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J Neurol (2008) 255:1940–1948DOI 10.1007/s00415-009-0040-1 ORIGINAL COMMUNICATION
JON
304
0
Ulrike LuekenMichaela SchwarzFrank HertelElisabeth SchweigerWerner Wittling
Impaired performance on the Wisconsin Card Sorting Test under left- when compared to right-sided deep brain stimulation of the subthalamic nucleus in patients with Parkinson’s disease
Introduction
The functional anatomy of the basal ganglia has been defined in terms of several segregated corticostriatal-thalamocortical circuits that do not only serve motor, but also cognitive and limbic functions [3]. Over the past decade, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective treatment option
for managing advanced stages of Parkinson’s disease (PD). Considering the architecture of the basal ganglia loops, it is plausible to assume that DBS of target sites within these structures might also influence functions beyond motor control. From a research perspective, this technique offers a unique window to study effects of lo-calized stimulation on specific neuronal networks that are involved in various neurobehavioral domains. Cog-nitive functions of the STN as one component of the as-
Received: 29 March 2007Received in revised form:
27 November 2007Accepted: 27 June 2008Published online: 18 January 2009
U. Lueken, Ph.D. (�)Institute of Clinical Psychology and PsychotherapyTechnische Universität DresdenChemnitzer Straße 4601187 Dresden, GermanyTel.: +49-351/463-38599Fax: +49-351/463-36984E-Mail: [email protected]
U. Lueken, Ph.D. · M. Schwarz, Dipl.-Psych. · E. Schweiger, Ph.D. · Prof. W. Wittling, Ph.D.Center for Neuropsychological ResearchUniversity of TrierJohanniterufer 1554290 Trier, Germany
F. Hertel, M.D.Service de NeurochirurgieCentre Hospitalier de Luxembourg4, rue Barble1210 Luxembourg, Luxembourg
■ Abstract Over the past decade, deep brain stimulation (DBS) has become an effective treatment op-tion for managing severe Parkin-son’s disease (PD). However, evi-dence is accumulating that DBS of target sites like the subthalamic nucleus (STN) can result in unin-tended cognitive effects that lie beyond motor control. The aim of the present study was to evaluate whether changes in executive task performance after chronic DBS might be predominantly associated with the stimulation of only one hemisphere. Eight patients with PD who had undergone DBS treatment of the STN were selected to partici-pate in the study. Using a repeated measurements design, they under-went a neuropsychological exami-nation under unilateral left- and right-sided stimulation in order to investigate laterality effects in their performance on the Wisconsin Card Sorting Test. All patients showed a significant improvement
in motor symptoms postopera-tively. Selected aspects of executive task performance were compro-mised under left- when compared to right-sided stimulation. Perfor-mance measures were unrelated to demographic, neurological, and be-havioral characteristics of the pa-tients. Findings are consistent with the emerging evidence that the STN is not only involved in motor control, but also participates in functions of the cognitive domain. Moreover, results raise the possibil-ity that the left and right hemi-sphere might differ in their vulner-ability to tolerate side effects on executive functions of DBS treat-ment. Potential consequences for future research questions and the management of cognitive side ef-fects are discussed.
■ Key words Parkinson’s disease · deep brain stimulation · subthalamic nucleus · executive functions · laterality
1941
sociative system can now be probed in PD patients, al-lowing selective and reversible modulation of this structure.
Studies attempting to evaluate cognitive outcomes after DBS of the STN report mixed results [2, 4, 5, 7, 9, 10, 25, 29]. Improvement in motor function does not neces-sarily seem to be coupled with improvements in the cog-nitive domain. Results regarding executive functions are inconclusive so far with some authors reporting discrete improvements [5], but also deterioration [7] in perfor-mance on tests tapping on executive functions like the Wisconsin Card Sorting Test (WCST). A large controlled multi-center study by Smeding et al. [29] demonstrated adverse effects on several neuropsychological scores re-flecting executive functions in the STN group six months postoperatively. Although a worsening of semantic and lexical word fluency has been repeatedly reported, no significant postoperative changes in WCST performance could be observed by these authors [4, 9, 10]. However, individual outcomes appear to be highly variable [5]. Moreover, study designs employing pre- and postopera-tive comparisons merely under stimulation “on” condi-tions impose interpretative limitations, since it cannot be distinguished between cognitive effects of the surgi-cal intervention and those of the DBS itself.
Studies reporting postoperative differences in exe-cutive task performance under different stimulation conditions are less common. Using a postoperative “on”/“off” design, Jahanshahi et al. [12] observed improve-ments in some, but not all tests on executive functions with the stimulator switched on in patients with DBS of the STN.
However, up to now no studies are available yet that have systematically examined cognitive effects of sub-thalamic DBS as a function of laterality. Thus, previous results could have been masked by differential effects of left- versus right-sided stimulation. One of the few pub-lished studies on lateralized functions of the STN exam-ined the effects of unilateral subthalamotomy on cogni-tive performance in a small sample of PD patients [19, 24]. Although no statistically significant group differ-ences were observed, left-sided lesions were associated with greater incidence of deterioration postsurgery, af-fecting executive functions as well as other cognitive domains. However, it is unclear if these preliminary re-sults also hold true for patients receiving DBS of the STN.
The current study therefore aimed to investigate whether effects on executive functions as measured by the WCST might be based on the stimulation of one hemisphere. Therefore, a modified postoperative “on”/“off” design was employed with the electrodes be-ing switched on unilaterally only at each assessment point.
Tabl
e 1
Dem
ogra
phic
and
clin
ical
char
acte
ristic
s of t
he p
atie
nts
Patie
ntSe
xAg
e(y
ears
)Ed
ucat
ion
(yea
rs)
HADS
-D:
Depr
.HA
DS-D
:An
x.AE
S1Di
seas
edu
ratio
n(y
ears
)
Tim
e sin
cesu
rger
y(m
onth
s)
Side
of
sym
ptom
on
set
Med
icat
ion
(mg)
2H&
Y3UP
DRS
(III)3
Pre-
oper
ativ
ePr
e-op
erat
ive
Post
-op
erat
ive
1M
67.0
9.0
2.0
7.0
10.0
12.0
13.0
R21
04.
042
.020
.0
2F
64.0
9.0
4.0
11.0
3.0
8.0
3.5
R50
03.
039
.015
.0
3F
55.0
9.0
n.a
. n
.a.
9.0
16.0
5.0
R80
03.
534
.0 8
.0
4M
64.0
9.0
n.a
. n
.a.
15.0
7.0
17.0
R80
04.
055
.015
.0
5M
53.0
9.0
15.0
11.0
8.0
5.5
22.0
L51
02.
528
.010
.0
6M
51.0
9.0
10.0
7.0
16.0
12.0
18.0
Ln.
a.3.
546
.027
.0
7F
62.0
9.0
11.0
7.0
2.0
10.0
12.0
n.a.
800
3.5
40.0
17.0
8F
66.0
13.0
5.0
7.0
6.0
10.0
9.5
L90
04.
056
.024
.0
Mea
n (S
D)–
60.3
(6.3
) 9
.5 (1
.4)
7.8
(5.0
) 8
.3 (2
.1)
8.4
(5.2
)10
.1 (3
.3)
13.0
(6.4
)–
645.
7 (2
46.8
)3.
5 (0
.5)
42.5
(9.7
)17
.0 (6
.5)
M m
ale
sex;
F fe
mal
e se
x; H
ADS-
D Ho
spita
l Anx
iety
and
Dep
ress
ion
Scal
e –
Germ
an V
ersio
n; A
ES A
path
y Eva
luat
ion
Scal
e –
Germ
an V
ersio
n; L
left
side;
R ri
ght s
ide;
H&Y
mod
ified
Hoe
hn a
nd Y
ahr R
atin
g Sc
ale;
UPD
RS U
nifie
d Pa
rkin
son’
s Dise
ase
Ratin
g Sc
ale;
n.a
. not
ava
ilabl
e1 T
he A
ES w
as a
dmin
ister
ed a
s an
inte
rvie
w w
ith th
e re
spec
tive
patie
nt
2 Lev
odop
a eq
uiva
lent
dai
ly d
oses
wer
e ca
lcul
ated
as f
ollo
ws:
100
mg
stan
dard
levo
dopa
equ
als 1
mg
cabe
rgol
ine
equa
ls 1
mg
pram
ipex
ole
3 Not
e th
at p
reop
erat
ive
and
post
oper
ativ
e m
otor
sym
ptom
s wer
e as
sess
ed a
lway
s und
er o
ptim
al st
imul
atio
n an
d/or
med
icat
ion
“on”
cond
ition
s
1942
Methods
■ Subjects
A consecutive series of eight patients (four male) who had been expe-riencing advanced, levodopa-sensitive PD with severe on/off fluctua-tions and who had undergone surgery for bilateral DBS of the STN were included in the study. They fulfilled the Core Assessment Pro-gram for Surgical Interventional Therapies in PD criteria according to their motor deficit [6]. Preoperative signs of cognitive decline or behavioral disturbances were carefully judged by the attending neu-rosurgeon (F.H.) and were followed by exclusion. In order to control for transient effects on cognition shortly after surgery, the minimum interval between assessment and surgery was determined at three months. The mean time interval since surgery averaged (SD) at 13 (± 6.4) months. All patients were receiving drug treatment in addition to the DBS (levodopa or dopa-agonists, see Table 1 for daily doses in levodopa equivalent). The medication parameters remained unchanged during the two assessments. Informed written consent according to the dec-laration of Helsinki was obtained from each subject. The local ethics committee of the medical chamber of Rhineland-Palatinate gave ap-proval to this study.
■ Surgical procedure
Preoperative MRI scans were performed several days before the sur-gery. On the day of surgery, patients underwent a stereotactic CT scan with contrast enhancement and 2-mm slices. All patients also under-went a postoperative non-stereotactic CT scan within 48 hours after surgery that was matched with the preoperative planning data for quality control of the lead placement. Prior to the surgery, MRI data sets were matched with the CT data at the Medtronic Stealth Station (Framelink 4; Medtronic, Minneapo-lis, MN). The target point was calculated indirectly via the anterior commissure – posterior commissure midpoint determination on the T1-weighted MRI scan and adjusted according to the T2-weighted MRI scan. The functional target coordinates of the STN in stereotactic space were: x (lateral distance from the midline) = –12, y (anteropos-terior distance from the AC) = –3, and z (height relative to the AC line) = –4 for the left electrode and x = 12, y = –3, and z = –4 for the right electrode (Medtronic 3389®). All leads were fixed at the cranium with the Medtronic burrhole cap. The pulse generator (Kinetra 7482®; Medtronic) was implanted and activated at the same day subcutaneously inferior to the clavide.
None of the patients had intraoperative complications; one developed a symptomatic transitory psychotic syndrome postoperatively. Stimulation parameters, electrode characteristics and the number of activated contacts are given in Table 2. Parameter settings had been optimized for each patient by the time the neuropsychological assess-ment was carried out.
■ Experimental procedure
A within-subjects design with repeated measurements was employed to assess side-specific effects of DBS of the STN on executive task performance. According to a modified postoperative stimulation “on”/“off” design, executive task performance was assessed at two occasions with the left stimulator switched on and the right stimula-tor switched off (L-on condition) at one occasion and vice versa (R-on condition) at the other occasion. The order of condition was counter-balanced, so that practice effects were held constant across both con-ditions. Neuropsychological evaluations were performed always un-der identical postoperative medication (“on”) in order to reduce error variance between both sessions and to ensure that performance was not compromised by severe motor deficits. Electrodes were switched off one hour prior to the assessment. The time interval between both sessions was on average (SD) 16 (± 4) days. All evaluations were car-ried out by the same psychologist (M. S.).
■ Motor, neuropsychological, and behavioral assessment
Preoperative motor deficits and postoperative improvements were as-sessed using current clinical rating scales, such as the Unified Parkin-son’s Disease Rating Scale (UPDRS) and modified Hoehn & Yahr scale. The mean follow-up period was 14 months (range 3–28 months). The duration of disease was also noted, as well as the onset site of initial symptoms. Handedness was determined once prior to the first neuropsycho-logical assessment using the Edinburgh Handedness Inventory (EHI) [22]. Overall cognitive status was assessed by means of the Mini Men-tal State Examination (MMSE) [8]. Scores of at least 20 points were considered to indicate sufficient overall cognitive performance to carry out further tests. The WCST-64 [13] was used as one of the most commonly employed neuropsychological diagnostic tools for assess-ing executive functions. In contrast to other tests on executive func-tions (e. g., the Stroop Test), the WCST is less verbally mediated, thus not favoring a distinct processing advantage for the left hemisphere. The short version of the WCST has proven to be comparable to its original form which contains 128 cards [23]; it was used in order to
Table 2 Stimulation parameters of the patients
Patient Left electrode Right electrode
Voltage(V)
Pulse width(μs)
Frequency(Hz)
Polarity Activecontacts
Voltage(V)
Pulse width(μs)
Frequency(Hz)
Polarity Activecontacts
1 2.6 120 160 uni 2 3.0 120 160 uni 1
2 3.5 60 130 uni 2 3.5 60 130 uni 2
3 3.0 60 130 uni 1 3.0 60 130 uni 2
4 2.8 90 180 uni 3 2.8 90 180 uni 3
5 3.0 60 130 bi 1– 2+ 0 0 3.0 60 130 bi 1– 2+ 0 0
6 3.2 60 200 uni 2 2.2 60 200 uni 2
7 2.8 90 130 uni 2 3.5 90 130 uni 3
8 2.0 90 130 uni 3 4.0 90 130 uni 3
Mean (SD) 2.9 (0.4) 78.8 (22.3) 148.8 (28.0) – – 3.1 (0.5) 78.8 (22.3) 148.8 (28.0) – –
uni unipolar; bi bipolar; 1– 2+ 0 0 activation of area between the negative and positive pole
1943
minimize timely demands on the patients. The WCST-64 consists of a pack of 64 cards on which are printed colored geometrical figures that differ in one or more dimensions (shape, color, or number of symbols displayed). The patient is asked to sort each card to one of four stim-ulus cards according to a specific rule that must be inferred from trial-by-trial feedback given after each response. After a certain number of correct responses, the experimenter is suddenly changing the rule such that the subject has to adopt its concept according to the new rule, again only inferred from trial-by-trial feedback. The WCST-64 covers a broad range of executive functions such as concept forma-tion, cognitive flexibility, set shifting, and inhibition of perseverative reactions. In particular, shifting from one rule to another in the con-text of the WCST by suppressing erroneous reactions requires reorga-nization of ongoing behavior such that it matches current behavioral objectives more appropriately. These behavioral requirements are in good accordance with common models of executive functions [21]. Performance measures of the WCST-64 can be divided into two groups: those for which higher values indicate good performance and those for which higher scores indicate impaired performance. Scores of the first group of measures encompass the total number of correct responses, conceptual level responses, and number of correct catego-ries completed. Scores of the second group contain total number of errors, perseverative responses, perseverative errors, nonpersevera-tive errors, trials to complete first category, and failure to maintain set. The behavioral assessment included an evaluation of depression, anxiety, and apathy to screen for non-cognitive symptoms that could interfere with task performance. Assessment was carried out under regular DBS conditions prior to the first neuropsychological assess-ment. A German version of the Hospital Anxiety and Depression Scale (HADS-D) [11] was employed as a short screening for affective symp-toms. The 14-item instrument has been specifically developed for patients with somatic disorders [34]. In addition, a German version of the Apathy Evaluation Scale (AES) [15] was conducted as an inter-view with the respective patient. Scores range between 0 and 54 points with higher scores indicating more severe symptoms of apathy.
■ Statistical analysis
Two sets of analyses were carried out in order to assess differences between both conditions for patients as a group (group differences) and as individuals (individual differences). Due to the small sample size, nonparametric Wilcoxon signed rank tests were carried out to evaluate group differences. Given the exploratory nature of the study, the standard non-corrected significance α level of p < 0.05 was used. However, since the risk of type I errors increases with multiple com-parisons, significant results should be interpreted with caution when α levels are only marginally less than 0.05. To evaluate performance changes between individual patients, raw scores were transformed into standard z scores, using the total sample mean and SD values. Increases or decreases of more than ± 1 SD were considered as indicating clinically significant individual changes in performance. Subsequently, the subgroup of patients showing a constant improvement in more than 50 % of the WCST–64 test scores was compared to patients showing no changes for demo-graphic, neurological, and behavioral characteristics using Fisher’s exact tests and nonparametric Mann-Whitney U-tests. All analyses were carried out using SPSS 12.0.
Results
Main demographic and clinical characteristics of each patient are given in Table 1.
The mean (SD) age of patients was 60.3 (± 6.3) years with an average duration of illness of 10.1 (± 3.3) years.
All patients were right-handed; no one had been re-trained at school. The average (SD) time of education for the sample was 9.5 (± 1.4) years. According to self re-ports of anxiety and depression and to the clinical inter-view assessing symptoms of apathy, the majority of pa-tients did not show signs of altered mood states. However, one patient exhibited heightened scores of self-reported depressive symptoms that were above recommended cut-off scores [11], and three further patients showed elevated anxiety and/or depression scores although still remaining below the cut-off.
As can be seen in Table 1, all patients had obtained a clinical benefit from the DBS, with the stimulation re-sulting in a significant decrease in UPDRS motor scores from the pre- to the postoperative assessment under op-timal medication parameters as indicated by Wilcoxon’s signed rank tests (Z = –2.52; p = 0.008).
The stimulation parameters were comparable be-tween both electrodes (pulse with: Z = 0.00, p = 1.000; frequency: Z = 0.00, p = 1.000; voltage: Z = –0.73, p = 0.465; see Table 2).
Mean values and results from Wicoxon’s signed rank tests of MMSE and WCST-64 scores under unilateral stimulation are given in Table 3. Regarding the MMSE scores, side of stimulation had no differential effect on performance measures.
As to executive task performance, patients exhibited marked differences in mean WCST-64 scores under left- versus right-sided stimulation. For variables in which higher scores equal good performance, patients showed higher scores under right-sided stimulation when com-pared to left-sided stimulation for the total number of correct responses, conceptual level responses, and num-ber of correct categories. Conversely, for variables in which higher scores equal impaired performance, left-sided stimulation was followed by significantly higher scores than right-sided stimulation for the total number of errors, nonperseverative errors, and the number of trials required to complete the first category. As dis-played in Fig. 1, patients exhibited numerically higher sores in all the remaining variables as well. However, Wilcoxon’s signed rank tests failed to show significant results for the number of perseverative responses, and the failure to maintain set, although a non-significant trend emerged for the number of perseverative errors.
Change scores under unilateral stimulation are pre-sented in Fig. 2. Examination of change scores confirmed results that were observed in the former analysis of group differences. No patient exhibited a substantial positive gain in performance (e. g., more than 1 SD change) under left-sided stimulation for the total num-ber of correct responses, the number of conceptual level responses, and the number of correct categories com-pleted, while nearly 50 % of the patients showed im-proved performance under right-sided stimulation. Similarly, scores were substantially increasing under
1944
left-sided stimulation for those variables that indicated deficits in performance.
In a second step we sought to further characterize those patients with a constant benefit under right-sided stimulation compared to those who did not improve their test performance. Using the criterion of an im-provement in at least 50 % of the test scores (e. g., 5/9 scores) three patients were identified that showed a con-stant positive gain under right-sided stimulation (Pa-tient 1: 7/9 scores; Patient 4: 5/9 scores; Patient 5: 9/9 scores; see Table 1 for demographic and medical charac-teristics of the respective patients). Although all three patients were male, distribution of gender was not sig-nificantly different distributed in the two subgroups as indicated by Fisher’s exact test (p = 0.143). Order of
stimulation condition (L-on vs. R-on first) was compa-rable for both subgroups with two out of the three pa-tients who improved under right-sided stimulation starting with the R-on condition (p = 1.000). Subgroups did not differ with respect to other demographic, neuro-logical, or psychiatric characteristics as indicated by Mann-Whitney U-tests (age: U = 5.5, p = 0.549; duration of illness: U = 3.5, p = 0.227; preoperative Hoen & Yahr stages: U = 6.0, p = 0.638; preoperative UPDRS motor scores: U = 7.0, p = 0.881; postoperative UPDRS motor scores: U = 5.5, p = 0.549; AES score: U = 4; p = 0.297; HADS-D depression score: U = 4, p = 1.000; HADS-D anxiety score: U = 3.0, p = 0.576).
In order to verify these results with respect to the po-tentially confounding effects of lateralized parkinsonian
Variables L-on R-on Wicoxon’s signedrank test
Z p
MMSE total score 27.0 (3.4) 27.4 (2.8) –0.32 0.844
WCST-64
Total number correct 24.9 (8.0) 33.6 (11.8) –1.83 0.043
Conceptual level responses 12.5 (10.6) 25.1 (14.7) –2.32 0.012
Number of correct categories completed 0.6 (0.7) 1.8 (1.4) –2.04 0.016
Total number of errors 39.1 (8.0) 30.4 (12.1) –1.83 0.043
Perseverative responses 36.9 (9.2) 33.8 (13.0) –0.77 0.250
Perseverative errors 29.5 (8.0) 25.0 (10.4) –1.48 0.078
Nonperseverative errors 10.6 (3.5) 5.4 (3.5) –2.31 0.012
Trials to complete first category 49.3(23.4) 26.6(24.2) –2.21 0.016
Failure to maintain set 0.4 (0.7) 0.2 (0.4) –0.82 0.375
MMSE Mini Mental State Examination; WCST-64 Wisconsin Card Sorting Test – 64
Table 3 Mean values (SD) showing performance in MMSE and WCST-64 under left- (L-on) or right- (R-on) sided stimulation of the STN
75
WCS
T - 6
4 sc
ores
70
65
60
* *
*
*
*
*L-on R-on
55
50
45
40
35
30
25
20
15
10
5
0
Total number correct
Conceptual level responses
Number of correct categories
Total number of errors
Perseverative responses
Perseverative errors
Nonperseverative errors
Trials to complete first category
Failure to maintain set
Fig. 1 Mean values for WCST-64 scores under left-sided (L-on) or right-sided (R-on) stimulation only. Error bars indicate the standard deviation. Note that for the first three subscores (total number cor-rect, conceptual level responses, number of correct categories) higher scores equal good performance, while for the remaining subscores higher scores equal poor performance. * p < 0.05
1945
symptom onset, patients that had exhibited initial symp-toms predominantly on their left body side were com-pared to patients that reported initial symptoms having occurred predominantly on their right side. However, Wilxocon’s signed rank tests revealed no significant dif-
ferences to either assessment point (see Table 4 for de-tails).
Failure to maintain set
left = right left > right left < right
Trials to complete first category
Nonperseverative errors
Perseverative errors
Perseverative responses
Total number of errors
Number of correct categories completed
Conceptual level responses
Total number correct
0 10 20 30 40 50percentage of patients
60 70 80 90 100
Left onset ofinitial symptoms(N = 3)
Left onset ofinitial symptoms(N = 3)
Wicoxon’s signedrank test
Mean (SD) Mean (SD) Z p
L-on
Total number correct 26.0 (7.5) 26.0 (9.5) 0.00 1.000
Conceptual level responses 38.0 (7.5) 38.0 (9.5) 0.18 0.940
Number of correct categories completed 33.7 (5.5) 36.3 (10.8) –0.76 0.647
Total number of errors 30.7 (10.6) 27.0 (7.1) 0.00 1.000
Perseverative responses 10.0 (5.6) 11.0 (2.6) –0.35 0.856
Perseverative errors 14.0 (9.5) 13.8 (12.8) 0.35 0.856
Nonperseverative errors 1.0 (1.0) 0.5 (0.6) –0.35 0.856
Trials to complete first category 30.3 (30.0) 59.5 (9.7) –1.10 0.398
Failure to maintain set 0.3 (0.6) 0.5 (1.0) 0.00 1.000
R-on
Total number correct 37.0 (13.1) 34.5 (11.7) –0.71 0.627
Conceptual level responses 26.3 (13.6) 30.0 (11.7) 0.71 0.627
Number of correct categories completed 30.7 (17.2) 34.5 (13.2) –0.59 0.828
Total number of errors 22.3 (13.7) 25.3 (10.2) –0.89 0.456
Perseverative responses 4.0 (1.0) 4.8 (3.2) –0.71 0.627
Perseverative errors 29.3 (16.1) 26.8 (13.8) 1.06 0.398
Nonperseverative errors 2.3 (1.2) 1.8 (1.5) –1.07 0.342
Trials to complete first category 11.0 (1.0) 28.8 (25.1) –1.25 0.267
Failure to maintain set 0.0 (0.0) 0.3 (0.5) –0.87 1.000
Table 4 Mean values (SD) showing performance under left- (L-on) or right- (R-on) sided stimulation in the WCST-64, displayed separately for patients with left or right onset of initial parkinsonian symptoms
Fig. 2 Percentage of patients with change scores greater than ± 1 SD in WCST-64 performance under unilateral stimulation conditions. Note that none of the eight patients displayed better performance under left-sided when compared to right-sided stimulation for the number of correct categories completed, conceptual level responses, and total number of correct responses (left > right). In contrast, approximately 50 % of patients benefited from right-sided stimulation (left < right)
1946
Discussion
The aim of the present study was to explore whether changes in selected aspects of executive task perfor-mance in PD patients who are treated with DBS of the STN might predominantly be associated with the stimu-lation of one hemisphere.
DBS was effective in controlling motor symptoms in the patient group since there was a significant improve-ment in UPDRS III scores between the pre- and postop-erative assessment.
Moreover, the impact of DBS on selected aspects of test performance as measured by the WCST-64 varied with the hemisphere that was actually stimulated. Re-sults demonstrated that declines in performance ap-peared to be closely linked to the stimulation of the left when compared to right STN. This held especially true for the establishment and maintenance of correct cate-gories, the total number of correct responses, the total number of errors and the number of nonperseverative errors. Although patients exhibited numerically higher numbers of perseverative responses and errors under left-sided stimulation, differences failed to reach statis-tical significance.
Our results are consistent with emerging evidence that the STN is not only involved in motor control, but also participates in functions of the cognitive domain. Moreover, findings indicate that the impact of DBS of the STN on executive functions might at least partly be a matter of laterality.
Recent positron emission tomography (PET) studies support the notion that DBS not only impairs perfor-mance on executive tasks like the Stroop task, verbal fluency or random number counting in PD patients, but is also accompanied by functional inhibition of pre-frontal-cingulate networks involved in cognitive flexi-bility, inhibitory control and conflict monitoring [27, 28, 31]. These findings provide important information about the underlying mechanisms of DBS-induced dec-rements of executive task performance. However, al-though the authors report lateralized activation pat-terns, comparison with present findings is limited, since the tasks employed were mainly verbally mediated and the effects of bilateral, not unilateral stimulation were evaluated.
As to the laterality profile of the STN for cognitive, especially executive functions, few studies exist. In a small sample of patients with unilateral subthalamot-omy McCarter et al. [19] observed that left-sided sub-thalamotomy was more often followed by a general de-terioration of cognitive functions including executive tests like the Stroop task and a modified version of the Tower of London. Although it is yet unresolved whether the precise mechanisms by which cognitive functions are altered are comparable after ablation or stimulation procedures, our findings are in accordance with those of
McCarter et al. [19] in that left-sided stimulation was likely to exert a negative effect on executive task perfor-mance.
These results are further supported by studies that report laterality effects towards the left hemisphere for the associative system. Using a functional imaging task in PD patients and healthy controls, Thiel et al. [31] ob-served a right-sided lateralization of the limbic basal ganglia loop, while PET activation of the dorsolateral prefrontal cortex was associated with activation pat-terns of the left caudate nucleus, thus pointing to a later-alization towards the left hemisphere. Other studies on patients with focal damage of the frontal cortex demon-strated that patients with left-, but not right-sided le-sions were impaired in the dynamic reconfiguration between already established task sets [26]. These find-ings conform to more comprehensive models of func-tional hemispheric asymmetry. As already noted by Lu-ria (1966), regulative and control functions are often mediated through language-associated processes. The pronounced left-hemispheric dominance of language functions could thus have contributed to a lateralization of other cognitive processes that underlie behavioral control towards the left hemisphere.
As to potentially asymmetric functions of bilateral DBS, the interpretation of laterality effects depends on whether DBS per se exerts a supportive or disruptive impact on executive functions. According to the classical basal ganglia model, STN stimulation is thought to “re-lease the brake” on frontal functions, thus improving aspects of motor control [14]. If the effect is supportive and a lateralization of the associative loop towards the left hemisphere is assumed, then left-sided stimulation should result in a facilitation of executive functions. Here, results point to a reverse effect, namely a degraded executive task performance under left-sided STN stimu-lation. An alternative model suggests that the differen-tial impact of STN stimulation on motor and on cogni-tive loops supports two opposite predictions regarding these two functional domains. According to the so-called paradox of stereotactic surgery in PD [17], automatic movements are improved by DBS of the STN. Non-auto-mated behavior, however, that is required in new and unexpected situations is likely to be impaired after dis-ruption of the basal ganglia input to the frontal cortex on the level of the STN. This may lead to the inability to reorganize ongoing behavior according to changing en-vironmental requirements. This view is further sup-ported by neuroanatomical findings about cortical efferents of the STN that can bypass cortico-striato-pal-lidal-STN projections [18]. As a consequence, stimula-tion of the STN may disrupt these pathways which are irrelevant for simple motor control.
Under particular consideration of the potential later-alization of the associative system towards the left hemi-sphere, our results are in accordance with the view that
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executive functions may be affected especially under left-sided stimulation.
Our data raise the possibility that laterality-specific neurobehavioral effects must be considered after bilat-eral DBS that might be obscured in studies to date. How-ever, we acknowledge that results of this study only pres-ent preliminary data from a small patient group. Results should thus be regarded as being exploratory in nature and require replication in a larger sample using a more sophisticated neuropsychological evaluation program. In order not to increase timely demands on the patients, only two assessment points were carried out to study effects of unilateral stimulation in a repeated measure-ments design. Thus, we lack preoperative baseline data and postoperative comparisons between bilateral “on” and “off” conditions because this would have required a total of 5 assessment points to achieve sufficient data. Moreover, we were not able to examine a comparable patient control group in order to evaluate if the patients that were assigned for DBS treatment differed in execu-tive task performance from other PD patients in ad-vanced stages of PD that did not undergo surgery. Inter-pretation of results is thus confined to this specific group treated with DBS.
However, the time interval between the two assess-ment sessions was kept relatively short in order to con-trol for effects of disease progression. In contrast to other studies that assessed laterality effects of unilateral ablation of critical structures such as the STN or the GPi, the present study took advantage of a within-subjects design in order to minimize subgroup related error vari-ance. Practice effects that impose limitations on the in-terpretation of pre- and postoperative comparisons were held constant between both conditions using a counterbalanced ABBA design. Comparison of patients displaying a constant improvement (e. g. changes of ± 1 SD in more than 50 % of the test scores) under right-sided stimulation with those who did not improve re-vealed no differences in demographic, neurological, or psychiatric characteristics that could account for changes in test performance. Most importantly, order effects of stimulation condition and potential practice effects ap-peared not to be related to advanced performance on the WCST–64, since two out of the three patients started with the R-on condition.
According to non-cognitive behavioral aspects, one patient presented elevated depressive symptoms and three other patients showed symptoms of depression and/or anxiety only marginally below the cut-off. Thus, we cannot rule out that differential mood states might
have influenced task performance of the respective pa-tient. Moreover, based on findings about mood effects of DBS treatment [30], it might be speculated whether changes in WCST performance might be mediated by side-specific stimulatory mood effects. Since changes in mood states following unilateral stimulation were not explicitly assessed in the present study, no inference can made about this hypothesis. However, future studies should further clarify the question of mood alterations as a function of unilateral stimulation.
It remains uncertain if effects of unilateral DBS on executive task performance could be mediated by an asymmetric dopaminergic deficit in the individual patient. Studies that have attempted to explore the re-lationship between cognitive impairments and the asymmetry of motor symptoms in PD have found contradictory results. While some studies reported no correlation between the laterality of motor symptoms and cognitive asymmetry scores [1, 20], Tomer et al. [33] found that initial symptoms on the left side of the body were associated with more pronounced cognitive de-cline. However, comparison of test results between pa-tients with left- or right-sided onset of initial symptoms yielded comparable mean values under both stimula-tion conditions. The small size of subgroups precluded approaches to statistically test the interaction of the stimulated side and the side of symptom onset. It may also be an objective of future studies to investigate the potentially confounding nature of this variable.
Finally, observed effects of DBS always depend on the precise and accurate location of electrode contacts. We tried to verify the lead placement by employing postop-erative non-stereotactic CT scans that were matched with the preoperative planning data (see methods sec-tion). However, dependence of functional consequences of DBS on this parameter should be considered when interpreting results.
We conclude that based on these preliminary results it is plausible to assume that the left and the right hemi-sphere might differ in their vulnerability to tolerate side effects on executive task performance after bilateral stimulation of the STN. Future studies should address the question if laterality effects can be observed as well in other cognitive or affective domains. Adjustment of particularly left-sided stimulation parameters might help to improve the balance between motor benefits and cognitive side effects for patients undergoing DBS treat-ment.
■ Conflict of interest The authors declare no conflict of interest.
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