The impact of Parkinson’s disease and subthalamic deep brain stimulation on reward processing

Neuropsychologia 75 (2015) 11–19

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The impact of Parkinson’s disease and subthalamic deep brain stimulation on reward processing Ricarda Evens a,n, Yuliya Stankevich a, Maja Dshemuchadse b, Alexander Storch c, Martin Wolz d, Heinz Reichmann c, Thomas E. Schlaepfer e,f, Thomas Goschke b, Ulrike Lueken a,1 a

Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany Department of Psychology, Technische Universität Dresden, Dresden, Germany c Department of Neurology, Technische Universität Dresden, Dresden, Germany d Department of Neurology, Elblandklinikum, Meissen, Germany e Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany f Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University, Baltimore, USA b

art ic l e i nf o

a b s t r a c t

Article history: Received 27 January 2015 Received in revised form 20 April 2015 Accepted 9 May 2015 Available online 12 May 2015

Background: Due to its position in cortico-subthalamic and cortico-striatal pathways, the subthalamic nucleus (STN) is considered to play a crucial role not only in motor, but also in cognitive and motivational functions. In the present study we aimed to characterize how different aspects of reward processing are affected by disease and deep brain stimulation of the STN (DBS-STN) in patients with idiopathic Parkinson’s disease (PD). Methods: We compared 33 PD patients treated with DBS-STN under best medical treatment (DBS-on, medication-on) to 33 PD patients without DBS, but optimized pharmacological treatment and 34 agematched healthy controls. We then investigated DBS-STN effects using a postoperative stimulationon/ -off design. The task set included a delay discounting task, a task to assess changes in incentive salience attribution, and the Iowa Gambling Task. Results: The presence of PD was associated with increased incentive salience attribution and devaluation of delayed rewards. Acute DBS-STN increased risky choices in the Iowa Gambling Task under DBS-on condition, but did not further affect incentive salience attribution or the evaluation of delayed rewards. Conclusion: Findings indicate that acute DBS-STN affects specific aspects of reward processing, including the weighting of gains and losses, while larger-scale effects of disease or medication are predominant in others reward-related functions. & 2015 Elsevier Ltd. All rights reserved.

Keywords: Subthalamic nucleus Deep brain stimulation Parkinson’s disease Delay discounting Iowa Gambling Task

1. Introduction Reward processing comprises perception, salience attribution, and reaction to stimuli that signal reward or punishment. Conveyed via learning mechanisms, it facilitates behavioral adaption to positive or negative feedback. The present study aimed to characterize different aspects of reward processing as a function of disease and deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with idiopathic Parkinson’s disease (PD).

n Correspondence to: Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Street 46, 01187 Dresden, Germany. E-mail address: [email protected] (R. Evens). 1 Present address: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany.

http://dx.doi.org/10.1016/j.neuropsychologia.2015.05.005 0028-3932/& 2015 Elsevier Ltd. All rights reserved.

Via the cortico-subthalamic and cortico-striatal pathways, the STN receives direct and indirect cortical information not only from motor, but also prefrontal, orbitofrontal and anterior cingulate cortices (Haynes and Haber, 2013), and is therefore considered to affect motor, as well as cognitive and motivational functions (Temel et al., 2005). A prominent functional model of the STN proposes that it modulates the timing of a response, preventing premature responding especially under conflicting motivational response options (Frank, 2006). In line with this, STN lesions in rats result in an increased motor impulsivity or impulsive action (Baunez et al., 1995; Uslaner and Robinson, 2006). Of note, in rodents opposite effects have been reported for impulsive choice, a form of impulsivity that refers to impulsivity in decision-making processes (Winstanley et al., 2006) rather than to behavioral disinhibition and that is commonly assessed using delay discounting

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tasks. Having the choice between a soon, but small, or a larger, but delayed reward, rats with STN lesions preferred the delayed option, indicating a decreased impulsive choice (Uslaner and Robinson, 2006; Winstanley et al., 2005). It has been discussed that this effect is caused by an increased incentive salience of the delayed reward (Uslaner and Robinson, 2006). While to date there are no studies on the influence of DBS-STN on delay discounting in humans, the influence of PD has been investigated, revealing a complex interplay between disease effect, dopaminergic medication and individual predispositions: while patients with impulsive symptoms and dopaminergic medication showed increased discounting rates, this effect was not as clear in patients without impulsive symptoms and without medication (Housden et al., 2010; Leroi et al., 2013; Milenkova et al., 2011; Voon et al., 2010). Notably, no evidence on decreased discounting rates in PD patients is available. One explanation for a shift to a more impulsive choice pattern might be found in an altered incentive value attribution. The incentive salience of an object describes how much we “want” it, a quality that can be differentiated from how we react to that object that is from how much we “like” it (Berridge and Robinson, 1998). In order to see whether incentive value attribution is affected in patients with PD and DBS-STN, we included a task in which participants were asked to ascribe a monetary value to certain everyday objects. If DBS-STN affects the reward system by altering valuation processes, stimulation should also affect the performance in an Iowa Gambling Task (IGT), a decision-making task requiring the simultaneous weighting of gains and losses in order to develop an optimal gambling strategy in the long run. For PD patients without DBS, decreased performance with more risky choices has repeatedly been reported (Kobayakawa et al., 2010, 2008; Mimura et al., 2006; Pagonabarraga et al., 2007; Perretta et al., 2005). Several findings indicate that this impairment is related to the intake of dopaminergic medication: it is stronger for PD patients that exhibit pathologic gambling (considered as hyper-dopaminergic symptom) (Rossi et al., 2010) and has not been found in PD patients with symptoms of apathy (considered as hypo-dopaminergic symptom) (Martínez-Horta et al., 2013) and in de novo PD patients that do not have dopaminergic medication yet (Poletti et al., 2010). However, the data are more inconsistent concerning the effect of acute DBS-STN in PD: while some studies did not find pronounced effects on the overall performance in the IGT (Castrioto et al., 2015; Czernecki et al., 2005; Pinkhardt et al., 2012), increased risky choices particularly during the last block of the experiment under DBS-on condition have been reported (Oyama et al., 2011). Delineating disease-related changes from stimulation effects, we compared 33 PD patients with DBS-STN (PD-DBS) under best medical treatment (DBS-on, medication-on) to 33 PD patients without DBS, but optimized pharmacological treatment (PDnonDBS) and 34 age-matched healthy controls (HC). Based on previous evidence we expected stronger devaluation of delayed rewards in a delay discounting task (Milenkova et al., 2011) and impaired performance in the IGT (Mimura et al., 2006; Perretta et al., 2005) for PD patients. Regarding DBS-STN effects, we hypothesized weaker devaluation of delayed rewards (Uslaner and Robinson, 2006; Winstanley et al., 2005), and increased incentive salience attribution (Serranová et al., 2011) under DBS-on condition, as well as impaired IGT performance (Oyama et al., 2011).

2. Methods 2.1. Sample PD patients were diagnosed with idiopathic PD according to UK Brain Bank criteria (Litvan et al., 2003). PD-DBS had a stable postoperative condition of at least three months after surgery. Exclusion criteria comprised for all subjects significant cognitive deficits (Mini-Mental State Examination (MMSE) r24, (Folstein et al., 1975)), for all PD patients the presence of other neurological and impulse control disorders (based on expert opinion of the treating neurologist); for PD-DBS patients the non-tolerance of a transient deactivation of DBS electrodes and for HC presence of any neurological or current (past 12-months) psychiatric disorders (DSMIV-TR criteria (Wittchen and Pfister, 1997)). HC and PD-nonDBS were matched to PD-DBS for gender, age and education. 2.2. Stereotactical electrode implantation procedure Trajectories for the STN were planned on the basis of the following coordinates on both hemispheres with individual adjustment to target points visible in T2-sequences: x (lateral distance from the midline)¼12, y (anteroposterior distance from the AC)¼3, and z (height relative to the AC line)¼ 4. Surgery was done under local anesthesia using the ZD stereotactic system. The target point was verified during the surgery by microelectrode recording (ISIS MER System, Inomed) and intraoperative neurological testing of stimulation effects. Electrodes (Medtronic 3389) were implanted and leads were fixed at the burr hole. The pulse generator (Activa PC Modell 37601; Medtronic) was implanted infraclavicularly or abdominally (according to patient preference) and activated. 2.3. Procedure Testing took place on two different testing days. Each of them lasted 2–3 h and the minimal time interval between both days was 2 weeks. PD-DBS completed one session under DBS-on/medication-on and the other under DBS-off/medication-on condition (counterbalanced order). PD-nonDBS completed both sessions under medication-on and also for HC were both visits identical. To control for learning effects, clinical and healthy control data were matched to the respective PD-DBS session (e.g. if PD-DBS session 1 was ”DBS-on” stimulation, session 1 data of the corresponding controls were matched to “DBS-on” and session 2 data to ”DBSoff”). On both visits participants completed a delay discounting task, a task on the Incentive Value of Everyday Objects and the Iowa Gambling Task. Motor symptoms were assessed using the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) (Movement Disorder Society Task Force, 2003). In order to control for phasic effects of dopamine medication, assessment time was adjusted to the individual dosing regimen, so that all patients took their regular intake of medication at the beginning of each test session. After modulation of stimulation electrodes, a waiting period of 1 h was applied (also for HC) before starting the tasks. On the first visit all participants were furthermore screened for neuropsychiatric symptoms using the Montgomery–Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979), the Apathy Evaluation Scale (Clinician version, AES-C) (Marin et al., 1991) and the Barratt Impulsiveness Scale (BIS-11) (Patton et al., 1995). PD patients also completed the Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease (QUIP) (Weintraub et al., 2009). All questionnaires were completed before manipulation of the electrodes. The protocol was approved by the ethics committee of the Technische Universität Dresden and all participants gave their written informed consent.

R. Evens et al. / Neuropsychologia 75 (2015) 11–19

2.4. Tasks 2.4.1. Delay Discounting In each trial of this computer-administered version participants had to choose between receiving a small amount of money soon or a large amount after a delayed period of time (soon delays: “today”, “in 30 days”; late delays: soon delays þ1, 4, 10, 27, 60, 90, or 180 days; soon amount: 10€; large amounts: 12, 15, 20, 50 or 100 €). In each of 3 blocks all 70 combinations were randomly presented, resulting in a total number of 210 trials. To increase commitment, participants were told that they would receive the money of one randomly selected choice at the displayed point in time (being held constant for all participants at 25€ in one month). K-values were calculated, assuming a hyperbolic discount function over indifference points of subjective equivalence between immediate and delayed rewards (Dshemuchadse et al., 2013). Larger k-values indicate stronger discounting or devaluation of delayed and a preference for immediate rewards and are indicative of impulsivity in decision-making processes or impulsive choice. 2.4.2. Incentive Value of Everyday Objects Following previous work of Shanteau and Troutman (1992) this task assessed the subjective incentive value of everyday items without forced behavioral choices that could be confounded by motor impulsivity. Six everyday objects (vase, soap, watch, shaving brush, book, and thermometer) were presented one by one (counterbalanced order between patients, but identical order for both testing sessions). For each object participants indicated how much money they were willing to pay. They were explicitly instructed not to estimate the exact price of the object, but its subjective value at this moment. The basic idea is that the amount of money people are willing to pay for something is related to how much they “want” it and thus can be seen as an indicator for the underlying incentive salience of an object. Based on the time lag between both sessions and in order to achieve comparability of data sets we decided to use identical objects for both assessment days. On the second visit participants were instructed not to recall the previous value, but to spontaneously decide about the actual value. The dependent variable included the amount of money ascribed to the objects. A higher amount is indicative of a greater incentive value. Measures of reliability for this newly developed task are reported in the results section. 2.4.3. Iowa Gambling Task This computer-administered version followed the original task by Bechara et al. (1994). In each of 100 trials participants are required to choose one card out of four available card decks. Each card is associated with a certain gain or loss of money and participants were instructed to maximize their gains throughout the game (starting points: 2000). After card selection, gains or losses of the current choice, as well as the resulting total gain were revealed. Two card decks were advantageous with lower gains, but also small losses, resulting in an overall gains4 losses ratio in the long run. The other two decks were disadvantageous with high gains, but also high losses, resulting in an overall losses 4 gains ratio. Thus, choosing from the disadvantageous decks encompassed a greater risk of losing money. Order of decks was counterbalanced and parallel versions were used between testing sessions. Dependent variables included the number of choices from advantageous vs. disadvantageous decks, as well as the total gain obtained. 2.5. Statistical analyses To assess disease effects, groups were compared under best medical treatment (BMT: DBS-on, medication-on) using one-way

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ANOVA. A nonparametric Kruskal-Wallis test was applied to k-values. To assess the effect of acute stimulation, PD-DBS-on and -off were compared using paired t-tests or Wilcoxon test for kvalues. For the IGT, performance was furthermore analyzed for the trend for each block of 20 cards using repeated measures ANOVA. The relationship between task performance and disease characteristics (disease duration, daily levodopa equivalent dose (LEDD) (Tomlinson et al., 2010), and motor symptoms) were investigated using Pearson’s product-moment or Spearman’s rank correlation coefficient. Data analyses were carried out using IBM SPSS Statistics 21. Significance level was set at p o0.05. One-tailed p-values are reported for pair-wise comparisons with clear directional hypotheses. Effect sizes are indicated using Cohen’s d or f. To account for differences in disease characteristics in both patients groups we additionally applied a propensity score matching. See supplemental material for more details. Furthermore, we investigated the relationship between task scores of the subgroups and their measures of neuropsychiatric symptoms (MADRS, AES, BIS, QUIP) in exploratory correlation analyses.

3. Results 3.1. Sample characteristics For information on patient enrollment please refer to the supplemental material. An overview of demographic and clinical characteristics of the final sample is given in Table 1. 3.2. Delay Discounting No complete delay discounting data were available for three subjects, resulting in 32 PD-DBS, 32 non-DBS, and 33 HC data sets. Results are presented in Fig. 1. 3.2.1. Disease effect For k-values a significant group effect was observed (means (SD): PD-DBS-on: 1.57 (6.57), PD-nonDBS: 0.42 (1.22), HC: 0.04 (0.05); χ² ¼7.08, ptwo-tailed ¼0.03): PD-DBS displayed higher k-values than HC (ptwo-tailed o 0.01). Results did not differ after propensity score matching (see Supplemental material). 3.2.2. DBS-STN No effects of stimulation were observed comparing DBS-on/-off conditions (means (SD): PD-DBS-on: 1.57 (6.57), PD-DBS-off: 1.05 (3.38); t31 ¼0.46, pone-tailed ¼0.33, d ¼ 0.10). Furthermore, we did not observe any significant correlations between task performance and disease characteristics for the subgroups (see Table 2). 3.3. Incentive Value of Everyday Objects One PD-DBS patient was not able to complete the task, resulting in 32 PD-DBS, 33 PD-nonDBS, and 34 HC data sets. See Fig. 2 for results. The task showed an acceptable test-retest reliability of 0.75 and a Cronbach’s alpha coefficient of 0.70 for the subsample of HC. 3.3.1. Disease effect We observed a significant group effect comparing the incentive values ascribed to everyday objects (means (SD): PD-DBS-on: 16.79 (9.71), PD-nonDBS: 16.87 (8.35), HC: 11.54 (7.28); F2,96 ¼4.34, p¼ 0.02, f ¼0.30): PD-DBS and PD-nonDBS patients assigned higher values to the presented objects than HC (ptwo-tailed o0.05). On average PD-DBS and PD-nonDBS increased the values by factor 1.5 compared to HC. Results did not differ after propensity score

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Table 1 Sample characteristics. PD-DBS (n¼33) Demographic variables Age Male gender (%) Education (years) Clinical variables Disease duration (years) Hoehn & Yahr stage #Hoehn & Yahr stage 1 (%) # Hoehn & Yahr stage 2 (%) # Hoehn & Yahr stage 2.5 (%) # Hoehn & Yahr stage 3 (%) # Hoehn & Yahr stage 3.5 (%) # Hoehn & Yahr stage 4 (%) # Hoehn & Yahr stage 4.5 (%) UPDRS motor scale BMT UPDRS motor scale Off LEDD LEDD-DA Neuropsychiatric symptoms MMSE QUIP BIS-11 MADRS AES-C

PD-nonDBS (n¼ 33)

HC (n¼ 34)

χ²/Z/t/F(df)

65.88 23 10.79

(6.40) (69.70) (1.85)

65.18 25 10.85

(8.13) (75.76) (1.62)

65.26 24 10.74

(6.15) (70.59) (1.38)

15.27 3.17 0 1 2 22 2 5 1 19.05 33.29 938.54 313.61

(5.37) (0.51) (0.00) (3.03) (6.06) (66.67) (6.06) (15.15) (3.03) (9.81) (14.01) (367.16) (147.20)

7.37 2.39 2 15 3 13 0.00 0.00 0.00 16.91 – 882.71 338.74

(4.26) (0.59) (6.06) (45.45) (9.09) (39.39) (0.00) (0.00) (0.00) (7.28) – (386.63) (161.69)

– – – – – – – – – – – – –

– – – – – – – – – – – – –

(1.20) (2.05) (8.81) (5.66) (6.36)

29.21 1.06 54.52 4.33 8.88

(0.99) (1.30) (8.93) (3.68) (4.68)

29.32 – 50.94 1.59 5.41

(0.84) – (5.44) (2.19) (3.72)

28.79 1.55 60.97 7.55 15.45

0.10 0.35 0.04

P

(2,97) (2) (2,97)

0.905 0.839 0.960

6.62  4.90

(64)

o0.001 o0.001

1.00  9.41 0.60  0.66

(64) (32) (64) (64)

0.319 o0.001 0.550 0.512

(2,97) (50) (2,96) (2,97) (2,97)

0.082 0.264 o0.001 o0.001 o0.001

2.57 2.10 13.70 17.84 34.37

Numbers in brackets indicate standard deviation of the mean; UPDRS: Unified Parkinson’s Disease rating Scale; BMT: Best Medical Treatment; Off: DBS-off, medication-on; LEDD: levodopa equivalent daily dose; LEDD-DA: LEDD only for dopamine agonists; Results of post-hoc t-tests: BIS-11: PD-DBS4PD-nonDBS, HC (all po 0.01); MADRS: PD-DBS4 PD-nonDBS4 HC (all p o 0.01); AES-C: PD-DBS 4PD-nonDBS 4HC (all p o 0.01).

matching (see Supplemental material). 3.3.2. DBS-STN No effect of stimulation was observed comparing DBS-on/-off conditions (means (SD): PD-DBS-on: 16.79 (9.71), PD-DBS-off: 17.64 (9.49); t31 ¼  0.66, pone-tailed ¼ 0.26, d ¼  0.09). Furthermore, no significant correlations between task performance and disease characteristics were observed for the PD-subgroups (see Table 2). 3.4. Iowa Gambling Task For four subjects no complete IGT data were available. Data of four PD-DBS and two HC were excluded from analyses, because

the numbers of missings exceeded 2.5 standard deviations, resulting in a final sample of 26 PD-DBS, 32 PD-nonDBS, and 32 HC data sets. See Fig. 3 for results. 3.4.1. Disease effect Comparing the total gain we observed no significant group differences (means (SD): PD-DBS-on: 359.62 (2343.10), PDnonDBS: 1170.31 (2162.29), HC: 442.19 (2271.85); F2,87 ¼1.20, p¼ 0.31, f ¼0.17), but results showed a significant group effect for the difference between advantageous and disadvantageous choices (means (SD): PD-DBS-on:  16.19 (21.93), PD-nonDBS:  2.09 (16.27), HC: 7.31 (20.78); F2,87 ¼ 3.72, p ¼0.03, f ¼0.29). PD-DBS made more disadvantageous choices than PD-nonDBS (ptwo-tailed o0.05) and in tendency than HC (ptwo-tailed o0.10).

Fig. 1. Delay Discounting: mean k-values; left: group comparison under best medical treatment, right: effect of acute DBS-STN; error bars indicate standard error of the mean; nnp o 0.01.

R. Evens et al. / Neuropsychologia 75 (2015) 11–19

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Table 2 Correlation coefficients of task performance with clinical variables. Delay discounting: k-value

IVEOT: Total score

PD-DBSon

PD-DBSoff

PDnonDBS

PDDBS-on

PD-DBSoff

Disease duration r 0.102 p-value 0.579

0.015 0.935

0.294 0.103

 0.170 0.351

 0.117 0.523

LEDD r p-value

 0.106 0.564

0.030 0.872

0.022 0.903

 0.020 0.913

UPDRS motor scale r  0.165 p-value 0.368

0.057 0.757

0.037 0.840

0.085 0.643

IGT: Difference score PDnonDBS

IGT: Total gain

PD-DBSon

PD-DBSoff

PDnonDBS

PD-DBSon

PD-DBSoff

PDnonDBS

0.037 0.839

 0.121 0.556

 0.264 0.193

0.083 0.652

0.188 0.357

0.062 0.765

 0.009 0.961

 0.022 0.907

 0.254 0.153

 0.424 0.031

 0.143 0.485

0.034 0.855

 0.017 0.936

0.269 0.184

 0.196 0.281

0.069 0.709

 0.181 0.313

 0.065 0.753

 0.064 0.758

0.144 0.439

0.203 0.319

 0.457 0.019

 0.138 0.459

Significant results in bold; IVEOT: Incentive Value of Everyday Objects; r - numbers indicate results from Pearson product-moment correlation (IVEOT & IGT) or Spearman’s rank correlation (Delay Discounting); task performance data of the “ON”-session were used for PD-nonDBS.

Differences between HC and PD-nonDBS were not significant. Results did not differ after propensity score matching (see Supplemental material). Further analyses of the trend for each block of 20 cards showed a significant main effect of block (F4,384 ¼ 3.26, p ¼ 0.01, f¼ 0.19), and a non-significant, yet strong trend for an interaction of block and group (F8,348 ¼1.96, p ¼0.05, f ¼0.21). Performance in block 2 and 5 was worse than in block 1 (ptwo-tailed o0.05). In contrast to PD-nonDBS patients and HC, PD-DBS patients showed a more fluctuating performance across the blocks (see Fig. 4). 3.4.2. DBS-STN There was no significant difference in the total gain between DBS-on/-off conditions (means (SD): PD-DBS-on: 359.62 (2343.10), PD-DBS-off: 822.12 (2326.04); t25 ¼  0.76, pone-tailed ¼0.23, d ¼  0.20), but results showed a stimulation effect for the difference score: patients made more disadvantageous choices under DBS-on (means (SD): PD-DBS-on:  16.19 (21.93), PD-DBS-off: 7.46 (15.78); t25 ¼ 1.91, pone-tailed ¼0.03, d ¼  0.45). Further analyses of the trend for each block of 20 cards showed no main effect block (F4,100 ¼ 1.59, p ¼0.18, f ¼0.25), but a tendency for an interaction of stimulation and block (F4,100 ¼ 2.34, p ¼ 0.06, f ¼0.30). Patients with DBS switched off showed better performance in block 2 and 5 and a more constant performance compared to the DBS-on condition. Furthermore, we observed a significant negative correlation

between the LEDD and the IGT differences score for PD-DBS-on, but not for PD-DBS-off or PD-nonDBS and a negative correlation between the UPDRS motor score and the total gain, but only for PD-DBS-off. There were no significant correlations with disease duration (see Table 2). 3.5. Neuropsychiatric symptoms The exploratory analyses did not reveal any correlations between task scores of the subgroups and their measures of neuropsychiatric symptoms that were significant after Bonferroni correction. Data can be found in the Supplemental material.

4. Discussion The study assessed the impact of disease and DBS-STN on different components of reward processing in patients with PD. The presence of PD was associated with increased incentive salience attribution and devaluation of future rewards in a delay discounting task. Acute DBS-STN on the other hand increased risky choices in the Iowa Gambling Task (IGT) under DBS-on condition, but did not further affect incentive salience attribution or the evaluation of future rewards. Findings indicate that acute DBS-STN affects specific aspects of reward processing, including the weighting of gains and losses, while larger-scale effects of disease

Fig. 2. Incentive Value of Everyday Objects: mean value ascribed to everyday objects; left: group comparison under best medical treatment, right: effect of acute DBS-STN; error bars indicate standard error of the mean; np o 0.05.

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Fig. 3. Iowa Gambling Task: Difference between advantageous and disadvantageous choices; left: group comparison under best medical treatment, right: effect of acute DBSSTN; error bars indicate standard error of the mean; np o 0.05.

or medication are predominant in others reward-related functions. Enhanced devaluation of future rewards can be regarded as an indicator of increased impulsive choice, an aspect of impulsivity that relates to the intolerance of delayed gratification. We observed rising discounting rates from healthy controls (HC) to patients with Parkinson’s disease without (PD-nonDBS) and with DBS-STN (PD-DBS), with a significant difference between PD-DBS and HC. Reviewing this together with results from previous studies assessing delay discounting in PD patients with impulse control disorders (ICD) (Housden et al., 2010; Leroi et al., 2013) this could indicate that not only ICDs (which were excluded in our study), but also disease progression favors the occurrence of increased impulsive choices. Disconfirming our initial hypothesis, temporal devaluation was not affected by DBS-STN. Since our assumptions were derived from STN lesion studies in rats (Uslaner and Robinson, 2006; Winstanley et al., 2005) it is possible that the action of DBS-STN on delay discounting may not be equivalent to that of STN lesions. Even though effects observed after DBS-STN often resemble those seen after STN lesion, the exact mechanisms of

action are not fully understood yet (McIntyre et al., 2004). Perhaps even more important, it should be considered that studies reporting decreased discounting rates after STN lesion investigated healthy rats. It is feasible that the effects of DBS-STN and STN lesion on discounting rates would be similar in healthy subjects, but that in PD effects of acute stimulation interact with disease and/or medication effects. It has been suggested that differences in reward sensitivity might arise from a changed incentive salience attribution (Uslaner and Robinson, 2006). We tested this hypothesis by including a task that allowed the investigation of incentive values as an indicator of incentive salience attribution, without the involvement of forced behavioral responses or time pressure. Our findings revealed a distinct effect of disease, without further modulation of acute DBS-STN: PD-DBS as well as PD-nonDBS increased the value of everyday objects by approximately factor 1.5 compared to HC. Contrary to our initial assumption, we observed no effect of DBSSTN on salience attribution. This is in contrast to Serranová et al. (2011) who described that patients with DBS-STN attributed lower

Fig. 4. Iowa Gambling Task: Difference between advantageous and disadvantageous choices for each block of 20 cards; left: group comparison under best medical treatment, right: effect of acute DBS-STN; error bars indicate standard error of the mean.

R. Evens et al. / Neuropsychologia 75 (2015) 11–19

valence scores to aversive pictures during the DBS-on condition than during the DBS-off condition. However, while the effect in their study was restricted to emotional stimulus material with negative valence, we assessed the positive incentive value of everyday objects. Again, as we did not observe stimulation effects on delay discounting, this could indicate either that DBS-STN does not influence salience attribution or that effects are superimposed by disease and/or medication effects. Alternatively, it cannot be ruled out that the use of identical objects on both assessment days might have reduced the sensitivity to capture changes over time and future studies should therefore use matched, but different objects for repeated assessments. Analyzing psychometric properties of this task, we observed an acceptable test–retest reliability and internal consistency in healthy controls. Furthermore, group differences indicate that the task is sensitive enough to detect disease specific effects. However, future studies will be needed to investigate psychometric properties more thoroughly, particularly for measures of convergent and discriminant validity. In a constantly changing environment, altered contingencies (e.g. signs that signal reward or punishment) demand for behavioral adaption. Using the IGT as an indicator for reward- and punishment-related learning, we observed no general disease effect, but an effect of acute DBS-STN. During DBS-on patients selected significantly more cards from disadvantageous card decks, showed a non-significant lower total gain than during DBS-off and a strong tendency for fluctuating performance over time. This increase in risky behavior was also apparent in comparison to PDnonDBS, even after controlling for differences in disease duration and symptom severity. In order to compare our results with previously reported data it is important to look closely at two sources of influence: the medication status during assessment and the total daily dosage of dopaminergic medication in both PD-DBS and PD-nonDBS groups. In the present study all patients were assessed one hour after intake of their usual dopaminergic medication. Furthermore, PD-DBS and PD-nonDBS were compared inter-individually and total LEDDs did not differ significantly between groups. Looking at the effect of acute stimulation (DBS-on vs. DBSoff) our data resemble those seen in previous work that were also assessed under the intake of dopaminergic medication (Oyama et al., 2011), but contradict two other studies that were assessed after suspension of usual dopaminergic medication and did not find an acute effect of DBS-STN (Castrioto et al., 2015; Czernecki et al., 2005). Likewise, differences to other studies were observed concerning chronic stimulation effects (DBS vs. nonDBS): while in our study PD-DBS-on showed worse performance compared to PD-nonDBS, other studies found no difference (Pinkhardt et al., 2012) or even a better performance in PD-DBS (Castrioto et al., 2015). Interestingly, these different results in the comparison of PD-nonDBS and PD-DBS parallel differences in the total daily dosages of dopaminergic medication between the groups: the less medication PD-DBS groups got in comparison to PD-nonDBS control groups the better was their performance. This supports the assumption that effects comparing stimulated and non-stimulated PD patients are at least partly a result of differences in the total daily dosage of dopaminergic medication, and improvement after DBS surgery is related to an often associated reduction of medication rather than by the stimulation itself. However, even though dopaminergic effects are very important to explain changes in the IGT performance after DBS surgery, they cannot fully explain the modulatory effect of acute DBS-STN under constant medication. Here data suggest that there might be an interaction of acute stimulation and the intake of medication in the sense that stimulation further intensifies the effect of dopaminergic medication, but has no effect in patients that currently suspend their medication or that have a substantially reduced dosage of dopaminergic

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medication. This idea is supported by our observation that task performance was negatively correlated with LEDD only for PD-DBS under stimulation-on. Nevertheless, this explanation of the role of the total daily dosage of dopaminergic medication and the current status of medication during assessment is a retrospective explanation of the variance in previous data and has to be confirmed in prospectively planned studies. Concerning general disease related effects it is noteworthy that contrary to previous studies (e.g. Castrioto et al., 2015; Kobayakawa et al., 2010) we did not observe a general effect of disease in the IGT. Although we excluded cognitive impairments in HC, this group seemed to perform not as well as control groups of previous studies, thus potentially shadowing disease-related effects in this task. Study limitations. Using a post-operative design, findings apply only to acute effects of DBS-STN and cannot be generalized to the treatment method (including surgery and change in medication). Furthermore, the study did not allow for the analysis of medication effects, since no medication-off condition was included. Due to the progressive character of PD and the increasing use of DBSSTN to treat advanced disease stages, the investigation of a clinical control group matched for disease features is difficult to realize and PD-DBS displayed longer disease durations and worse disease stages than PD-nonDBS. We controlled for these variables by using additional propensity score matching and results did not differ from initial analyses. Although the tasks were sufficiently sensitive to map PD-related effects on reward processing, we cannot exclude the possibility that the paradigms did not exactly cover DBSspecific deficits. Finally, in order to investigate the basic effects of DBS-STN, we excluded patients with manifest ICD. It is however conceivable that DBS-STN does significantly affect reward processing only in those patients developing ICD. Future studies should focus on the interaction of DBS, basic affective processing and neuropsychiatric symptom load in affected individuals. When interpreting the results, it is important to consider that disease effects and/or dopaminergic medication might interfere with or superimpose effects of DBS-STN, changing its action on PD patients compared to its potential action on the healthy brain. The complex interplay of DBS, disease and dopaminergic medication is illustrated by reports of a reduction of pathological gambling and other impulsive and compulsive behaviors in PD patients after DBS-STN that becomes apparent only with a combined reduction of dopaminergic medication (Bandini et al., 2007; Eusebio et al., 2013; Lhommée et al., 2012). Thus, while DBS-STN with concomitant reduction of dopaminergic medication results in a decrease, DBS-STN without reduction of medication might even result in an increase of impulsive symptoms in patients with PD. Decoding the treatment approaches for those patients at risk for neuropsychiatric complications could help to develop tailored treatment approaches for those patients at risk for neuropsychiatric complications.

Funding The study was supported by the German Research Foundation (LU 1509/3-1; and Collaborative Research Centre 940: “Volition and Cognitive Control: Mechanisms, Modulators, Dysfunctions”).

Financial disclosure/conflict of interest concerning the research related to the manuscript M. Dshemuchadse: none R. Evens and Y. Stankevich received DFG grants from the Collaborative Research Centre 940: “Volition and Cognitive Control: Mechanisms, Modulators, Dysfunctions”.

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A. Storch was acting on Advisory Boards and gave lectures and received research grants from Boehringer Ingelheim, GlaxoSmithKline, Abott, Lundbeck, TEVA, Meda, UCB Pharma, Orion, Novartis, Merz, Medtronic, Bayer HealthCare, Mundipharma and Archimedes. T. Wolz was acting on Advisory Boards and gave lectures and received research grants from GlaxoSmithKline, Valeant, Pfizer, Teva, UCB Pharma, Orion, Novartis, Medtronic and Abott. H. Reichmann was acting on Advisory Boards and gave lectures and received research grants from Abbott, Abbvie, Bayer Health Care, Boehringer/Ingelheim, Brittania, Cephalon, Desitin, GSK, Lundbeck, Merck-Serono, Novartis, Orion, Pfizer, TEVA, UCB Pharma, and Valeant. T.E. Schlaepfer received partial funding for three investigatorinitiated studies on DBS for major depression from Medtronic Inc. and the Hope for Depression Research Foundation (HDRF) and the Institute for Affective Neuroscience (ISAN). He is chair of the project group «Deep Brain Stimulation in Psychiatry: Guidance for Responsible Research and Application» funded by the Volkswagen Foundation (Hanover, Germany) and a member of the working Group Neuromodulation of the German Research Foundation. T. Goschke received research grants from the German Research Foundation (DFG): DFG grant GO 720/8-1: „Sucht als Volitionsstörung: Beeinträchtigungen kognitiver Kontrollfunktionen bei Substanzstörungen am Beispiel der Nikotinabhängigkeit“ (2011– 2014); Collaborative Research Centre „Volition and Cognitive Control” (2012-2016); DFG grants SFB 940 1/2012; SFB 940 1/2013; SFB 940 1/2014 (subprojects A6, B1, B3, C1, C3) and received grants and honoraria from Dr. Willmar Schwabe GmbH & Co. KG Medical Sciences for the study “Effects of Ginkgo biloba extract (EGb 761s) on cognitive control functions, activity of the prefrontal cortex and stress reactivity in adult healthy volunteers” (2010-2014). U. Lueken received research grants from the DFG: LU 1509/3-1, and from the Collaborative Research Centre 940: “Volition and Cognitive Control: Mechanisms, Modulators, Dysfunctions”.

Acknowledgments We would like to thank Dipl.-Psych. Sylvia Rietzel for supporting the data collection.

Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.neuropsychologia. 2015.05.005.

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