programming for stimulation-induced transient nonmotor psychiatric...

Research ArticleProgramming for Stimulation-Induced Transient NonmotorPsychiatric Symptoms after Bilateral Subthalamic Nucleus DeepBrain Stimulation for Parkinson’s Disease

XiWu,1 Yiqing Qiu,1 Keith Simfukwe,2 Jiali Wang,1 Jianchun Chen,1 and Xiaowu Hu1

1Department of Neurosurgery, Second Military Medical University, Changhai Hospital, No. 168 Changhai Road, Yangpu District,Shanghai, China2Department of Neurosurgery, Changhai Hospital, Second Military Medical University, International College of Exchange,No. 800 Xiangyin Road, Shanghai 200433, China

Correspondence should be addressed to Xiaowu Hu; huxiaowu [email protected]

Received 24 April 2017; Revised 21 June 2017; Accepted 10 July 2017; Published 15 August 2017

Academic Editor: Helio Teive

Copyright © 2017 Xi Wu et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamicnucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine theelectrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motorfunctions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwentprogramming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In thesepatients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients werediagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In onepatient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in onepatient, while five patients recorded eight episodes of hypomania.Therewere no statistical differences between theUPDRS-III underthe final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (𝑝 = 1.000). Conclusion. Theflow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatmentof these symptoms are effective.

1. Introductions

Subthalamic nucleus deep brain stimulation (STN-DBS) isan effective therapy which ameliorates motor manifestationssuffered by patients with idiopathic Parkinson’s disease (PD).The hallmark symptoms in PD patients include tremor,rigidity, and bradykinesia. STN-DBS has been documentedto be well tolerated by PD patients withmarked improvementof motor functions even after over ten-year follow-up [1–3].The limbic system innervates the limbic part of STN andother anatomic surrounding structures that lay in proximity[4]. As a result, the likelihood of accidental tempering ofthese nearby anatomical structures during STN-DBS mayresult in psychiatric symptoms called stimulation-inducedtransient nonmotor psychiatric symptoms (STPS), which are

clinically manifested as depression [5], anxiety [6], apathy[7], explosive-aggressive behavior [8], manic episode [9],mirthful laughter [10], impulse control disorders [11], andso forth. Like other nonmotor functions, in some instances,STPS may have a drastic impact on a patient’s life qualityof life. [12]. It has been noted that the stimulation param-eters which induce STPS are usually higher than normal.Decreasing stimulation intensity on the Implantable PulsarGenerator (IPG) may eliminate STPS. However, patients’motor functions may also be exacerbated. Changhai HospitalNeurosurgery Department conducts more than 160DBSimplantation surgeries every year. Since December 2014,the therapeutic center for Parkinson’s disease in ChanghaiHospital, Shanghai, China, has designed and implemented(1) an algorithm that identifies specific electrode contacts

HindawiParkinson’s DiseaseVolume 2017, Article ID 2615619, 14 pageshttps://doi.org/10.1155/2017/2615619

https://doi.org/10.1155/2017/2615619

2 Parkinson’s Disease

Figure 1: Merging SWI sequence with postoperation CT to deter-mine the electrode position.

that induce STPS (2) a programming protocol to eliminateSTPS. This study aim is to assess the effectiveness of thesealgorithms.

2. Materials and Methods

2.1. Patients. After acquiring approval from the Ethics Com-mittee of Changhai Hospital, we retrospectively analyzed allpatients with idiopathic Parkinson’s disease who receivedclinical programming of implanted bilateral STN-DBS in theDBS programming clinic of Changhai Hospital, Shanghai,China, from January 1, 2015, to December 31, 2015. Patientswho are being initiated on DBS, as well as those receivingfollow-up programming sessions due to various reasons afterachieving optimal stimulation parameters, were included inthe present study. The UK PD Brain Bank diagnostic criteriawere adopted for the diagnosis of idiopathic Parkinson’sdisease.

2.2. Mapping the Active Contact. If the active contact is notwithin the STN, the programming protocol may be lesseffective. Therefore we reviewed intraoperative MRI of allthe patients with Leksell G frame and indicator to confirmthe electrode location. The Medtronic S7 Neuro NavigationSystem (Medtronic Navigation, Louisville, USA) was used tomerge preoperative 3.0T-MRI images with postoperative CTimages.TheCT scan imageswere calibrated at 1mm thicknessand without pneumocranium (Figure 1). It was essential thatthe active contact center is placed within the boundaries ofthe STN. Patients with the active contact center outside STNboundary were excluded from this study.

2.3. Motor Assessment. Patient’s motor function was gradedusing the Unified Parkinson’s Disease Rating Scale Part III(UPDRS-III, 1998 edition). All patients included in this

study were assessed preoperatively, postoperatively and then,finally, before and after the occurrence of STPS. All clinicianswho administered the Unified Parkinson’s Disease RatingScale in this study are board-certified with the InternationalParkinson and Movement Disorder Society.

2.4. Cognitive and Psychiatric Assessment. All patients withSTPS were enrolled in this study. Patients that had any mildpsychiatric episodes that occurredmore than twice as a resultof programming (increasing) the electrode power parametersat home by oneself or caregivers were enrolled in this study.Episodes of acute psychiatric symptoms during or after theclinic programming procedures were also enlisted. Patientswith psychiatric symptoms similar to the preoperative onesor had changed medication dose in less than one month wereexcluded. This was because it would be difficult to confirmwhether the symptoms were induced by electric stimulationor not. So, only new postoperative psychiatric symptomswere regarded as suspicious STPS. The litmus test for STPSidentification was defined by (1) psychiatric symptoms ofpatients which improved after decreasing stimulation inten-sity in 30 minutes; however, this could also confirm that theSTPS was induced by stimulation because it occurred at thetime when stimulation intensity was increased to improvethe patient’s motor functions, (2) patients who must have nosimilar history of psychiatric symptoms and upon clinicalprogramming have shownmarked improvementwithin threemonths without any change in the medication, and (3)identification of causative STPS active contact.

Cognitive and depressive symptoms were evaluated pre-operatively and graded using Unified Parkinson’s DiseaseRating Scale Parts I and II (UPDRS-I and UPDRS-II), theMini-Mental State Examination (MMSE), and the 17-itemHamilton Depression Scale (HAM-D-17). Mania type STPSwas graded using the Young Mania Rating Scale (YMRS)[13].TheYMRSwas calculated using patient collateral historyfrom caregivers and direct observation by the physicians.Patients with STPS while being initiated on IPG wererecorded using preoperative evaluation results only.

2.5. Assessment of STPS and Recording of Stimulation Param-eters. Patient’s collateral history regarding unusual psychi-atric symptoms recorded in programming sessions wasreviewed. Stimulus parameters (active, stimulating contacts,stimulating pattern, voltage/current, pulse width, and fre-quency) were recorded following the occurrence of STPS.Changes and the final status of stimulation parameters inprogramming sessionswere also recorded. Electrode contactsinducing STPS and programming protocols were determinedaccording to previously established flow diagrams (Figures2 and 3). The disappearance of STPS was determined by norelapse of similar psychiatric symptoms for three monthsafter programming.

2.6. Statistical Analysis. Paired-sample 𝑡-test was used toexamine for changes of variables in UPDRS-III duringclinical evaluation. 𝑝 < 0.05 was considered statisticallysignificant.

Parkinson’s Disease 3

Suspected episode of STPS

Symptoms inremission

Acute symptomsPresent

Bilateral adjustment in the last programming

Unilateral adjustmentin the last programming

Bilateral adjustment in the last programming

Unilaterally adjustment in last programming

Adjust single contact Adjust multiple contacts

Con�rm responsible contact Turn o� lower contacts

STPSs disappear?

Do STPSs disappear inassessment when all le�contacts switched to OFF?

NoYes

Yes, le�No, right

STPSs remain with allcontacts turned o� Diagnosis error of STPS

Increased single contactstimulation power last time

Increased multiple contactsstimulation power last time

10 min

Teach patient waiting forsimilar STPS for 2 weeks

Turn voltage to 0 V bypatient or caregiver, thenSTPS relieved in 15 min?

Had other suspectedactivated contacts?

Do STPSs appear?

Con�rm responsible contact

No Yes

Yes

No

Retain the lowest contacts and recoverthe other contacts parameters

Test for single contact

Test the other contacts

Resumption of right electrode parameters and follow-up for 2 weeks

Relapse, le� sideNo relapse, mean right side

Yes

No

DescriptionCon�rmation of electrode positionCon�rmation of causative contact

Figure 2: Flow diagram to determine electrode contacts inducing STPS.

3. Results

3.1. Baseline Data. There were three groups of patientsenrolled in this study: (1) the first group is comprised of 145patients undergoing DBS initiation 1 month postoperativelyfor optimal programming parameter; (2) the second grouphad 231 patients who underwent DBS less than one yearpostoperatively; (3) finally, the third group had 166 patientswho underwent DBS more than one year postoperatively.There were a total number of 1142 episodes of clinicalprogramming for the purpose of adjusting the stimulationparameters in the second and third groups. There were 20episodes of STPS that occurred in 11 patients (6 females and5 males). The mean age at the time of DBS surgery was63.45 ± 8.27 years. Themean duration between identificationof Parkinsonian symptoms and DBS surgery was 11.91 ±3.33 years. Cognitive functional impairment was excluded inall patients. Only six patients received antidepressant drugsbefore and after surgery, while the rest of the patients had noobvious depression symptoms. Preoperatively, patients weregiven an average Levodopa Equivalent Daily Dose (LEDD) of942.5 ± 232.7mg. Postoperatively, before the STPS occurred,the LEDD was reduced to 404.5 ± 353.3mg. By the time pro-gramming eliminated STPS at 3 months after programming,

the LEDD had further reduced to 284.5 ± 187.8mg.The UPDRS-III improvement rate between postoperative(med-off time) status and preoperative (med-off time) statuswas 35.14∼72.34% at 3 months after programming. When wecompared the baseline data of STPS + patients versus STPS −patients to characterize patients inherent risk factors forSTPS, no significant statistical difference was found betweengroups (see Table 1).

3.2. STPS Occurrence. During the programming, 20 episodesof STPS occurred in 11 patients. These psychiatric symptomsconsisted of four (04) episodes of crying in two (02) patients,four (04) episodes of inexplicable euphoria or mirthfullaughter in two (02) patients, two (02) episodes of spatialdisorientation in one patient, two (02) episodes of hallucina-tion in one patient, and eight (08) episodes of hypomania infive (05) patients. In five (05) patients, STPS occurred duringtitration adjustment for optimal programming parameterin the first year after devices were implanted, while two(02) patients showed psychiatric symptoms two days afterbeing started on IPG and discharged from the hospital.For patients who had implanted devices for more thanone year, three (03) developed STPS during programmingsessions. Manifestations of patients during STPS episodes


Maintain the voltage andswitch to bipolar electrodes

Reduce voltage and increasepulse width from (A)

Decline voltage and frequency and increase pulse width from (D)

Decrease voltage, frequency, andinterleaving of dorsal contacts

Change to dorsal contacts from (A)

Reduce voltage by 0.3 V–0.5 V until SITNPS disappears

Monopolar Bipolar Double polarInterleaving

Motor symptoms poorlyimproved

STPSs relapse

STPSs relapse ormotor symptomspoorly improved

STPSs relapse

Motor symptoms poorlyimproved

Motor symptomspoorly improved orSTPS remained

(A)

(B)

(C)

(D)

(E)

(G)

(F)

Figure 3: Programming protocol flow diagram (After determining STPS causative active contacts with Figure 2, (A) record the initialparameters and programming according to the stimulation mode; (D) recover the initial parameters and reduce voltage 0.3 V–0.5V andincrease pulse width by 10–20 𝜇s; (E) if STPS relapsed, then reduce voltage 0.1–0.3 V and reduce frequency 10–30Hz, increase pulse width10–20𝜇s, and keep the total electrical energy delivered (TEED) equal to the counterpart of (D), TEED = voltage2 × frequency × pulsewidth/impedance; (F) decrease frequency to 125Hz and decrease voltage 0.3–0.5 V, and keep the TEED equal or slightly higher to thecounterpart of (D) or (E); activate the other dorsal contact with interleaving mode.).

were described in Table 2.The stimulation parameters beforethe onset of STPS were listed in Table 3.

3.3. Programming of STPS and Motor Functions. Followingthe adjustment of stimulation parameters (Table 3), tenpatients maintained the improvement of motor functionswith psychiatric symptoms eliminated.The adjustments werebased on the algorithms as follows: (1) the stimulation voltagedecreased while the pulse width increased in 2 patients(numbers 1 and 11); (2) the voltage was maintained whileswitching to bipolar stimulation in 2 patients (numbers 2and 7); (3) voltage and frequency were decreased with pulsewidth increased in 1 patient (number 9); (4) voltage andfrequency were decreased while switching to interleavingstimulation in 3 patients (numbers 3, 4, and 10); (5) theactivation contacts were replaced with dorsal ones in 2patients (numbers 5 and 8). One patient (number 6), aftermultiple programming sessions, developed concurrentmotorand nonmotor functions, and UPDRS-III score increasedby 2 points under the final stimulation parameters by herchoice (see details of the programming duration in Table 4).There were no statistical differences between the UPDRS-IIIunder the final stimulation parameter (without STPSs) andoptimum UPDRS-III under the STPSs (26.45 ± 10.59 versus26.45 ± 10.17, 𝑝 = 1.000).

4. Discussion

4.1. The Clinical Value of Programming Algorithms for STPS.Since the application of STN-DBS in the treatment of PDpatients, there have been sporadic reports [10] noting STPSs,as one of the side effects. The development of these pro-gramming algorithms is aiming to reduce the ambiguityin the management of STPS. The ambiguity was on thepredisposition of the following. (1) In earlier studies, STPSwas implicated with stimulation of the medial and inferiorpart (limbic part) of STN. However, recent studies show theiractive contacts located in the dorsolateral (sensorimotor) areaof STN [14] which also induces STPS. Because of this reason,the limbic and sensorimotor regions of the STN overlapwere greater than what has been previously reported [15].In this study, we also found that the active contacts whichinduced STPS were located at a medial and inferior partof the STN in seven (07) patients. In the other four (04)patients, the active contacts were located in the lateral partof STN which also induced STPS. This is similar to whatwas reported by Abulseoud and colleagues [14]. For thisreason, we concluded that the side effects of STPS are difficultto avoid by just implanting contacts into dorsolateral STN.(2) Secondly, under the routine stimulation parameter, thespherical radius of active volume (without contacts volume)


Table1

(a)Ba

selin

eclin

icaldataof

patie

ntsw

hodevelopedST

PS.

Age

Gender

Duration

(year)

MMSE

HAMD

(𝛼)

LEDDpre-op

(mg)

LEED

STPS

Emerged

LEDD3m

post-

STPS

(mg)

UPD

RSI

UPD

RSII

UPD

RS-III

UPD

RSIV

Pre-op

med-off

Pre-op

med-on

PD1

61M

1729

19(14

)1200

1200

550

817

4713

3PD

252

M14

2910

900

125

125

418

4115

6PD

359

F8

3021

(16)

768

325

300

724

5326

9PD

474

M7

2610

563

175

175

631

3724

11PD

561

M8

2917

(10)

825

825

280

511

4315

10PD

658

M11

2630

(17)

1100

325

325

1018

7542

4PD

752

F15

2711

963

7575

213

7034

3PD

875

F13

2716

1287

300

200

420

8137

8PD

972

F10

288

787

250

250

413

2716

4PD

1064

F13

2624

(13)

750

150

150

516

5128

7PD

1170

F15

2730

(16)

1225

700

700

922

6331

10𝛼:post-a

ntidepressiontre

atment;LE

DD:L

evod

opaE

quivalentD

ailyDose.

(b)Com

pare

theb

aselined

atao

fSTP

Spo

sitiveV

ersusS

TPSnegativ

epatients.

STPS

+ST

PS−

𝑝value

Patie

nt11

443𝛽

Age

63.45±8.28

62.05±7.7

80.555

Dise

ased

urationto

DBS

11.91±

3.33

9.95±4.03

0.112

LEDDpre-op

(mg)

942.55±232.67

836.32±393.79

0.374

UPD

RS-IIImed-offpre-op

53.45±16.94

52.46±14.24

0.819

UPD

RS-IIImed-onpre-op

25.55±9.9

125.80±11.14

0.940

MMSE

27.64±1.4

327.07±2.57

0.463

HAMDbefore

receivingantid

epressantd

rug

17.82±7.8

520.71±

6.21

0.130

𝛽:443

patientsincludedthreeg

roup

s:145p

atientsinitiatedtheIPG

and99

ofthem

achieved

theo

ptim

alprogrammingp

aram

etersb

eforethe

study

was

finish

ed;the

99patie

ntsa

ndother132

patie

ntwho

achieved

theo

ptim

alprogrammingparametersreceivedST

N-D

BSforlessthanon

eyear.166patie

ntsh

adreceived

STN-D

BSform

orethanon

eyear:145+132+166=44

3.


Table2:Clinicalmanifestations

ofST

PS.

Num

ber

Descriptio

nof

episo

deRe

latio

nshipwith

medication

Duration

Times

Chiefcom

plaintsa

ndsymptom

sYM

RSIntervalbetween

episo

deand

operation

Timeo

foccurrence

(1)

1Inexplicableeuph

oria(sense

offlo

ating)

22Po

stoperativ

e1mon

th(new

lyactiv

ated)

Day

1afte

rhospital

discharge

Med-on1.5

h2h

2Inexplicableeuph

oria(sense

offlo

ating)

Day

2aft

erho

spita

ldischarge

Med-on1h

2.5h

(2)

1Wail

none

Posto

perativ

e18

mon

ths

During

programming

MED

+ON

20min

(3)

1Hallucinatio

n(cloud

-like

light

andshadow

)no

nePo

stoperativ

e2mon

ths

Firstn

ight

after

hospita

ldisc

harge

Med-on

Abou

t20m

in

2Hallucinatio

n(cloud

-like

light

andshadow

)Second

morning

after

programming

Med-on

30min

(4)

1Hypom

ania(hardto

restr

ainanger)

30Po

stoperativ

e17

mon

ths

During

programming

Med-off

10min

until

adjustmento

fparameter

2Hypom

ania(sense

ofanger)

28During

programming

Med-off

10min

until

adjustmento

fparameter

(5)

1Wail(indu

cedby

ordinary

conversatio

n)

none

Posto

perativ

e1mon

th(new

lyactiv

ated)

During

programming

Med-off

5min

until

adjustmento

fparameter

2Wail(indu

cedby

ordinary

conversatio

n)During

programming

Med-off

7min

3Wail(indu

cedby

talkingabou

tthe

past)

During

programming

Med-on

5min

(6)

1Hypom

ania(lo

singtempertowife)

33

Posto

perativ

e26

mon

ths

Atho

me,aft

erprogramming

Med-on

Improved

after

10min

2Hypom

ania(kicking

roadsid

ecars)

Atho

me,aft

erprogramming

Med-on

2min,improved

1min

after

deactiv

ation

(7)

1Inexplicableeuph

oria(la

ughing

foolish

ly)

20Po

stoperativ

e3mon

ths(du

ring

programming)

During

programming

1haft

erintake

10h

2Inexplicableeuph

oria(la

ughing

foolish

ly)

During

programming

1.5haft

erintake

3min

(8)

1Hypom

ania(lo

sttempera

ndsm

ashedob

jects)

34Po

stoperativ

e3mon

ths(du

ring

programming)

The2

nddayaft

erho

spita

ldisc

harge

Med-on

2h

2Hypom

ania(flight

ofideasa

ndfid

getin

g)Th

e2nd

dayaft

ergetting

home

Med-on

2h

(9)

1Hypom

ania(emotionaland

quarrelin

g)34

Posto

perativ

e14

mon

ths

Day

6aft

erho

spita

ldischarge;20

min

after

raising

the

voltage

of0.5V

with

programming

bypatie

nts

Med-on1.5

h

1.5h.Family

mem

bers

resto

redthes

timulation

parameter

originallysetb

ydo

ctors


Table2:Con

tinued.

Num

ber

Descriptio

nof

episo

deRe

latio

nshipwith

medication

Duration

Times

Chiefcom

plaintsa

ndsymptom

sYM

RSIntervalbetween

episo

deand

operation

Timeo

foccurrence

(10)

1Ab

norm

alsenseo

fspatia

lorie

ntation(unaware

ofhislocationwhenou

tofclin

ic)

none

Posto

perativ

e3.5

mon

ths(du

ring

programming)

During

programming

Med-off

10min,returnedclinicfor

readjustmento

fparam

eters

2Ab

norm

alsenseo

fspatia

lorie

ntation

During

programming

Med-off

15min,improved

2min

after

parameter

adjustment

(11)

1Hypom

ania(sho

utingandfid

getin

g)29

Posto

perativ

e2.5

mon

ths(du

ring

programming)

Inthec

aron

his

way

homea

fter

programming

Med-on

1.5h,im

proved

after

readjustmento

fparam

eters

inthec

linic


Table3:Th

estim

ulationparametersa

ndST

PS.

Num

ber

ofPD

Patie

nts

Status

STPS

times

Chiefcom

plaints

andsymptom

sof

STPS

Stim

ulation

patte

rnCV

/CC

Intensity

(V/m

A)

Pulse

width

(𝜇s)

Frequency

(Hz)

Left/rig

htCa

thod

eAno

deIPG

Electro

deAc

tivec

ontact

locatio

nUPD

RS-IIIscore

(med

off/IP

G-on)

(1)

Pre-ST

PSIPG-off

Activ

aRC

3389

MedialSTN

STPS

1Inexplicable

euph

oria

Mon

opolar

CV2.5

60160

Left

1Ca

seNon

e∗

STPS

2Inexplicable

euph

oria

Mon

opolar

CV2.2

60160

Left

1Ca

se14

Final

Mon

opolar

CV1.9

70160

Left

1Ca

se14

(2)

Pre-ST

PSMon

opolar

CV2.3

80140

Left

1Ca

se

Activ

aRC

3389

Medialp

arto

fST

NMon

opolar

CV2.5

90140

Right

9Ca

seST

PS1

Wail

Mon

opolar

CV2.5

90140

Left

1Ca

se13

Final

Bipo

lar

CV2.6

90140

Left

12

13

(3)

Pre-ST

PSMon

opolar

CV2.5

60150

Right

9Ca

se

Activ

aRC

3389

MedialInferior

partof

STN

Mon

opolar

2.3

60150

Left

2Ca

seST

PS1

Hallucinatio

nMon

opolar

CV2.9

70150

Right

9Ca

se25

STPS

2Hallucinatio

nMon

opolar

2.6

90130

Right

9Ca

se23

Final

Interle

aving

CV2.5

90125

Right

2Ca

se23

1.870

125

3

(4)

Pre-ST

PSMon

opolar

CV2.3

100

90Left

1Ca

se

Activ

aRC

3389

Inferio

rparto

fST

N/sub

stantia

nigra

Mon

opolar

CV2.5

11090

Right

10Ca

seST

PS1

Hypom

ania

Dou

blep

olar

CV2.4

100

90Left

0,1

Case

25ST

PS2

Hypom

ania

Dou

blep

olar

CV2.2

110

85Left

0,1

Case

25

Final

Interle

aving

CV2.0

100

90Left

0Ca

se25

2.3

100

901

(5)

Pre-ST

PSIPGoff

Activ

aPC

3389

Lateralp

arto

fST

N/C

lose

toZo

naincerta

STPS

1Wail

Mon

opolar

CC1.9

60140

Right

10Ca

seNon

e∗

STPS

2Wail

Mon

opolar

CC1.7

60130

Right

10Ca

se13

STPS

3Wail

Bipo

lar

CC1.8

60130

Right

1011

13Final

Mon

opolar

CC1.9

60130

Right

11Ca

se13

(6)

Pre-ST

PSDou

ble-po

lar

CV2.5

60160

Left

0,1

Case

Activ

aRC

3389

Inferio

rparto

fST

N/C

lose

tosubstantianigra

Mon

opolar

CV2.7

70160

Right

9Ca

seST

PS1

Hypom

ania

Dou

blep

olar

CV2.8

60160

Left

0,1

Case

40

STPS

2Hypom

ania

Interle

aving

CV2.5

80125

Left

0Ca

se39

2.8

80125

1Ca

se

Final

Interle

aving

CV2.5

70125

Left

0Ca

se41

2.7

80125

1,2Ca

se

(7)

Pre-ST

PSMon

opolar

CC2.1

60145

Left

3Ca

se

Activ

aRC

3389

Lateralp

arto

fST

N/C

lose

toInternalcapsule

Mon

opolar

CC2.0

70145

Right

10Ca

se

STPS

1Inexplicable

euph

oria

Mon

opolar

CC2.1

60145

Left

3Ca

se40

STPS

2Inexplicable

euph

oria

Mon

opolar

CC1.9

70145

Left

3Ca

se38

Final

Bipo

lar

CV2.3

70145

Left

32

38


Table3:Con

tinued.

Num

ber

ofPD

Patie

nts

Status

STPS

times

Chiefcom

plaints

andsymptom

sof

STPS

Stim

ulation

patte

rnCV

/CC

Intensity

(V/m

A)

Pulse

width

(𝜇s)

Frequency

(Hz)

Left/rig

htCa

thod

eAno

deIPG

Electro

deAc

tivec

ontact

locatio

nUPD

RS-IIIscore

(med

off/IP

G-on)

(8)

Pre-ST

PSMon

opolar

CV2.6

60150

Left

1Ca

se

Activ

aRC

3389

Medialp

arto

fST

N

Mon

opolar

CV2.5

60150

Right

10Ca

seST

PS1

Hypom

ania

Mon

opolar

CV3.1

60150

Left

1Ca

se40

STPS

2Hypom

ania

Mon

opolar

CV2.8

70145

Left

1Ca

se40

Final

Mon

opolar

CV3

60140

Left

2case

40

(9)

Pre-ST

PSMon

opolar

CV2.7

90160

Right

9Ca

se

Activ

aRC

3389

Lateralp

arto

fST

NDou

ble-po

lar

CV2.5

80160

Left

2,3

Case

STPS

1Hypom

ania

Mon

opolar

CV3.2

90160

Right

9Ca

se25

Final

Mon

opolar

CV2.9

110130

Right

9Ca

se24

(10)

Pre-ST

PSMon

opolar

CC2.0

60160

Right

9Ca

se

Activ

aPC

3389

Medialp

arto

fST

N

Mon

opolar

CC2.2

60160

Left

2Ca

se

STPS

1Ab

norm

alspatial

orientation

Mon

opolar

CC2.2

60160

Right

9Ca

se26

STPS

2Ab

norm

alspatial

orientation

Mon

opolar

CC2.0

70140

Right

9Ca

se25

Final

Interle

aving

CV2.8

60125

Right

9Ca

se25

2.1

60125

10Ca

se

(11)

Pre-ST

PSMon

opolar

CV2.8

70135

Left

2Ca

se

Activ

aRC

3389

Lateralp

arto

fST

NMon

opolar

CV2.5

60135

Right

10Ca

seST

PS1

Hypom

ania

Mon

opolar

CV3.0

70135

Left

2Ca

se34

Final

Mon

opolar

CV2.7

80135

Left

2Ca

se34

CV,con

stantvoltage;C

C,constant

current.∗Th

epatientsw

ithno

UPD

RS-IIIscore(med-off/IPG-on)

becausetheywereinthefi

rstp

rogram

mingandhave

notb

eenevaluatedwith

UPD

RS-IIIscorey

et.


Table4:Programmingprocedureo

fpatient

number6

.

Patte

rnVo

ltage

(V)

Pulse

width

(𝜇s)

Frequency

(Hz)

Cathod

eAno

deUPD

RS-IIIscore

(med-off/IPG-on)

Chiefcom

plaints

Pre-programming

Dou

blep

olar

2.5

60160

0,1

Case

41Spastic

pain

inther

ight

shou

lder

(1)

Dou

blep

olar

2.8

80160

0,1

Case

40ST

PSoccurred

(2)

Interle

aving

2.5

80125

0Ca

se39

STPS

occurred

with

hat-likec

onstr

ictio

nsurrou

ndingtheh

ead

2.8

80125

1Ca

se

(3)

Interle

aving

2.5

70125

0Ca

se40

Rigidityof

neck

andpo

sterio

rextensio

n2.8

90125

1Ca

se

(4)

Interle

aving

2.5

70125

0Ca

se39

Dizzinessandpalpitatio

n3.1

80125

1Ca

se

(5)

Dou

blep

olar

2.5

70130

0,1

Case

40Fidgeting,feellik

eprelim

inaryappearance

ofST

PS

(6)

Interle

aving

2.5

70125

0Ca

se40

Dizzy

andpalpitatio

n2.7

100

125

1Ca

se

(7)

Interle

aving

2.5

70125

0Ca

se42

Rigidityof

neck

andpo

sterio

rextensio

nwith

pain

inther

ight

shou

lder.

2.8

80125

12

(8)∗

Interle

aving

2.5

70125

0Ca

se41

Pain

inshou

ldersimproved,w

ithno

newly

developedsymptom

s2.7

80125

1,2Ca

se

(9)

Interle

aving

2.5

70125

0Ca

se41

Dizziness

2.8

80125

1,2Ca

se∗Th

epatient

chosethe

8thprogrammingparameters.


could reach to 3mm. As a result, the limbic part of STNcould easily be affected and cause STPS. (3) Thirdly, evenin the most experienced PD treatment center could notguarantee that both anticipated contacts location and curativestimulation effect could be satisfied. Meanwhile, STPS couldbe easily induced when increasing stimulation intensity ortesting side effects.

China has the largest number of patients with PD in theworld. In recent years, there have been more than 100 centerswhich carry out STN-DBS surgery for the treatment of PD.Asa result, there is a strong likelihood of an increasing numberof PD patients suffering STPS after STN-DBS programming.It is therefore very important to rapidly diagnose, locatecontacts, and program parameters to eliminate STPS. Itis also paramount to maintain the PD patient’s optimalmotor function according to algorithms set by programmingdoctors at different levels.

4.2. Confirmation of STPS and the Impact Factors. Psychiatricdisorders are one of the symptomsmanifested in PD patients.However, antiparkinsonism medications also manifest simi-lar symptoms as drug side effects. Levodopa and dopaminer-gic drugs could induce dopamine dysregulation syndrome,hallucinations and psychosis, mania and hypomania, andimpulse control disorders, which were similar to STPS [16].The treatment of psychiatric symptoms induced by the abovedrugs is in the reduction of medication in most times. STPSis known to manifest similarly. Therefore the diagnosis ofpsychiatric symptoms induced by drug side effects or PDshould not bemisinterpreted for STPS.The diagnosis of STPSshould only be made upon confirmation.

Patients in our study had neither any preexisting psychi-atric symptoms nor their PDmedication altered for than onemonth. Although preoperative LEDD given to our patientson average was more than the reported average dose beforeDBS surgery in previous studies [17, 18], the subsequent doseswould reducemore than 50% similar to that reported by Jiangand colleagues [17]. Levodopa withdrawal symptoms mainlyinclude apathy and depression. In our study, all 11 patients hadno symptoms of apathy and depression. Moreover in the firstthree-month follow-up after STPS programming, except forthe two patients who had STPS at IPG initiation, there was nochange in the LEDD in the other patients (Table 1).We, there-fore, deduced that the antiparkinsonismmedication is not themain factor inducing psychiatric symptoms.Otherwise, somepsychiatric symptoms may have reoccurred within the first 3months of follow-up.

To avoid drugs side effect interference during DBS effectevaluation, all the patients were programming in the state of“off time.” Patients were given daily doses of anti-Parkinson’sdisease drugs after the final stimulation parameters wereset. To achieve the satisfactory therapeutic effects, the motorcomplications were evaluated during “on time” state. How-ever, the interesting point is that 70% (14/20) STPS occurredin “on time” state or over 1 hour after taking medications(though some patients had not felt medicine effect already);see Table 2.Whether medications for PDwork with electricalstimulation to cause psychiatric symptoms or not needs fur-ther study.We excluded the effect of PD drugs bymaintaining

the same dosage that was given on the first occurrence ofSTPS. So we believe the electrical stimulation should be themain factor of psychiatric symptoms.

To improve the diagnosis of STPS, we developed thealgorithm (Figure 2). The causative active contact of patientswith acute symptoms of STPS could be easily identifiedusing the flow chart. However, the causative active contactin patients with transient STPS symptoms was more difficultto identify. In the process of locating suspicious contacts insuch patients, we do not recommend increasing stimulationintensity to induce STPS to identify contacts. The reason isthat (1), theoretically, increasing stimulation intensity of anycontact to a certain threshold, the volume of tissue activated(VTA) may affect limbic part of STN and induce STPS. So itmaymislead the doctor to regard the contacts which were notthe initial responsible contacts. The doctor may even locatewrong responsible electrodes and contacts. (2) If there aremultiple active contacts (double polar, interleaving mode) onone side of the electrode, the adjacent contacts have a higherchance to induce STPS (although the ventral contacts arewith a higher chance). If randomly increasing stimulationintensity of random contacts to induce STPS, it can alsolead to wrong contact. (3) Intentionally induced STPS mightcause patients extra distress, leading them to distrust doctors,increased complaints, and decreased satisfaction. Therefore,we recommend the utilization of the algorithm (Figure 2) tolocate the contacts carefully and accurately. In our study, theactive contacts which induced STPS were identified by usingan algorithm (Figure 2) and eliminated by programming inall the 11 patients.

The clinical significance incidence rate of STPS whichnecessitated programming was about 2%. This was signifi-cantly lower as compared to 28.6% in previous studies [14].This difference may be attributed to the stimulation intensityused and the exclusion criteria we used to enroll patients withSTPS symptoms in this study. In this study, the stimulatingvoltage was rarely more than 3.0V. However, the stimulatingvoltage did not exceed 3.3 V.

We noted that time interval for the occurrence STPS fellwithin 48 hours after new settings of stimulation parameters.Therefore, the psychiatric and psychological status of patientsshould be thoroughly assessed in MED-ON/STIM-ON aftereach programming session before patients were discharged.It is also necessary to instruct the family to timely identifythe occurrence of STPS, since some symptoms may not berecognized by patients themselves [19].

4.3. Principles of STPS Programming. We observed that STPSis likely to develop when programming clinicians increasethe voltage or pulse width of the active contact. The increasein active contact voltage or pulse width gives patients abrief false sense of relief masked by improvement in motorfunctions. Even though the improvement of motor functionsare most often minor (1 or 2 point differences in UPDRS-III), STPS set in as residual effects of the increase in voltage.Patients usually find themselves in a quagmire on whetherto maintain improved motor functions or settle for removalof STPS and have less appealing motor functions. However,few reports were mentioning how to maintain the optimal


improvement for motor functions while avoiding STPS at thesame time.

We conducted a literature review using PubMed databaseof earlier authors who encountered and managed STPSwhile maintaining optimal motor functions. We designed aprogramming procedure andprotocol to determine the activecontacts that induce STPS to rapidly alleviate patients’ psychi-atric symptoms and maintain improved motor functions.

Previous reports [20] suggest that STPS was associatedwith high level of voltage. This suggests that the VTA mightimpact the limbic neuronal networks that induce STPS.They further reported that various programming methodsdecrease or change the VTA enabling eliminating STPS.These methods include (1) reducing voltage [20], (2) switch-ing to bipolar stimulation [19], and (3) changing dorsal activecontacts [9, 21, 22].

Although there are many ways to improve STPS throughprogramming, the order of choice must not be random butwith precise principles and in chronological order (Figure 3).These principles include that (1) the solutions for eliminatingSTPS must be rapid; (2) simple and replicable; (3) and withminimal or no STPS reoccurrence and (4) must preserveoptimal motor functions.

There are six methods to adjust the stimulation param-eter: (1) bipolar stimulation, (2) reducing voltage by 0.3 V–0.5 V until SITNPS disappears; (3) decreasing of voltageand increasing the pulse width; (4) declining voltage andfrequency and increasing pulse width; (5) interleaving oforiginal and dorsal contacts; (6) changing the active contactsto dorsal the position.

4.3.1. Bipolar Stimulation. The first option is bipolar stimu-lation. We choose to select bipolar stimulation to easily setstimulation parameters and quickly narrow the sphere VTA(Figure 3). This could promote STPS regression and reducerecurrence. However, due to the rapid narrowing of VTA, itoften leads to the aggravation of motor functions.

4.3.2. Reducing Voltage. We reduced the voltage on the basisof initial stimulation parameter (with STPS).This adjustmentcan also quickly reduce the VTA and intensity of the activa-tion domain.

4.3.3. Decreasing of Voltage and Increasing the Pulse Width.The adjustment of programming parameters mentionedabove may reduce activation domain [23] while in the mean-time declining the stimulating intensity of motor functions-related neural pathways [24].Therefore a slight increase in thepulse width tomaintain stimulation intensity in the narrowedVTA might be needed when the voltage is decreased. Someinexperienced programming physicians may conceive that itis hard tomodulate pulse width appropriately. It will be easierto operate according to the formula of total electrical energydelivered (TEED) to calculate how to increase the pulse widthaccording to the voltage reduced (new TEED should be notmore than the original one with STPS).

4.3.4. Declining Voltage and Frequency and Increasing PulseWidth. If necessary, we can even adjust the frequency

(+5–10Hz) to fit the change of the voltage and pulse width,to achieve the appropriate stimulation intensity to eliminateSTPS while maintaining the improvement of motor func-tions. In addition to reducing the stimulation frequency toreduce intensity, interleaving technology could be used whenadjusting the voltage.

4.3.5. Interleaving of Original and Dorsal Contacts. Theadjustment of the pulse width is critical in improving patient’soptimal movement symptom after the frequency has reducedto 125Hz. In the case where the active contact responsiblefor inducing STPS was ventrally positioned, stimulationparameters remain unaltered. Subsequently, the dorsallylocated contacts are activated into interleaving stimulationmode.This adjustment has proven tomaintain optimalmotorfunction.

4.3.6. Changing the Active Contacts to Dorsal the Position.In isolated patients, motor functions reacted better to stim-ulation frequency than the later adjustment. As reported,the contacts located anterior, medial, and inferior to STNwere easier to precipitate STPS [14]; thus if using theabove-mentioned scheme cannot eliminate STPS and achieveoptimal improvement of motor functions at the same time,we change the active contact to more dorsal position toacquire a larger range in the adjustment of stimulationparameters. If the inactive contacts were suspended for along time, curative and side effects might change fromprevious stimulation record and need retitration which istime-consuming. Also, after the inactivated contacts havebeen activated, the contact impedance may change with timecausing instability of symptom control among patients [25].We recommend that the interleaving mode generates twoisolated VTA: the ventral and dorsal contact. The ventralcontactmaintains the previous stimulation parameters beforethe occurrence of STPS. We activate the dorsal contact bygradually increasing the voltage and pulse width to archiveoptimal motor function [26]. In contrast to the COMPAREtrial [27], we have put in consideration preserving patient’smotor function while eliminating STPS. Therefore the use ofinterleaving stimulation was our priority than changing theactive contact to dorsal one.

4.4. Patient Follow-Up. The impedance of the active contactsreduces over time [25]. Therefore, after STPS programming,patients needed to be followed up for a period to ensureno appearance of similar psychiatric symptoms. STPS wasconsidered eliminated after clinical programming at three(03) months. In the event there was a need to adjust theintensity of stimulation upwards, increasing the width ofpulse was given priority. This is because the expansion of theactivated domain was not as significant as that of the voltage[28].

4.5. Limitations. The limitations of the study are inadequatesample size and limited categories of STPS. Additionally, theflow diagrams adopted in this study are limited to MedtronicActiva PC and RC models. This was a single center study.


5. Conclusion

The stimulation contacts in STPS could be determined withuse of flowdiagram.Appropriate programming could removeSTPS while maintaining optimal improvement of motorfunctions for most patients.

Additional Points

Recommendations. The flow diagrams for patients with othermodels of IPG should be adjusted accordingly. A meta-analysis could increase the sample size and attain statisticalsignificance.

Disclosure

Thisworkwas presented as a poster at the 2017 ChineseMedi-cal Association of Nerve Regulation Professional CommitteeAnnual Meeting and the 8th Session of the Chinese NerveRegulation Conference. Xi Wu and Yiqing Qiu are co-firstauthors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by the National Key Research andDevelopment Program of China (2016YFC0105900).

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