Effects of asymmetric dopamine depletion on sensitivity to rewarding and aversive stimuli in Parkinson's disease

Neuropsychologia 51 (2013) 818–824

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Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Effects of asymmetric dopamine depletion on sensitivity to rewarding and aversive stimuli in Parkinson’s disease Sari Maril a, Sharon Hassin-Baer b,c, Oren S. Cohen b,c, Rachel Tomer a,n a

Department of Psychology, University of Haifa, Mount Carmel, Haifa 31905, Israel The Parkinson Disease and Movement Disorders Clinic, The Sagol Neuroscience Center and Department of Neurology, Chaim Sheba Medical Center, Tel Hashomer, Israel c Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 September 2012 Received in revised form 1 February 2013 Accepted 5 February 2013 Available online 17 February 2013

The onset and progression of Parkinson’s disease (PD) motor symptoms is generally asymmetric, reflecting differential extent of nigral pathology and resulting dopamine depletion in each of the hemispheres. Given the role of dopamine in processing rewarding and aversive events, and considering findings associating asymmetric neural activity with differential sensitivity to positive and negative stimuli, the current study examined the possibility that dopamine asymmetry in PD is related to differential approach and avoidance tendencies. An original task assessing and comparing sensitivity to positive and negative probabilistic feedback was administered to 29 right-handed participants with idiopathic PD, 16 with predominant right-side and 13 with predominant left-side motor symptoms, to compare the two groups. As dopamine replacement therapy (DRT) has shown different effects on reward and punishment processing, all participants were assessed in both off- and on-medication states. As predicted, when off medication, participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while those with a greater right hemisphere deficit showed a trend toward the opposite pattern. Medication reversed the relationship between gain and loss sensitivity in the left-hemisphere PD group, but not in the right-hemisphere group. Particularly in the left-hemisphere PD group, findings support the possibility that subcortical dopaminergic asymmetry is reflected in behaviorally-expressed approach and avoidance tendencies. Furthermore, the effects of DRT on approach and avoidance appear to interact with asymmetry, shedding light on previous conclusions regarding the role of dopamine in reinforcement processing. & 2013 Elsevier Ltd. All rights reserved.

Keywords: Dopamine Parkinson’s disease Hemispheric asymmetry Approach Avoidance

1. Introduction Dopamine is central to neural processes underlying motivational control, with a widely accepted role in processing rewarding events and guiding goal-directed behavior, as well as known involvement in responding to aversive stimuli (Bromberg-Martin, Matsumoto, & Hikosaka, 2010). Accordingly, it has been proposed that the processing of positive and negative feedback and, more broadly, the relative tendency towards approach-related behaviors versus avoidance of aversive stimuli, is affected in populations in which the dopaminergic system is known to be compromised, among them patients with Parkinson’s disease (PD). In PD, degeneration of dopaminergic cells in ventrolateral parts of the substantia nigra (SN) leads to depleted dopamine levels in striatal projection areas, particularly the posterior putamen (Bjorklund & Dunnett, 2007; Hornykiewicz & Kish, 1984).

n

Corresponding author. Tel: þ972 48240939; fax: þ 972 48240966. E-mail addresses: [email protected], [email protected] (R. Tomer).

0028-3932/$ - see front matter & 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropsychologia.2013.02.003

Projections from the dorsal striatal area to cortical areas involved in motor control lead to the cardinal motor symptoms associated with PD. Loss of dopaminergic neurons in the ventral tegmental area and disruption of pathways from more ventral parts of the SN to the nucleus accumbens and caudate nucleus, which are associated with higher emotional and motivational functions (Middleton & Strick, 2000a,b), result in various non-motor manifestations of the disease (Bernal-Pacheco, Limotai, Go, & Fernandez, 2012; Cools, 2006). In this context, abnormalities in processing and learning from reinforcement have indeed been reported in PD (Bodi et al., 2009; Frank, Seeberger, & O’Reilly, 2004; Palminteri et al., 2009; Shohamy, Meyers, Kalanithi, & Gluck, 2008). In the majority of individuals with PD, the onset of motor symptoms is asymmetric (Elbaz et al., 2005; Toth, Rajput, & Rajput, 2004; Uitti et al., 2005), presenting as more severe on either the left side or the right side of the body. While its etiology is unclear (Djaldetti, Ziv, & Melamed, 2006), this asymmetry is known to be associated with asymmetric degeneration of dopaminergic neurons in the substantia nigra (Kempster, Gibb, Stern,

S. Maril et al. / Neuropsychologia 51 (2013) 818–824

& Lees, 1989) and, more generally, with asymmetry in dopaminergic transmission in the striatum (Leenders et al., 1990; Tatsch et al., 1997). Furthermore, it often persists throughout the progression of the disease (Djaletti et al., 2006). Davidson (2004) has proposed that differential sensitivity to positive and negative stimuli is associated with relatively asymmetric patterns of activation in anterior cortical regions, with several clinical and laboratory observations suggesting that left prefrontal cortex plays a more significant role in approach behavior, while right prefrontal cortex underlies withdrawal behavior and behavioral inhibition (Sutton & Davidson, 1997). As cortical asymmetries have been attributed to input from asymmetric subcortical neurochemical systems (Trevarthen, 1996), the dopaminergic system among them, it is suggested that dopamine asymmetry may play a role in modulating sensitivity to reward and punishment. The asymmetric dopamine depletion that leads to lateralized motor symptoms in PD presents a distinctive opportunity to examine this possibility. In a study examining approach and avoidance tendencies in PD, as expressed in the self-reported personality measures novelty seeking and harm avoidance, respectively, Tomer and Aharon-Peretz (2004) reported asymmetry-based effects, in line with Davidson’s (2004) model. The aim of the current study was to determine whether this relationship between differential patterns of dopaminergic asymmetry and self-reported approach and avoidance tendencies would be expressed behaviorally, on a measure specifically designed to compare sensitivity to positive and negative feedback. Based on the aforementioned findings associating relatively greater left- and right-hemisphere activity with approach and withdrawal behavior, respectively, it was hypothesized that patients with a relatively greater degree of dopamine loss in the left-hemisphere (‘‘left-hemisphere PD,’’ predominantly right-side motor symptoms) would be more sensitive to punishment than to reward, while the opposite would be true for patients with relatively greater dopamine loss in the right-hemisphere (‘‘right-hemisphere PD,’’ predominantly leftside motor symptoms). It was further predicted that relative sensitivity to reward versus punishment would be correlated with a relative measure of motor asymmetry in the PD group as a whole. The dopamine-based medications used to treat PD have repeatedly been shown to affect reward and punishment processing in differential ways (Bodi et al., 2009; Frank et al., 2004; Palminteri et al., 2009; van Wouwe, Ridderinkhof, Band, van den Wildenberg, & Wylie, 2012), raising the possibility that medication interacts with asymmetry to determine approach and avoidance tendencies among asymmetric, medicated patients. Participants in the current study were thus assessed in both off-medication and on-medication states, such that the main and interactive effects of both asymmetry and medication could be evaluated. Predictions about possible interactions between medication and asymmetry can be considered in the context of the ‘dopamine overdose hypothesis’ (Cools, 2006; Gotham, Brown, & Marsden, 1988). Attempting to explain the detrimental effects of systemically increased dopamine levels on some cognitive functions, this model suggests that dopaminergic medications such as L-dopa normalize dopamine levels in depleted areas, while increasing levels excessively in areas that are less affected (Cools, Barker, Sahakian, & Robbins, 2001; Swainson et al., 2000). While this model was formulated based on evidence that striatal dopamine depletion in PD is expressed earlier and more significantly in dorsolateral areas than in more ventral areas (Kish, Shannak, & Hornykiewicz, 1988), the idea that performance on cognitive tasks may be disrupted by either reducing or increasing optimum dopamine levels can also be applicable with respect to asymmetry. Namely, when dopamine depletion is

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greater in one hemisphere than in the other, the addition of dopaminergic medications may ameliorate deficits in the more depleted hemisphere while excessively increasing dopamine levels in the other. Thus, medication is expected to alter the relationship between the two task conditions in each of the groups.

2. Methods 2.1. Participants Twenty-nine right-handed participants with idiopathic Parkinson’s disease were recruited from the patient population of the Parkinson’s Disease and Movement Disorders Clinic at the Sheba Medical Center. All participants gave written informed consent and the study was approved by the local ethics committee. Major psychiatric disorder predating the onset of PD, insulin-dependent diabetes, history of head trauma involving loss of consciousness, other neurological disease, history of drug or alcohol abuse, and surgical relief of PD symptoms were grounds for exclusion. All participants were non-demented and scored 28 or above on the Mini-Mental State Exam (MMSE; Folstein, Folstein, & McHugh, 1975), which was administered at the time of testing. Participants satisfying MiniInternational Neuropsychiatric Interview (MINI; Sheehan et al., 1998) criteria for any Axis I psychiatric diagnosis were also excluded. All participants were on stable doses of medication when recruited for the study. Use of some form of levodopa-based (L-dopa-based) medication was required for inclusion; additional medications included dopamine agonists (17 participants), rasagiline (14 participants), selegeline (7 participants), amantadine (13 participants), entacapone (13 participants), anticholinergic medications (5 participants), and antidepressant medications (5 participants). L-dopa dose, agonist dose, and a calculated L-dopa equivalence dose incorporating both types of medications (Evans et al., 2004) were documented for each participant. The group was divided according to the side of onset of motor symptoms (13 left-onset motor symptoms, or right-hemisphere PD; 16 right-onset of motor symptoms, or left-hemisphere PD), as determined by documentation of their neurological examinations at the time of diagnosis and confirmed in a neurological examination at the time of testing. 2.2. Measures General demographic information was collected including age, sex, and years of formal education, and the Hamilton Rating Scale for Depression (HAMD; Hamilton, 1960) and Hamilton Anxiety Rating Scale (HAMA; Hamilton, 1959) were administered. The motor examination portion (items 18–31) of the United Parkinson’s Disease Rating Scale (UPDRS; Fahn et al., 1987) was used to assess the severity of Parkinsonian motor deficits in the PD groups, for each side of the body and for both sides combined. 2.2.1. Gain–loss sensitivity (GLS) task An original computerized task that assesses and compares sensitivity to positive and negative probabilistic feedback under separately-administered conditions was used. In each condition, four decks of cards, numbered 1–4, are graphically presented on the screen and the participant is instructed to select one card in each of 100 trials by pressing the key on the keyboard corresponding to the number of the deck of choice. After each selection, one of two feedback options is presented. In the reward condition, the participant either gains ( þ10) or does not gain (0) ten points (virtual money), while in the punishment condition, the participant either loses ( 10) or does not lose (0) ten points. Unbeknownst to participants, the probabilities of the two feedback types vary between the decks, with decks corresponding to 80%, 70%, 60%, and 50% chances of gaining ten points or losing ten points in the reward or punishment conditions, respectively. Thus, the task enables direct comparison of responses to positive versus negative feedback, as well as examination of sensitivity to small changes in feedback probability. In the reward condition, participants begin with no points, and are given the following instructions: ‘‘You will be presented with four decks of cards: 1, 2, 3, 4. In each trial, select one card from the deck of your choice by pressing the corresponding key on the keyboard. Each time you choose a card, you may earn money—sometimes you will and sometimes you will not. Some decks are better than others and you are completely free to move from deck to deck whenever you want to and as many times as you choose. The goal of the game is to earn as much as possible. Please treat the game money as though it were real, and make your decisions as though they involved your own money.’’ In the punishment condition, participants begin with 1000 points, and are given instructions that vary from the reward condition instructions only in that they explain that money may or may

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not be lost in each trial, and that the goal of the game is to lose as little money as possible. The number of times each deck was chosen during each of five 20-trial blocks was recorded.

correlations were used to examine associations between clinical measures and learning scores, and between learning preference scores and motor asymmetry scores.

2.3. Procedure Participants were referred by the consulting staff at the Movement Disorders Clinic. Each met with the researcher two separate times, once in the OFFmedication state, after having stopped taking all PD-related medications at least 10 h prior, and once in the ON-medication state, having taken regular doses of all PD-related medications. Medication states and session order were counterbalanced. The motor evaluation section of the UPDRS (Fahn et al., 1987) was administered during each of the sessions to evaluate motor symptoms and serve as a basis for comparison between the two medication states and to verify the effectiveness of the manipulation (an improvement index was calculated for this purpose by subtracting the motor score ON medication from the motor score OFF medication), and also to confirm that the documented side of onset continued to exhibit greater severity of motor symptoms. Each condition of the GLS task was administered twice, once during each of the sessions. To minimize time spent in the OFF-medication state and the associated discomfort, the remaining questionnaires and tasks were only administered during the ON-medication session. Following completion of both sessions, participants were given financial compensation for their time and to cover travel expenses. 2.3.1. Data analysis Demographic and clinical measures were compared between the groups using independent samples t-tests and a Pearson chi-square test was used to compare sex distributions. UPDRS motor asymmetry scores were calculated ([right side symptoms  left side symptoms]/[right side symptomsþ left side symptoms]) and compared between groups using independent samples t-tests. Motor improvement scores (motor score OFF medication–motor score ON medication) were also calculated and compared, for right-side symptoms, left-side symptoms, and total symptoms. For the GLS task, overall learning was first examined within each group, using repeated measures ANOVA with four within-subjects variables (medication: off, on; trial type: gain, loss; deck: best, worst; block: 1–5). Learning scores were then calculated for the best deck in each of the conditions (most profitable, 80% gain in the gain condition; least detrimental, 50% loss in the loss condition) by subtracting the number of times the best deck was chosen in the first block from the number of times the best deck was chosen in the final (fifth) block. These learning scores served as the dependent variable in a mixed repeatedmeasures ANOVA, with group (right-hemisphere PD, left-hemisphere PD) as a between-subjects factor and trial type (gain, loss) as a within-subjects factor. This analysis was conducted on data collected in the off-medication state. To examine the effect of dopamine replacement therapy (DRT) on the sensitivity to gain versus loss, as well as possible differential DRT effects on left- and right-hemisphere dopamine deficits, learning scores were analyzed in each of the groups using repeated measures ANOVA with two within-subject variables (medication: OFF, ON; trial type: gain, loss). Paired sample t-tests were performed to analyze predicted effects. To get a measure of differential sensitivity to gain versus loss within individual participants, learning preference scores were calculated (gain learning score minus loss learning score), and the number of participants with positive (gain preference) and negative (loss preference) scores was compared between groups using chi-square tests in each of the medication states. Pearson

3. Results 3.1. Demographic and clinical variables Group means and standard deviations for the demographic and clinical characteristics are presented in Table 1. The two PD groups did not differ with respect to disease duration or medication dose and had similar sex distributions. UPDRS motor asymmetry index scores showed that all patients with left side onset had more severe symptoms on the left side both off and on medication, while the opposite pattern was seen for patients with right side onset, confirming that asymmetry at onset is a valid indicator of the asymmetric dopamine deficit throughout the illness. Comparison of the absolute values of the asymmetry indices (OFF: t[27]¼1.271, p¼.214, NS; ON: t[27]¼ .506, p¼.617, NS) showed that the groups did not differ in magnitude of asymmetry (only in direction). The between-group difference in UPDRS motor improvement index was not significant, which would appear to indicate that medication had a similar effect on the total motor scores of the two groups. However, analysis of motor symptoms on each side of the body separately indicated an unexpected, differential medication effect, with greater medication-related improvement in right-sided symptoms in the left-hemisphere PD group than in the right-hemisphere PD group.

3.2. Gain–loss sensitivity (GLS) task 3.2.1. Within-group learning analyses—best versus worst decks As shown in Fig. 1, repeated measures ANOVA with four within-subjects variables (medication: off, on; trial type: gain, loss; deck: best, worst; block: 1–5) showed that over medication states and trial types, participants clearly learned to prefer the best deck over the worst deck (right-hemisphere PD: F[1, 12]¼9.90, p¼.008; left-hemisphere PD: F[1, 15]¼78.302, p¼ .000), indicating that patients in both onset groups were able to detect the small differences between the decks and follow the instructions. Therefore, further analysis specifically examined learning in the best deck alone.

Table 1 Demographic and clinical characteristics (mean 7S.D.).

Age (years) Sex (female/male) Education (years) HAM-D score HAM-A score Years since diagnosis L-dopa dose (mg/day) L-dopa equivalence dose (mg/day) UPDRS motor asymmetry index OFF medication ON medication UPDRS motor improvement index Total Left-side symptoms Right-side symptoms

Right-hemisphere PD (n¼ 13)

Left-hemisphere PD (n¼ 16)

62.38 710.04 5/8 13.507 2.43 1.467 2.50 2.697 3.15 7.007 4.78 331.717304.54 479.467458.40

63.31 7 9.26 5/11 13.50 7 3.08 .81 71.56 2.44 7 3.27 8.44 7 6.27 409.06 7 297.80 567.447 315.48

t(27) ¼.259, p ¼.798, ns w2(1) ¼ .165, p ¼ .684, ns t(27) ¼.000, p ¼ 1.00, ns t(27) ¼.855, p ¼.400, ns t(27) ¼.212, p ¼.833, ns t(27) ¼.681, p ¼.502, ns t(27) ¼.690, p¼ .496, ns t(27) ¼.611, p ¼.546, ns

 .27 7 .09  .37 7 .15

.32 7.13 .33 7.24

t(27) ¼14.071, p ¼.000 t(27) ¼9.089, p ¼.000

6.927 3.66 3.007 1.78 2.927 1.61

9.63 7 4.56 2.69 7 2.15 5.13 7 2.60

t(27) ¼1.729, p ¼.095, ns t(27) ¼.420, p¼ .678, ns t(27) ¼2.660, p ¼.013

HAM-D ¼ Hamilton Rating Scale for Depression; HAM-A¼ Hamilton Anxiety Scale; UPDRS ¼Unified Parkinson’s Disease Rating Scale; UPDRS motor asymmetry index ¼(right side symptoms left side symptoms)/(right side symptomsþleft side symptoms); UPDRS motor improvement index ¼ total motor score OFF medication  total motor score ON medication;

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Fig. 1. GLS task learning curves for the best and worst decks, in (a) the right-hemisphere PD group and (b) the left-hemisphere PD group, over medication states and feedback types. # Deck main effect, F[1;12]¼ 9.899, p ¼ .008; ## Deck main effect, F[1;15] ¼78.302, p ¼.000.

Fig. 2. Group  trial type interaction for learning scores, OFF medication, F[1, 27]¼ 9.111, p ¼.005. # p ¼ .025; ## p ¼.091.

3.2.2. Learning scores: Side-of-onset effects Learning scores were not significantly correlated to age, years of education, or depression and anxiety scores in either medication state. To test the hypothesis that relatively greater dopaminergic deficit in the left hemisphere results in greater deficit in approach motivation and thus relatively greater sensitivity to aversive situations (evidenced by better learning to avoid loss in the current paradigm), whereas relatively more severe dopaminergic deficit in the right hemisphere leads to greater deficit in avoidance motivation and relatively greater sensitivity to reward (indicated by better learning to increase gain), we conducted a mixed repeated-measures ANOVA, with group (right-hemisphere PD, left-hemisphere PD) as a between-subjects factor and trial type (gain, loss) as a within-subjects factor. This analysis was conducted on data collected in the off-medication state, in which the dopaminergic deficit is most pronounced. The inclusion of trial order and the addition of medication-state order as covariates in the analysis did not reveal order effects or significantly altered results. Neither the group effect (F[1, 27]¼.668, p¼.421, NS) nor trial type effect (F[1, 27]¼.000, p¼ .994, NS) were significant. However, the group  trial type interaction was significant (F[1, 27]¼ 9.111, p¼.005, see Fig. 2), suggesting that while for the entire PD group, sensitivity to small differences in the probability of gaining money did not differ from the sensitivity to small differences in losing money, the degree to which patients learned to differentiate between the different options when trying to maximize gain or minimize loss depended on the pattern of asymmetric dopamine deficit. As predicted, participants with

more severe dopamine deficit in the left hemisphere indeed learned to minimize losses better than they learned to increase their gains (t[15]¼2.487, p¼.025). The reversed pattern, albeit reaching only marginal statistical significance, was found for patients with greater dopaminergic loss in the right hemisphere (t[12]¼1.838, p¼.091). For all patients, regardless of onset side, learning preference score (gain learning score minus loss learning score) was negatively correlated with UPDRS asymmetry index (r¼ .508, p¼.005), indicating that regardless of onset asymmetry, greater dopamine loss in the left hemisphere was associated with relatively poorer gain learning, whereas more severe dopamine loss in the right hemisphere is associated with relatively worse loss learning. After determining that there were no significant trial or medication order effects or interactions, repeated measures ANOVA with two within-subject variables (medication: OFF, ON; trial type: gain, loss) in each of the groups revealed that the lefthemisphere PD group showed a significant medication  trial type interaction (F[1, 15] ¼14.269, p¼.002, Fig. 3a), in the absence of medication (F[1, 15]¼3.387, p¼ .086, NS) and trial type (F[1, 15]¼.053, p ¼.821, NS) main effects. When on medication, the pattern of relatively better learning to minimize loss than to increase gain was reversed, resulting in better learning in the gain condition (t[15] ¼2.645, p ¼.018). However, the right-hemisphere PD group did not exhibit a significant medication  trial type interaction (F[1, 12]¼.017, p ¼.898, NS, Fig. 3b), nor did it show a main effect of medication (F[1, 12] ¼1.698, p¼.217, NS). The relationship between gain and loss learning was not altered by medication in this group, as learning scores remained higher in the gain condition than in the loss condition, resulting in a main effect of trial type (F[1, 12] ¼13.060, p ¼.004). Learning preference scores were used to compare the two PD groups with respect to the number of participants with greater learning scores in each of the task conditions. In the off-medication state, one participant in the right-hemisphere PD group and two in the left-hemisphere PD group performed equally well under both conditions and were therefore excluded from the analysis. A chi-square test [Likelihood Ratio(1)¼6.363, p¼.012] showed, as predicted, that a greater number of participants in the righthemisphere PD group (83% versus 36% in the left-hemisphere PD group) performed better in the gain condition, whereas a greater number of participants in the left-hemisphere PD group performed better in the loss condition (64% versus 17% in the right-hemisphere PD group). This result further supports our hypothesis that asymmetric dopamine deficit modulates the relative sensitivity to approach-related versus aversive consequences. In the on-medication state, after removing one participant in the left-hemisphere PD group with equal learning scores in both

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Fig. 3. Learning score (best deck choices block 5 minus block 1) in the two medication states in the (a) left-hemisphere PD group and (b) right-hemisphere PD group. # medication  trial type interaction, p ¼ .002; ## trial type main effect, p ¼.004.

Fig. 4. Percentage of participants in each PD group with higher learning scores in each of the task conditions (reward, punishment), per medication state. # number of patients who reversed preference under medication, p ¼ .031. LH ¼left hemisphere; RH ¼ right hemisphere.

conditions, the difference between groups was no longer found [Likelihood Ratio(1)¼.430, p ¼.512, NS], as both groups had a greater number of participants that performed better in the gain condition (69% in the right hemisphere PD group and 80% in the left-hemisphere PD group, see Fig. 4). McNemar tests directly comparing the two medication states within each group showed that the number of participants with greater learning scores in each of the task conditions changed significantly in the lefthemisphere PD group (p ¼.031), in which medication led to an increase in the number of participants that performed better in the reward condition, but was not altered by medication in the right-hemisphere PD group (p ¼.687, NS).

4. Discussion The present findings partially support the hypothesized association between differential sensitivity to positive versus negative feedback and the direction of asymmetric dopamine deficit. Upholding predictions, OFF-medication participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while participants with greater dopamine deficit in the right hemisphere showed a trend

toward the reversed pattern. Importantly, regardless of onset asymmetry, correlational analysis showed that higher right side motor disability scores (reflecting greater dopamine loss in the left hemisphere) were associated with relatively better learning to avoid loss, whereas greater severity on the left side of the body (indicating greater loss of dopamine in the right hemisphere) was associated with better gain learning. These results are largely consistent with previous findings attributing approach tendencies to left-lateralized neural activity and withdrawal tendencies to right-lateralized activity (Davidson, 2004; Sutton & Davidson, 1997), and support a role for subcortical dopamine asymmetry in determining relative tendencies toward approach-related behavior versus avoidance of aversive stimuli in patients with asymmetric PD. Furthermore, the effects of dopaminergic medication on task performance differed between the two PD groups, suggesting that disease-based dopamine asymmetry interacts with medication to determine observed reward and punishment response tendencies in medicated patients. As predicted, when off medication, patients with greater dopamine depletion in the left-hemisphere did not perform as well when attempting to gain rewards as they did when attempting to minimize losses, showing both higher group average scores for learning to minimize loss than for gain learning and a greater number of participants that learned relatively better in the loss condition. This is in line with findings associating relatively lower left-hemisphere activation with avoidance-related functioning (Davidson, 1992, 2004), which relied primarily on EEG studies relating specifically to anterior cortical areas. Given the strong structural and functional connections known to exist between the striatum and frontal cortex (Alexander, DeLong, & Strick, 1986; Dias, Robbins, & Roberts, 1996), the current evidence supports the possibility that asymmetries in subcortical dopamine contribute to asymmetric activation in frontal areas and thus play a role in determining approach and avoidance tendencies. While the current study is the first to examine the effects of lateralized dopamine loss in asymmetric PD on a behavioral measure specifically designed to compare sensitivity to positive and negative feedback, personality-based measures of approach and avoidance tendencies have previously been investigated in this population. Thus, Tomer and Aharon-Peretz (2004) reported reduced levels of novelty seeking, an approach-related trait, among patients with right-side onset of PD (greater left-hemisphere dopamine depletion), corroborating the current results. When the left-hemisphere PD group was tested on medication, the aforementioned pattern was reversed, such that performance was better in the gain condition than in the loss condition. This effect is in accordance with predictions based on the ‘dopamine overdose hypothesis’ (Cools, 2006; Gotham et al., 1988), as it may

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apply to interhemispheric differences in dopamine depletion. In the left-hemisphere PD group, medication was expected to ameliorate the left hemisphere-associated relative deficit in reward learning, while detrimentally affecting punishment learning by excessively increasing dopamine levels in the relatively less depleted right hemisphere, leading to the observed reversal of the relationship between the two task conditions. Interestingly, similar reversals of sensitivity to positive versus negative feedback upon introduction of DRT have previously been reported in PD (Bodi et al., 2009; Frank et al., 2004; Palminteri et al., 2009). Unfortunately, these studies did not make reference to asymmetry of PD pathology in their patients. However, as the prevalence of right-sided onset of PD motor symptoms has been shown to be significantly higher than that of left-sided onset (Uitti et al., 2005; Yust-Katz, Tesler, Treves, Melamed, & Djaldetti, 2008), study samples not specifically designed to include similar numbers of participants with predominantly left-hemisphere and predominantly right-hemisphere PD were likely biased toward lefthemisphere PD. The right-hemisphere PD group showed a clearly different pattern than the left-hemisphere PD group. Greater dopaminergic depletion in the right hemisphere was expected to lead participants in the right-hemisphere PD group to show a relative deficit on the punishment task, as compared to the reward task, when in the off-medication state. Indeed, the learning preference data showed that a greater number of participants in the group performed relatively better in the reward than in the punishment condition when off medication. However, while group averages appeared consistent with this prediction, the difference between learning scores in the two task conditions was only marginally significant. This discrepancy between the learning preference and quantitative learning score findings may result from participants who indeed performed better in the reward condition, despite exhibiting quantitatively smaller differences between learning scores in the two task conditions. Unlike the left-hemisphere PD group, medication did not, as hypothesized, interact with task condition in the righthemisphere PD group, such that the relationship between the two task conditions remained the same as it had when participants were off medication. As discussed above, it has been suggested that dopamine-based cognitive tasks exhibit a U-shaped function, such that performance may be disrupted by either reducing or increasing optimum dopamine levels (Robbins, 2000; Rowe et al., 2008). In the right-hemisphere PD group, in which the left-hemisphere presumably had a lesser degree of dopaminergic depletion, there was no evidence that the addition of dopaminergic medication was detrimental in the reward condition. This may be related to the unexpected finding that medication had a lesser effect on right-sided motor symptoms (reflecting left-hemisphere dopamine depletion) in the righthemisphere PD group. Studies examining both medication effects and asymmetry-based differences in PD are rare and, to our knowledge, differential medication effects in right- and lefthemisphere PD groups have not been reported. While the generalizability of this finding will clearly require further study on significantly larger samples, it is possible that in the current right-hemisphere PD sample, the smaller effect of DRT on the lefthemisphere was insufficient to influence gain learning, therefore causing neither improvement nor decline. There was also no evidence that DRT was beneficial to punishment learning in the right-hemisphere PD group. While dopamine is known to be involved in responses to both appetitive and aversive stimuli (Robbins & Everitt, 2007; Salamone, Correa, Farrar, & Mingote, 2007), a key role in the aversive domain has also been attributed to the serotonergic system (Cools, Nakamura, & Daw, 2011; Crockett, Clark, & Robbins, 2009; Daw, Kakade, & Dayan, 2002).

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It is therefore possible that task performance in the loss condition was less sensitive to dopaminergic manipulation. Indeed, while there are certainly indications that variations in dopamine levels caused by PD and by dopaminergic medications affect punishment processing in PD (Bodi et al., 2009; Frank et al., 2004; Palminteri et al., 2009; Smittenaar et al., 2012), there is considerably less agreement between studies regarding the nature of these effects, as compared to reward processing. Methodological issues should be considered in interpreting current results and in directing further study. Most notably, the sample size was relatively small and the results could be strengthened and perhaps elaborated through replication in a greater number of participants. It should also be considered that direct measures of dopaminergic activity were not employed in the current study. Rather, motor symptoms were used as the basis for evaluating the extent of relative dopamine depletion between the hemispheres. While the relationship between asymmetric motor symptoms and the extent of lateralized dopaminergic depletion is well-founded (Kempster et al., 1989; Leenders et al., 1990; Tatsch et al., 1997), future studies should employ neuroimaging techniques to directly assess associations between asymmetric dopaminergic activity and processing of positive and negative stimuli. To conclude, the central finding of this study is that the subcortical dopaminergic asymmetry associated with asymmetric PD is reflected in different patterns of behaviorally-expressed approach and avoidance tendencies, with greater sensitivity to reward associated with relatively higher dopamine levels in the left hemisphere and greater sensitivity to punishment associated with relatively higher dopamine levels in the right hemisphere. This asymmetry appears to mediate abnormalities in reinforcement processing that have previously been reported in PD, highlighting asymmetry as a clinical factor that may account for variability in earlier reports on this subject. Importantly, this suggests that the grouping of patients with different sides of disease onset may lead us to miss or incorrectly interpret changes in approach and avoidance tendencies associated with PD and the medications used to treat it.

Acknowledgments We thank the patients who participated in this study. We also thank Andrei Markus for programming the original task. This work was supported by the Bharier Medical Fund, in memory of Nat and Sophie Bharier.

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