o dep ession expe ienced sudden dep essi e symp oms ela ed o DBS p og amming se ings;
hese we e quickly alle ia ed a e changing he s imula ion pa ame e s. In addi ion, wo pa ien s wi h no p e i-
ous his o ies o psychosis g adually de eloped clea pa anoid and anxie y symp oms ha also elie ed slowly
a e changing he p og amming se ings.
Conclusion: The majo i y o ou ANT DBS pa ien s did no expe ience psychia ic ad e se e ec s. Ce ain DBS pa-
ame e s migh p edispose o sudden dep essi e o slowly mani es ing pa anoid symp oms ha a e e e sible
ia p og amming changes.
© 2018 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY license (h p://
c ea i ecommons.o g/licenses/by/4.0/).
Keywo ds:
Deep b ain s imula ion
An e io halamus
Re ac o y epilepsy
Psychia ic symp oms
Side e ec s
1. In oduc ion
One- hi d o pa ien s wi h epilepsy do no espond adequa ely o an-
iepilep ic d ugs (AEDs) [1]. Epilepsy is defined as e ac o y when un-
con olled seizu es con inue a e wo o mo e app op ia e AED
ea men s [2].
Deep b ain s imula ion (DBS) is a p omising he apy o epilepsy. The
bila e al an e io nucleus o halamus (ANT) DBS has been s udied p e i-
ously [3–7]; in a double-blind andomized con olled ial, i was epo ed
o educe he equency o seizu es in pa ien s wi h e ac o y epilepsy
[8]. Since 2010, i has been CE (Con o mi é Eu opéenne)-app o ed o
epilepsy he apy in Eu ope, and i ecen ly ecei ed app o al om he
Food and D ug Adminis a ion (FDA) in he USA. The e is only limi ed
knowledge o he basic mechanisms o DBS o o he op imal s imula ion
pa ame e s. I has been sugges ed ha DBS dis up s o inhibi s epilep i o m
ac i i y in epilep ogenic halamoco ical ne wo ks [9].
The halamus is connec ed and unc ionally ela ed wi h he co ex
and limbic s uc u es. The ANT has a ole in seizu e ac i i y in bo h ab-
sence and ocal seizu es; mo eo e , i is a pa o he hippocampal sys-
em o episodic memo y and has connec ions wi h he an e io
cingula e and o bi omedial p e on al co ex. Th ough i s connec ions,
i may con ibu e o bo h emo ional and execu i e unc ions [10,11].
The ANT s imula ion has been epo ed o ac i a e he cingula e gy us,
insula co ex, and la e al neoco ical empo al s uc u es [12], which
Epilepsy & Beha io 88 (2018) 373–379
Abb e ia ions: AED, an iepilep ic d ug; ANT, an e io nucleus o halamus; AUDIT,
Alcohol Use Diso de s Iden ifica ion Tes ; BDI, Beck Dep ession In en o y; DBS, deep
b ain s imula ion; MADRS, Mon gome y and Åsbe g Dep ession Ra ing Scale; MRI,
magne ic esonance imaging; NPI, Neu opsychia ic In en o y; SCL-90, The Symp om
Checklis -90; SANTE, s imula ion o he an e io nucleus o halamus o epilepsy, ial;
VNS, agus ne e s imula ion.
⁎Co esponding au ho a : Depa men o Neu ology and Rehabili a ion, Tampe e
Uni e si y Hospi al, PL 2000, 33521 Tampe e, Finland.
E-mail add esses: soila.ja enpaa@pshp.fi(S. Jä enpää), jukka.pel ola@pshp.fi
(J. Pel ola), si pa. ainesalo@pshp.fi(S. Rainesalo), esa.leinonen@pshp.fi(E. Leinonen),
kai.leh imaki@pshp.fi(K. Leh imäki), kaija.ja en aus a@pshp.fi(K. Jä en aus a).
h ps://doi.o g/10.1016/j.yebeh.2018.09.006
1525-5050/© 2018 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/).
Con en s lis s a ailable a ScienceDi ec
Epilepsy & Beha io
jou nal homepage: www.else ie .com/loca e/yebeh
all ha e p ojec ions o amygdala,a s uc u e in ol ed in he ini ia ion o
emo ional esponses [13].
The e is a bidi ec ional associa ion be ween epilepsy and dep ession,
and he e could be some common pa hophysiological mechanisms un-
de lying he onse o epilepsy and psychia ic diso de s including de-
p ession and anxie y [14,15]. The e o e, ANT DBS migh impac
psychia ic signs and symp oms. The e a e a ew epo s o psychia ic
ad e se e ec s ela ed o ANT s imula ion. In he s imula ion o he an-
e io nucleus o halamus o epilepsy, ial (SANTE) s udy [8], he pa-
ien s in he ac i e s imula ion g oup epo ed mo e dep essi e
symp oms compa ed wi h he con ol g oup (sham). One dep ession
e en in he ac i e s imula ion g oup was se ious (suicide). Some, bu
no all pa ien s, who expe ienced dep ession had also a p io his o y
o dep ession. Subjec i e epo s o dep ession and memo y impai -
men s ha e also been epo ed [16].
The aim o he p esen s udy was o e alua e p e ious o p esen
psychia ic symp oms in pa ien s in ending o unde go an ANT DBS op-
e a ion and o e alua e i hese can p edic possible psychia ic ad e se
e ec s ha hey migh expe ience a e he ope a ion. The ypes o psy-
chia ic ad e se e ec s and also hei managemen a e desc ibed and
also epo ed he e.
2. Ma e ials and me hods
Twen y- wo pa ien s (14 males and 8 emales; 36 ± 11.5 yea s old)
wi h bila e al ANT DBS o e ac o y epilepsy pa icipa ed in his s udy.
The age o onse o epilepsy was 14 ± 8.6 yea s. The pa ien s we e se-
e ely ill; he mean equency o hei seizu es was 42/mon h. The
g oup was he e ogenic wi h espec o epilepsy ype, age o onse , med-
ica ions, and bu den o disease.
The pa ien s had hei ongoing AED ea men s, and he possible
psychia ic medica ions we e also con inued a he ime o ope a ion.
All pa ien s ga e w i en in o med consen . The s udy p o ocol was
app o ed by Tampe e Uni e si y Hospi al E hics Commi ee.
The DBS de ices we e implan ed by a neu osu geon in Tampe e Uni-
e si y Hospi al du ing Feb ua y 2010 o Ma ch 2016. The DBS elec-
odes (3389, Med onic, Inc.) we e implan ed unde gene al
anes hesia using a Leksell S e eo ac ic F ame (Elek a). The ini ial s e eo-
ac ic a ge was 5–6mmla e al,0–2 mm an e io , and 12 mm supe io
espec i e o he midcommissu al poin (MCP). The a ge was hen ad-
jus ed acco ding o each indi idual's ana omy in he 3-T magne ic eso-
nance imaging (MRI) (Siemens) sho au in e sion eco e y (STIR)
images by isualizing he mammillo halamic ac .
When he ope a ion was being planned, a psychia ic in e iew was
pe o med a baseline by an expe ienced psychia is concen a ing on
o me and cu en psychia ic symp oms and medica ions. The ol-
low-up isi was conduc ed a one yea a e he su ge y. The Symp om
Checklis -90 [17] (SCL-90) was pe o med o e alua e he subjec i e
psychia ic symp oms. Beck Dep ession In en o y [18] (BDI) and Mon -
gome y and Åsbe g Dep ession Ra ing Scale [19] (MADRS) we e used o
assess he p esence and se e i y o dep essi e symp oms. The Alcohol
Use Diso de s Iden ifica ion Tes (AUDIT) [20] was used o e alua e
he isks associa ed wi h alcohol use. Neu opsychia ic symp oms
we e inqui ed by using he Neu opsychia ic In en o y [21] (NPI). In-
c ease in sco e indica es inc eased se e i y in symp oms in all o he
es s used.
The s imula ion was ini ia ed using he op imal con ac s wi h a
ol age o 5 V, 90 μs pulse wid h, and 140 Hz equency. The cycling
was 1 min on and 5 min o . The con ac s o pa ame e s we e
changed acco ding o clinical judgmen o imp o e he s imula ion
esponse in elie ing epilep ic seizu es o due o psychia ic ad e se
e ec s.
Th ee-dimensional (3D) models o DBS elec odes, ANT, and olume
o ac i a ed issue we e cons uc ed wi h Med onic Su eTune II
so wa e using p eope a i e 3-Tesla MRI and pos ope a i e compu e
omog aphy (CT) scan usion images.
3. Resul s
The e was no significan psychia ic mo bidi y in he whole s udy
g oup. A baseline, he mean BDI sco e was 6.3 ( ange: 0–19), and
MADRS was 2.7 ( ange: 0–8) in 18 pa ien s (missing da a in ou pa-
ien s). A e one yea , he co esponding alues we e BDI: 7.8 ( ange:
0–24, 20 pa ien s, missing da a in wo pa ien s) and MADRS: 5.1
( ange: 0–11, 18 pa ien s, missing da a in ou pa ien s). Fi e pa ien s
we e being p esc ibed wi h psychia ic medica ion be o e he ope a-
ion: an idep essan s, an ipsycho ics, and diazepam (DZP). Clobazam
(CLB) and clonazepam (CLN) we e used o epilep ic seizu es. One pa-
ien had a his o y o se e e ansien psycho ic episodes o agg ession
and pa anoid delusions and men al con usion one yea be o e he DBS
ope a ion bu did no expe ience DBS- ela ed psychia ic ad e se e -
ec s la e . Some AED changes we e made du ing he ollow-up
(Tables 1 & 2), bu hese did no cause he imp o emen in seizu e con-
ol o mood changes in any o ou pa ien s.
Two pa ien s expe ienced sudden-onse dep essi e and melancholic
symp oms ha we e associa ed wi h p og amming. These symp oms
appea ed wi hin a ew days a e adjus ing he ini ial s imula ion pa-
ame e s; hese we e managed by ei he educing he s imula ion cu -
en o changing he con ac s. In one o he pa ien s (pa ien 2, Fig. 2),
his ook place a 1 mon h a e he ope a ion, and in he o he pa ien ,
a 1.5 yea s a e he implan a ion (pa ien 4, Fig. 4). Mo eo e , o he
kinds o psychia ic symp oms we e de ec ed in wo pa ien s; hese in-
cluded i i a ion, sleep dis u bances, anxie y, ea , and pa anoid symp-
oms. These symp oms de eloped slowly, o e mon hs, and we e
success ully managed also by adjus ing he s imula ion pa ame e s
and changing he ac i e con ac s (Figs. 1 & 3). The pa ien s wi h hese
ad e se e ec s and hei managemen a e desc ibed below ( ou case
examples). Bo h pa ien s wi h dep essi e ad e se e ec s had o me
his o ies o dep ession, bu none o hem had p e iously expe ienced
pa anoid o anxie y symp oms.
3.1. Pa ien 1 (Fig. 1)
A woman in he la e 40s had expe ienced ocal epilepsy since 33 yea s.
She was wo king as an assis an , and she li ed alone. He epilepsy was e-
ac o y despi e se e al AED ials. He seizu e equency anged om 14 o
34/mon h. This pa ien was no a candida e o esec i e su ge y. Vagus
ne e s imula ion (VNS) had been ied wi hou any esponse. She had
no o me psychia ic his o y. Le e i ace am (LEV) had induced some de-
p essi e hough s ha anished a e discon inua ion o he medica ion.
Immedia ely a e ANT DBS, she el mo e ac i e bu was no diagnosed
as being hypomanic. Monopola s imula ion was ini ia ed wi h ac i e con-
ac s 2/10 ( ol age: 4/4 V, he apeu ic cu en : 4/6.6 mA cu en , 90 μs
pulse wid h, and 140 Hz equency). A e six mon hs, he seizu e e-
quency was hal ed. Un o una ely, a e 10 mon hs o s imula ion, he pa-
ien epo ed sleep dis u bances and eeling dep essi e, and soon
a e wa ds, she began o eel pa anoid and annoyed. The change was insid-
ious and happened wi hou any clea igge ing ac o s. He ini ial psychia -
ic symp oms we e mild bu wo sened g adually o an ou igh psycho ic
s a e including delusions and e o omanic hough s. The e we e no signs
o deli ium, and he pa ien emained conscious and o ien ed h oughou .
She also began o expe ience psychogenic nonepilep ic seizu es along
wi h anxie y and low mood. The pa ien had expe ienced simila
nonepilep ic seizu es 8 yea s be o e, and hese we e confi med a ha
ime by ideo-elec oencephalog aphy (VEEG) as psychogenic nonepilep ic
seizu es. Ci alop am (CIT) 20 mg was p o ided o ea he dep ession and
anxie y. The s imula ion con ac s we e also changed o mo e c anial, ac i e
con ac s we e mo ed o 3 and 11, and he cu en was dec eased o 5.9 mA/
6.3 mA ( igh /le ). A e his ep og amming, he pa ien el be e , and
g adually, he psycho ic symp oms disappea ed. Ci alop am was con inued
40 mg/day, pa ien also had he ongoing AEDs: zonisamide (ZNS) 400 mg,
p egabalin (PGB) 600 mg, and lacosamide (LCM) 400 mg, que iapine 25
mg was adminis e ed in he e ening o sleep dis u bances, when
374 S. Jä enpää e al. / Epilepsy & Beha io 88 (2018) 373–379
necessa y. He seizu e equency imp o ed u he o h ee seizu es/mon h
(a 90% educ ion compa ed wi h p e-DBS baseline). He mood s abilized,
and he psycho ic symp oms had elie ed when e alua ed in he one-
yea ollow-up.
3.2. Pa ien 2 (Fig. 2)
A woman in he mid-20s had e ac o y epilepsy a e p esumed en-
cephali is since 8 yea s. She li ed alone and wo ked pa - ime as an assis-
an . He seizu es had ailed o imp o e wi h mul iple AED ials, and she
was no a candida e o esec i e su ge y. Vagus ne e s imula ion was
ied wi hou any meaning ul esponse. Epilep ic seizu es (bipa ie al sei-
zu e onse zone) occu ed 14 o 32 imes/mon h. She had had dep essi e
symp oms and an idep essan medica ion a e he onse o epilepsy bu
no be o e ha ime. She was ecei ing long-s anding and s ill ongoing
CIT 20-mg medica ion a he ime o ANT DBS ope a ion. A he baseline
psychia ic e alua ion, no dep essi e symp oms we e p esen .
S imula ion was induced wi h ac i e con ac s 2/10 ( ol age: 5/5 V,
90 μs pulse wid h, and 140 Hz equency). Vol age was g adually in-
c eased o 6.5 V, which induced melancholia, i edness, sadness, and so-
ma ic complain s which appea ed wi hin wo days. The e ec was seen
in BDI, she had a sco e o 33 poin s i.e., e idence o se e e dep ession.
This dep essi e e ec anished (BDI: 9) when he ol age was de-
c eased o 5 V, again wi hin wo days. Wi h hese pa ame e s, he e
was no change in he seizu e equency. When he con ac s we e
changed o 3, 10, and 11 wi h he same pa ame e s, he seizu e e-
quency was u he dec eased. Fu he mo e, changing he con ac s o
3 and 11, 5/4 V, he esponse o he s imula ion in seizu e equency
was e en be e , a 61% educ ion.
A simila eme gence o melancholia, sadness, c ying, and dep essi e
hough s was seen h ee imes when he cu en o pulse wid h in any
o he chosen con ac s was inc eased; and hese we e managed by de-
c easing he ol age and ul ima ely, by changing he con ac s mo e c a-
nial o 3 and 11. The AEDs used we e oxca bazepine (OXC) 1500 mg,
opi ama e (TPR) 400 mg, and CLB 20 mg. Ci alop am 20 mg was also
con inued.
3.3. Pa ien 3 (Fig. 3)
A man in hisla e 20s had e ac o y empo al lobe epilepsy due o bi-
la e al subependymal he e o opia since 10 yea s. The pa ien was no a
candida e o esec i e su ge y. Epilepsy was e ac o y; seizu es in he
pa ien had ailed o imp o e wi h mul iple AED ials, and epilepsy su -
ge y was also conside ed. Pos ic al neu opsychia ic symp oms o ag-
g ession and con usion had been p esen , bu he pa ien had no
o me o p esen psychia ic symp oms a he ime o he ANT DBS op-
e a ion. S imula ion was ini ia ed wi h ac i e con ac s 2/10 ( ol age:
2.5/2.5 V, 90 μs pulse wid h, and 140 Hz equency). The ol age was in-
c eased g adually o 6.5 V. One yea a e he ope a ion, he pa ien
s a ed o complain abou low mood, bu bo h BDI and MADRS sco es
indica ed aeu hymic mood (2and 5, espec i ely). In heSCL-90 assess-
men , obsessions and dep ession we e e iden , and he pa ien also el
anguished. He epo ed ea , i i a ion, and memo y p oblems. In e mi -
en pe iods wi h pa anoid hough s we e also p esen . Mi azapine
(MZP) 30 mg and ispe idone (RIS) 1 mg we e s a ed, which imp o ed
he si ua ion. Con ac s 3 and 11 we e added. The cu en was 10 mA on
each side. The seizu e equency was imp o ed by 80% as compa ed
wi h baseline, bu he pa ien s ill had pa anoid hough s, soma ic
Table 1
Responde s (n = 15). Age, yea s wi h epilepsy, and medica ion a e defined a he ime o implan a ion. Only AEDs and psychia ic medica ion a e de ailed. Responde s a us is defined by a leas a 50%
seizu e educ ion in he dominan seizu e ype a 1 yea a e he su ge y [22]. The case his o ies o he pa ien s 1–3a edesc ibedinmo ede ailin he ex .
Abb e ia ions: CBZ, ca bamazepine; CD, co ical dysplasia; CIT, ci alop am; CLB, clobazam; CLN, clonazepam; DZP, diazepam; ESL, eslica bazepine ace a e; LCM, lacosamide; LEV, le e i ace am; LTG,
lamo igine; MZP, mi azapine; NA, no a ailable; OXC, oxca bazepine; PGB, p egabalin; PHT, pheny oin; PSY, psychia ic; RIS, ispe idone; TPR, opi ama e; VPA, alp oic acid; ZNS, zonisamide.
Pa ien Sex Age Yea s wi h
epilepsy
AED/PSY medica ion (mg)
baseline →a 1 yea
BDI baseline→
a 1 yea
MARDS baseline→
a 1 yea
E iology Epilep ic zone
1 F 48 33 ESL 1600 →0, LCM 0 →400, PGB 600, ZNS 400 0 →02→5 Unknown Le occipi al
2 F 24 7 CLB 20, CIT 20, OXC 1500, TPR 400 7 →12 3 →5 Encephali is Mul i ocal
3 M 29 9 CBZ 100, CLB 10 →20, MZP 0 →30 0 →20→5 CD Mul i ocal
5 F 32 31 CLN 8 →6, PHT 200 1 →34→9 CD Le on al
6 M 30 18 CBZ 1200, CLB 30, CIT 10 →15 NA →13 NA CD Mul i ocal
7 F 26 19 OXC 1500 →1800, CLB 15, ZNS 400 →300 NA →4NA→0 CD Mul i ocal
8 F 36 10 CBZ 800, CIT 40 →30, DZP 0 →20, KTP 0 →600,
LCM 200, LEV 1000, RIS 2 →1, ZNS 400
5→01→0 CD Righ on al
9 M 23 14 CLB 20, LTG 150, VPA 1500, ZNS 400 14 →11 4 →2 Encephali is Mul i ocal
10 F 31 3 CLB 20, LCM 0 →500, OXC 1000, ZNS 500 →200 16 →16 6 →8Encephali is Mul i ocal
11 M 47 38 CBZ 400, CLB 15, ZNS 400 1 →71→4 Unknown F on al
12 M 49 44 CBZ 600, LCM 400 4 →72→9 Encephali is Righ empo al
13 M 40 32 CLB 20 →25, OXC 1650, ZNS 400 NA NA CD Mul i ocal
14 M 56 42 OXC 1800 0 →NA 0 →NA Unknown Mul i ocal
15 M 29 20 OXC 1800, VPA 1300, ZNS 200 19 →01→0 Unknown Righ on al
16 M 22 7 LCM 200, OXC 900, ZNS 500 7 →94→10 Encephali is Le hemisphe e
Table 2
Non esponde s (n = 7). Age, yea s wi h epilepsy, and medica ion a e defined a he ime o implan a ion. Only AEDs and psychia ic medica ion a e de ailed. Responde s a us is defined
by a leas a 50% seizu e educ ion in he dominan seizu e ype a 1 yea a e he su ge y [22]. One pa ien is ma ked wi h an as e isk; ha pa ien was s ill a non esponde du ing he fi s
yea , howe e , eaching esponding s a us la e wi h op imal s imula ion pa ame e s. The case his o y o pa ien 4 is desc ibed in mo e de ail in he ex .
Abb e ia ions: CIT, ci alop am; CLB, clobazam; ESL, eslica bazepine ace a e; LCM, lacosamide; LEV, le e i ace am; NA, no a ailable; OXC, oxca bazepine; PAM, pe ampanel; TPR,
opi ama e; VPA, alp oic acid; ZNS, zonisamide.
Pa ien Sex Age Yea s wi h epilepsy AED/PSY medica ion (mg)
baseline →a 1 yea
BDI baseline→a 1
yea
MARDS baseline→a 1
yea
E iology Epilep ic zone
4* F 54 35 LCM 500 →600, TPR 400 →300 7 →13 5 →9 Hippocampal scle osis + CD Le empo al
17 M 22 10 VPA 2500 NA NA Encephali is Mul i ocal
18 M 48 37 CLB 20 →40, LCM 400, OXC 1500 0 →12→2 CD Righ empo al
19 M 24 5 CLB 30, LEV 2000, OXC 1800, TPR 600 18 →24 8 →NA Unknown Le pa ie al
20 M 45 9 CIT 20, LCM 400, LEV 3000, OXC 1200 5 →11 2 →8 Unknown Righ on al
21 M 50 49 CLB 10, LCM 400, PAM 8 2 →40→0 Ischemic lesion Righ on al
22 F 31 8 ESL 2000, LEV 3000, ZNS 400 7 →NA 3 →NA Encephali is Mul i ocal
375S. Jä enpää e al. / Epilepsy & Beha io 88 (2018) 373–379
complain s, and sel -obse a ion. He did no con inue o ake he psy-
chia ic medica ions. His psychia ic symp oms we e g adually wo sen-
ing, and pa ien had become mo e pa anoid wi h agg essi e hough s.
The ac i e con ac s we e changed o 3 and 11, ol age was 6.5/6.5 V,
and pulse wid h was 90 μs wi h a equency o 140 Hz, which esul ed
in a educ ion in his psychia ic symp oms. In his case, he slowly ini i-
a ing, al e na ing, and g adually wo sening i i a ion, anxie y, and pa a-
noid hough s we e seen as ad e se e ec s o he s imula ion. His
symp oms became educed when mo e c anial con ac s we e chosen,
and he cu en was dec eased. This pa ien was a he simila wi h
case 1. He was p esc ibed wi h ca bamazepine (CBZ) 100 mg and CLB
10 mg as AEDs.
3.4. Pa ien 4 (Fig. 4)
This pa ien was simila o case 2. A woman in he mid-50s had em-
po al lobe epilepsy due o hippocampal scle osis and co ical dysplasia
since 34 yea s. She was also diagnosed wi h heuma oid a h i is. She
had had no o me psychia ic symp oms. Tempo al esec ion and
amygdalohippocampec omia was conduc ed a he age o 45 yea s.
A e epilepsy su ge y, she was ini ially seizu e- ee o o he seizu e
ypes excep au as. The ollowing AEDs we e used: CBZ 1050 mg and
TPR 200 mg. Fi e yea s a e he su ge y, seizu es wi h impai ed awa e-
ness (FIAS) eappea ed wi h inc easing equencies. Simul aneously,
he pa ien el dep essi e, and CIT 20 mg was s a ed om which she
benefi ed. Fi e yea s la e , ANT DBS was chosen o ea he pa ien 's
empo al lobe epilepsy. In he p eope a i e psychia ic in e iew, he
pa ien had no dep essi e symp oms, BDI: 7, MADRS: 5. She el ense
a e he su ge y and was a aid o he seizu es, and his induced some
anxie y in he pa ien . S imula ion was ini ia ed wi h bipola se ings,
con ac s 2 and 10 we e posi i e, and 3 and 11 we e nega i e ( ol age:
3.5/4 V, 90 μs pulse wid h, and 140 Hz equency). The cu en was
g adually inc eased o 6 mA, and a e 6 mon hs, he seizu e equency
was dec eased by 75% compa ed wi h baseline. The minimal dep essi e
symp oms and he ea o seizu es had become alle ia ed; CIT was
discon inued. None heless, he seizu e equency was no op imal.
S imula ion was changed o being monopola , ac i e con ac s we e 3
and 11, ol age 4.5/5 V, o he pa ame e s we e no changed. Wi h
hese se ings, he pa ien expe ienced again sudden dep essi e
hough s, bu when he cu en was dec eased o 7 mA bila e al, he de-
p ession anished. Ra ing scale was no collec ed du ingsudden dep es-
si e hough s. The o al seizu e equency was imp o ed by 32% when
compa ed wi h baseline.
4. Discussion
A he g oup le el, no significan changes on mood we e obse ed
a e ANT DBS ea men in ou s udy. Two pa ien s expe ienced ab up
dep essi e symp oms ela ed o he DBS p og amming se ings; hese
we e quickly alle ia ed by dec easing he in ensi y o he s imula ion
bu wi hou changing he ac i e con ac s. In addi ion, wo pa ien s g ad-
ually expe ienced pa anoid and anxie y symp oms which again im-
p o ed slowly a e changing he p og amming se ings om con ac s
in e io o ANT o ones inside ANT.
In line wi h p e ious s udies [8,23], he e we e no se e e psychia ic
ad e se e ec s in hese 22 pa ien s who unde wen ANT DBS o e ac-
o y epilepsy. Mo eo e , he ou mode a e psychia ic ad e se e ec s
could be clinically managed by ep og amming he s imula o in collab-
o a ion wi h specialis s. P e iously, dep ession has been epo ed o
wo sen in some pa ien s who had had a p e ious dep essi e his o y
[23,24], howe e , i has no been p e iously epo ed ha he e can be
a sudden appea ance and disappea ance o dep ession wi h hese fluc-
ua ions being dependen on he s imula ion pa ame e s. I is ue ha
he p esen pa ien s wi h dep essi e ad e se e ec s had p e iously ex-
pe ienced dep ession, and he e o e, i may be conside ed as a p edis-
posing ac o . Pa anoid and anxious eac ions occu ed a e he
s imula ion, a phenomenon ha has also no been demons a ed be o e.
This eac ion scena io appea s o be ela ed o he s imula ion o deep
s uc u es benea h he ANT, and i has a g adual onse . I is impo an
o ecognize hese symp oms and eac ea ly since se e e dep essi e
and pa anoid symp oms may endange he success o he whole ea -
men . On heo he hand, he desc ibed symp oms we e ansien in na-
u e and e e sible a e changes o he s imula ion pa ame e s.
Fig. 1. Pa ien 1. The s imula ion wasini ia ed wi h con ac s 2 and 10. G adually, he pa ien s a ed o expe iencea change in mood and had eelings o being moni o ed and ea esd opped.
Biza e hough s i.e., eeling ha she was magne ic s a ed o appea (a). The s imula ed con ac s we e changed o being mo e c anial o 3 and 11 and he psycho ic symp oms s a ed o
dissipa e (b).
376 S. Jä enpää e al. / Epilepsy & Beha io 88 (2018) 373–379
Pa ien s wi h e ac o y epilepsy a e a e y he e ogeneous g oup
wi h ega d o e iology, seizu e bu den, medica ion, and le el o cogni-
i e abili ies. When e alua ing mood and cogni i e unc ions be o e and
a e DBS, he e a e se e al con ounding ac o s ha need o be consid-
e ed. The psychia ic e alua ion is challenging in his pa ien g oup al-
hough BDI and MADRS can be used o assess dep essi e symp oms
and hei se e i y. By using he SCL-90, he psychia ic symp oms can
also be de ec ed, bu e y o en, pa ien s wi h epilepsy a e ea ul
abou hei seizu es and a e suscep ible o sel -obse a ion, and hese
symp oms can be alsely in e p e ed as anxie y. The benefi o SCL-90
is he possibili y o compa e he symp oms a di e en ime poin s.
The bu den o disease is also a ac ha should be conside ed.
Mood diso de s and cogni i e decline a e common como bidi ies o
epilepsy, and hus, he e ec s o DBS on psychia ic and neu opsycho-
logical s a es ha e a ac edinc easing in e es . Acco ding o he cu en
e idence, significan s imula ion- ela ed and pe sis en psychia ic
symp oms a e in equen in ANT DBS pa ien s [25–27]. In ou sample,
when hese symp oms did eme ge, hey we e e e sible wi h educ ion
in s imula ion. Mild educ ions did no impede seizu e con ol. In a an-
domized con olled ial, a subjec i e de e io a ion o mood and memo y
was epo ed du ing a blinded phase [8]. In he long- e m ollow-up,
mos neu opsychological es esul s imp o ed [8,23,24]. The majo i y
o pa ien s wi h sel - epo ed and objec i ely assessed dep ession had
p eexis ing dep ession [24]. This was also he case in ou wo pa ien s
wi h dep essi e ad e se e ec s. One s udy epo ed a de e io a ed e-
sponse inhibi ion and imp o ed a en ion alloca ion owa ds a h ea in
ANT DBS pa ien s [28]. I has been claimed ha ANT DBS migh exe pos-
i i e e ec s on mood [8,24], e balfluency, and delayed e bal memo y
[29] a 1–2 yea s a e su ge y, hough he concu en seizu e educ ion
means ha he in e p e a ion o hese esul s is suscep ible o con ound-
ing. A ol age-dependen sleep dis up ion caused by ANT DBS has been
epo ed; his may be ela ed o subjec i e symp oms o cogni ion and
mood [30]. Psycho ic and dep essi e symp oms ha e been sugges ed o
be associa ed wi h d ama ic educ ion o seizu e equency —aphenom-
enon e e ed o as o ced no maliza ion [31].
These pa ien s we e ca e ully e alua ed be o e he su ge y, and he
clinical e alua ion and managemen o possible psychia ic ad e se e -
ec s we e conduc ed in close collabo a ion wi h a neu osu geon, a neu-
ologis , and a psychia is . The ad e se e ec s desc ibed he e we e all
managed by changing he s imula ion pa ame e s. The e seemed o be
a pa e n o he sudden appea ance o a dep essi e e ec in esponse
o a high cu en , and he e may be caudal con ac s ha we e also man-
aged apidly by adjus ing he pa ame e s. A he g oup le el, a his o y o
psychia ic symp omsdid no seem o p edispose o psychia ic ad e se
e ec s o ANT DBS, al hough wo pa ien s wi h dep essi e ad e se e -
ec s had p e ious his o ies o dep ession. Mo eo e , he eelings o
pa anoia and anxie y we e mo e slowly appea ing and ha de o de ec
psychia ic ad e se e ec s; hey we e also managed wi h
ep og amming, bu he eco e y was slowe . Al hough, e en hese ad-
e se e ec s we e clinically managed, in a wo s -case scena io, hey
could well jeopa dize he success o DBS ea men . The sudden appea -
ance o se e e dep ession may lead o se ious consequences. Mo eo e ,
he pa ien wi h pa anoid hough s insis ed ha he de ice should be
emo ed. In addi ion, he compliance wi h psychia ic medica ions
and ea men s can be poo in hese occasions. Mo eo e , when he i -
i able eelings, anxie y, and pa anoid hough s a e ansien andfluc u-
a ing, hey migh be ha d o de ec du ing clinical ou pa ien
appoin men s o se ings. The e o e, he close collabo a ion be ween
psychia is s, neu ologis s, and neu osu geons is c ucial.
O e all, he majo i y o ou ANT DBS pa ien s did no expe ience
psychia ic ad e se e ec s. Al hough, ce ain DBS pa ame e s migh
p edispose o he sudden appea ance o dep essi e o slowly mani es -
ingpa anoid symp oms, hese we e ound obe e e sible ia p og am-
ming changes. I le un ea ed, hese symp oms migh comp omise he
ANT DBS ea men . Because o sel - epo ed dep ession and memo y
p oblems and he c ucial posi ioning o he ANT wi hin he Ci cui o
Fig. 2. Pa ien 2. (a) Con ac s 3/10/11 we e ac i a ed o s imula ion, which esul ed in an
inc ease in he cu en om 5.8 mA on he le and 5.9 on he igh o 6.1 mA on he le
and 9.3 mA on he igh . The pa ien de eloped dep essi e symp oms. (b) The ol age
was swi ched o 5 V on he le and 4 V on he igh . This esul ed in a dec ease in he
cu en and a disappea ance o dep essi e symp oms. (c) Vol age was aised om
bila e al 5 V o bila e al 6.5 V, which led o he appea ance o new dep essi e
symp oms. (d) Adjus ing he ol age back o bila e al 5 V elimina ed he dep essi e
symp oms. (e) Pulse wid h was inc eased om 150 μs o180μs again inducing
dep essi e symp oms. ( ) Reducing he pulse wid h back o 150 μs elimina ed he
dep essi e symp oms.
377S. Jä enpää e al. / Epilepsy & Beha io 88 (2018) 373–379

Papez, a epu ed egula o o mood and memo y, i is ecommended
ha a neu opsychological and psychia ic e alua ion o ANT DBS
pa ien s should be done ou inely p io o and a e he su ge y.
The cu en e idence on psychia ic ad e se e ec s has been mos ly
limi ed o s udies wi h small sample sizes and con ounding ac o s.
Mo e s udies wi h eliable designs, s anda dized neu opsychological
and psychia ic assessmen p o ocols, and la ge sample sizes will be
needed o in es iga e he independen e ec s o ANT DBS and he
significance o pa icula s imula ion pa ame e s on mood and
cogni ion.
Fig. 3. Pa ien 3. (a) Ini ially s imula ed wi h con ac s 2 and 10, deepe con ac s 1 and 9 we e also ac i a ed o s imula ion. The pa ien s a ed o eel anxious soon a e he change.
Psychia ic symp oms we e elie ed by ini ia ion o RIS he apy. The pa ien con ac ed doc o s and nu ses equen ly wi h o e ly long incohe en messages; he s a ed o expe ience
psycho ic symp oms and epea edly e used ep og amming o DBS con ac s. Th ee yea s a e he ini ia ion o s imula ion wi h deep con ac s, he pa ien was ne ous and ense a
he ollow-up appoin men and was ound in he clinic's ba h oom in a con used s a e. (b) Finally, he pa ien consen ed o changing he s imula ed con ac s o he uppe mos 3 and
11. A e his change, he psycho ic symp oms became g adually elie ed.
Fig. 4. Pa ien 4. The cu en inc eased om 6.8 mA o 9 mA on he le and om 6.6 mA o 8.3 mA when ansi ioning om bipola s imula ion o anodes 2 and 10 and ca hodes 3 and 11
(a) o monopola s imula ion o 3 and 11 (b). The pa ien s a ed expe iencing dep essi e symp oms, which we e elie ed by lowe ing he ol age on he le om 4 V o 3.5 V while
ol age on he igh emained a 4.5 V. This lowe ed he cu en s o 7.1 mA on he le and 7.4 mA on he igh and esul ed in elie o he dep essi e symp oms and a dec ease in he
seizu e equency.
378 S. Jä enpää e al. / Epilepsy & Beha io 88 (2018) 373–379
Au ho s and con ibu o s
SJ con ibu ed o s udy concep ion, c ea ing o 3D-models, and
d a ed he manusc ip . JP con ibu ed o s udy concep ion, neu ological
ollow-up, and d a ed he manusc ip . SR con ibu ed o pa ien ollow-
up and analysis and d a ed he manusc ip . EL con ibu ed o d a ing
o he manusc ip . KL con ibu ed o s udy concep ion and d a ed he
manusc ip . KJ con ibu ed o s udy concep ion, psychia ic in e iews
and e alua ions, and d a ed he manusc ip .
Acknowledgmen s
The skill ul assis ance o epilepsy nu ses Ki si Na i and Sa u Hie ala
is g ea ly acknowledged. The con ibu ion o so wa e de elope Joni
Jä enpää and o figu e edi ing is app ecia ed.
E hics s a emen
The s udy was app o ed by he E hics Commi ee o Pi kanmaa Hos-
pi al Dis ic . W i en in o med consen was ob ained om each o he
pa ien s.
Funding
This wo k was suppo ed by he Compe i i e S a e, Resea ch Financ-
ing o he Expe Responsibili y a ea o Tampe e Uni e si y Hospi al.
Conflic o in e es decla a ion
SJ and SR decla e no conflic o in e es . JP has ecei ed speake and
consul a ion ees om Med onic. KL has ecei ed speake hono a ia
om Med onic, Bos on Scien ific, and Abbo . KJ has ecei ed lec u e
ees om Med onic, O suka Pha maceu ical, and Lundbeck and has
been sponso ed o a el and a end o a medical cong ess by
Med onic.
Da a sha ing
Addi ional unpublished da a om he s udy a e a ailable o psychi-
a ic, neu ological, and neu osu gical pa ien files and psychia ic in e -
iew es esul s accessible o all he au ho s. Also, ull pa ien
demog aphics and dia ies o pa ien isi s, da ed s imula ion pa ame-
e s, and mon hly seizu e equencies a e a ailable. Th ee-dimensional
modeling o implan ed DBS con ac s c ea ed in Med onic Su eTune 2
a e a ailable o SJ and KJ.
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