Neuropsychologia 50 (2012) Contents lists available at SciVerse ScienceDirect. Neuropsychologia

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1 Neuropsychologia 50 (2012) Contents lists available at SciVerse ScienceDirect Neuropsychologia journal homepage: The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson s disease Laurie Mondillon a,n, Martial Mermillod a,i, Serban C. Musca b, Isabelle Rieu c,d, Tiphaine Vidal e, Patrick Chambres a, Catherine Auxiette a,hélene Dalens f, Louise Marie Coulangeon f, Isabelle Jalenques d,g, Jean-Jacques Lemaire d,h, Miguel Ulla c, Philippe Derost c, Ana Marques c,d, Franck Durif c,d a LAPSCO (UMR 6024), Blaise Pascal University, Clermont-Ferrand 63000, France b CRPCC (EA 1285), European University of Brittany, Rennes 35000, France c Neurology Department, CHU Clermont-Ferrand, Clermont-Ferrand F-63001, France d UFR Medecine, University of Clermont 1, Clermont-Ferrand F-63009, France e Neurology Department, Resource and Research Memory Center (CMRR), CHU Clermont-Ferrand, Clermont-Ferrand F-63001, France f Ophtalmology Department, CHU Clermont-Ferrand, Clermont-Ferrand F-63001, France g Psychiatry A Department, CHU Clermont-Ferrand, Clermont-Ferrand F-63001, France h Neurosurgery Department, CHU Clermont-Ferrand, Clermont-Ferrand F-63001, France i Institut Universitaire de France, Paris 75005, France article info Article history: Received 30 November 2011 Received in revised form 17 July 2012 Accepted 19 August 2012 Available online 28 August 2012 Keywords: Parkinson s disease Emotion recognition Subthalamic nucleus Deep brain stimulation Dopamine Basal ganglia frontal loop abstract Deep brain stimulation of the subthalamic nucleus (DBS) is a widely used surgical technique to suppress motor symptoms in Parkinson s disease (PD), and as such improves patients quality of life. However, DBS may produce emotional disorders such as a reduced ability to recognize emotional facial expressions (EFE). Previous studies have not considered the fact that DBS and L-dopa medication can have differential, common, or complementary consequences on EFE processing. A thorough way of investigating the effect of DBS and L-dopa medication in greater detail is to compare patients performances after surgery, with the two therapies either being administered ( on ) or not administered ( off ). We therefore used a four-condition (L-dopa on /DBS on, L-dopa on /DBS off, L-dopa off /DBS on, and L-dopa off /DBS off ) EFE recognition paradigm and compared implanted PD patients to healthy controls. The results confirmed those of previous studies, yielding a significant impairment in the detection of some facial expressions relative to controls. Disgust recognition was impaired when patients were off L-dopa and on DBS, and fear recognition impaired when off of both therapies. More interestingly, the combined effect of both DBS and L-dopa administration seems much more beneficial for EFE recognition than the separate administration of each individual therapy. We discuss the implications of these findings in the light of the inverted U curve function that describes the differential effects of dopamine level on the right orbitofrontal cortex (OFC). We propose that, while L-dopa could overdose in dopamine the ventral stream of the OFC, DBS would compensate for this over-activation by decreasing OFC activity, thereby restoring the necessary OFC amygdala interaction. Another finding is that, when collapsing over all treatment conditions, PD patients recognized more neutral faces than the matched controls, a result that concurs with embodiment theories. & 2012 Elsevier Ltd. All rights reserved. 1. Introduction The basal ganglia structures, which are severely affected by Parkinson s disease (PD) following nigrostriatal dopaminergic denervation, share several connections with other brain areas, including the anterior cingulate cortex, the orbitofrontal cortex n Corresponding author. Tel.: þ ; fax: þ address: Laurie.Mondillon@univ-savoie.fr (L. Mondillon). (OFC) (Le Jeune et al., 2008; Middleton & Strick, 2000), the tegmental ventral areas (Swanson, 1982; Swanson, 2006; Wise, 2009), and indirectly with the amygdala via the nucleus accumbens (Alheid, 2003; Floresco, 2007; Goto & Grace, 2008; Humphries & Prescott, 2010; Parent & Hazrati, 1995). OFC and amygdala are known to be involved in the processing of emotions (Adolphs, 2002a; Adolphs, 2006) through the identification of facial cues, and more specifically in the recognition of emotional facial expressions (EFE) via other cortical and subcortical /$ - see front matter & 2012 Elsevier Ltd. All rights reserved.

2 2870 L. Mondillon et al. / Neuropsychologia 50 (2012) structures (Mermillod, Bonin, Mondillon, Alleysson, & Vermeulen, 2010; Vuilleumier, Armony, Driver, & Dolan, 2001). So far, studies designed to examine the impact of PD therapies on emotional processing have reported controversial results, in particular on emotion-specific impairments and on the differential effects of DBS and L-dopa therapies. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is commonly used as a technique to treat PD patients for whom pharmacological therapy has been unsuccessful (Krack, Fraix, Mendes, Benabid, & Pollak, 2002). Despite its efficiency in the treatment of motor symptoms such as tremor, rigidity, bradykinesia and postural instability has been largely demonstrated (Derost et al., 2007; Krack et al., 2003; Kleiner-Fisman et al., 2006; Limousin et al., 1998), the debate continues as to this therapy s side effects in terms of cognitive (Alegret et al., 2001; Dujardin, Defebvre, Krystkowiak, Blond & Destée, 2001; Fields & Troster, 2000; Funkiewiez et al., 2004; Funkiewiez et al.; 2006; Naskar, Sood, Goyal, & Dhara, 2010; Pillon et al., 2000), addictive (Doshi, Chhaya, & Bhatt, 2002; Houeto, Mesnage, Mallet, Pillon, & Gargiulo, 2002; Ulla et al., 2006) and emotional disorders (Voon, Kubu, Krack, Houeto, & Tröster, 2006), such as depression (Berney et al., 2002; Castelli et al., 2006; Funkiewiez et al., 2004; Schneider et al., 2003; Schneider, Althaus, Backes, & Dodel, 2008; Schneider et al., 2010), apathy/emotional blunting (Drapier et al., 2008), hypomania (Temel et al., 2006), and aggravation of other pre-existing psychiatric disorders and social maladjustment (Houeto et al., 2002; Piasecki & Jefferson, 2004; Takeshita et al., 2005). The involvement of the STN in emotional processing has also been suggested by both peri- and post-operative intracerebral case reports (Brücke et al., 2007; Kühn et al., 2005). A significant modulation of STN alpha activity, which correlated with depression symptoms (Huebl et al., 2011), was noted when participants viewed affective vs. neutral stimuli, suggesting a STN involvement in the basal ganglia-thalamo-cortical circuitry that mediates the processing of emotional stimuli. The effect of DBS on EFE recognition has been investigated in some studies, but they differed in the procedure and materials (i.e., stimuli) used, and yielded different or even contrasting results. For instance, while Schneider et al. (2003) did not observe any DBS effect on the discrimination of sadness and happiness, 1 impaired EFE recognition has been consistently reported in a number of studies (Biseul et al., 2005; Drapier et al., 2008; Dujardin et al., 2004; Le Jeune et al., 2008; Péron et al., 2010; Schroeder et al., 2004). Drapier et al. (2008) found an impaired recognition of fear and sadness. Biseul et al. (2005) identified fear impairment only. Schroeder et al. (2004) found anger recognition impairment only. To sum up, the bulk of the results are suggestive of a recognition impairment that affect negative EFEs. In line with this hypothesis, Dujardin et al. (2004, see also Schroeder et al. (2004) found that most of negative EFEs (anger, disgust, sadness) were recognized less well by patients receiving DBS, and this under conditions that makes it hard to attribute the results to patients anxiety or depression scores, or to a possible visuospatial or broader cognitive decline. The results of Péron et al. (2010) bring support to this selective impairment hypothesis, controlling that the findings cannot be attributed to the natural decline due to the disease, or to post-surgery modifications in dopamine replacement therapy. However, one must take this interpretation with caution, because discrimination and categorization tasks may bring into play a categorization bias. Indeed, when the task consists in selecting the appropriate label among alternatives that are mostly all negative (only one positive label among all basic 1 In other studies reported in their article, Schneider et al. (2003) found affective processing and subjective feelings to be improved under stimulation. emotions), the probability of an incorrect response is higher on negative EFEs (as compared to the positive EFE). The effect of L-dopa medication on PD patients EFE recognition is also controversial, with some studies evidencing a beneficial effect, others a prejudicial, and others no effect. A recent metaanalysis designed to evaluate the effect size of the emotional deficit in PD (Gray & Ticke-Degnen, 2010) found that medication had no effect on PD patients EFE recognition when the studies did not suffer from methodological limitations (sample size or other biases). Sprengelmeyer et al. (2003) reported that patients at an early stage of PD who were receiving no treatment exhibited a selective disgust EFE recognition impairment (compared to healthy controls), but this difference was no longer observed in patients with a more severe PD who were receiving L-dopa medication. Following other studies, dopaminergic modulations in the brain have to some extent a prejudicial effect on emotional processing (Delaveau, Salgado-Pineda, Wicker, Micallef-Roll, & Blin, 2005; Delaveau, Salgado-Pineda, Micallef-Roll, & Blin, 2007; Delaveau et al. 2009; Lawrence, Calder, McGowan, & Grasby, 2002; but see Salgado-Pineda, Delaveau, Blin, & Nieoullon, 2005 for a review). To sum up, these results do not rule out an effect of dopaminergic medication on the processing of emotional information, and consequently on EFE recognition. With this in mind, we suggest that previous studies suffer from a common weakness. Indeed, though DBS and L-dopa may have differential, common, or complementary consequences for EFE processing (Péron et al., 2010), previous studies did not take into account the potential (moderating) role of the medication (e.g., Biseul et al., 2005; Le Jeune et al., 2008; Schroeder et al., 2004) when testing for the effect of DBS in PD patients (i.e., patients were all receiving L-dopa). Schroeder et al. (2003) suggested DBS could disturb OFC s emotional functions by making STN decrease OFC s activity, a suggestion supported by a reduction in OFC s glucose metabolism in patients receiving DBS evidenced by Le Jeune et al. (2008). At the same time, certain neurophysiologic studies suggest that dopamine (DA) administered to rectify the dopamine deficiency induced an OFC dysfunction through a DA overdosing of the ventral striato-frontal circuitry (Cools, Barker, Sahakian, & Robbins, 2001; Cools et al., 2003; Cools, Lewis, Clark, Barker, & Robbins, 2007; Delaveau et al., 2009; Gotham, Brown, & Marsden, 1988; McDonald et al., 2011). Consequently, the two therapies may impact negatively the orbitofrontal functions through different mechanisms. Along these lines, one may suspect that those studies designed to assess EFE processing that have employed a pre- vs. postsurgery comparison (Biseul et al., 2005; Drapier et al., 2008; Dujardin et al., 2004; Le Jeune et al., 2008; Péron et al., 2010) may have been biased by the pre- vs. post-surgery change in dopamine replacement therapy. Roughly, half the studies were conducted in this way. The remaining half were post-operative studies (Geday, Ostergaard, & Gjedde, 2006; Schroeder et al., 2004; for an investigation of emotional prosody, see Brück, Wildgruber, Kreifelts, Krüger, & Wätcher, 2011), and the assessments were performed off medication. The shortcoming of the latter studies is that they did not consider the effect of DA level in the brain (as a function of the medication) by including both modalities ( on vs. off ) of both therapies in their experimental design. We suggest that in such a fully-factorial design, L-dopa would not directly impair EFE recognition (Gray & Ticke-Degnen, 2010) but might interfere subtly with DBS effects. Finally, another limitation of previous studies is that they did not consider the possibility that PD patients compensate for their lack of fast and immediate EFE identification through slower cognitive strategies. Indeed, in these studies EFEs were presented until patients answered, thus enabling them to use perceptual strategies by extensively examining the face and focusing on

3 L. Mondillon et al. / Neuropsychologia 50 (2012) obvious details (Adolphs et al., 2005; Clark, Neargardera, & Cronin-Golomb, 2010; Niedenthal, Mermillod, Maringer, & Hess, 2010; Vicente et al., 2009). A more ecological design would consist in a rapid (e.g., 500 ms) presentation of the stimuli, which corresponds to the spontaneous short-lived micro-expressions encountered in everyday life (Frank & Ekman, 2004; Polikovsky, Kameda, & Ohta, 2010). The aim of this study is to assess the impact of DBS and L-dopa and their differential (and joint) effects on PD patients EFE recognition by using a fast presentation of EFEs (500 ms). Results are compared to a control population matched on age, gender and education level. As far as we know, this work is the first attempt to examine PD patients EFE recognition with all the evaluations being performed post-surgery in the four DBS by L-dopa therapy conditions. As the L-dopa doses administered in our study were relatively well-controlled, by the reasoning already outlined we do not expect a L-dopa-induced significant EFE recognition impairment. DBS, in contrast, is expected to yield some EFE recognition impairment. Finally, the joint effect of the two therapies would modulate patients EFE recognition in a way different from the effect of each of the therapies considered alone. 2. Methods 2.1. Population Participants Eighteen patients with Parkinson s disease (9 men, 5 women) aged years took part in this study. All presented with clinical features (severe motor fluctuations) that met the criteria of the Parkinson s Disease Society Brain Bank diagnosis (Hughes, Daniel, Kilford, & Lees, 1992) and had been accepted for surgery in accordance with the inclusion criteria defined by the French consensus conference of treatment of Parkinson s disease (Consensus Conference Proceedings, 2000) Neuropsychological assessments and inclusion criteria The main inclusion criterion was an average response to acute DBS of more than 50% assessed with part III of the Unified Parkinson s disease rating scale (UPDRS, Fahn & Elton, 1987) (see below), which corresponds to a correct location of effective electrode contacts in the STN area. At the methodological level, we made every effort to minimize the biases that might impair EFE processing. We systematically excluded patients with abnormal visual contrast sensitivity (VISTECH Contrast Sensitivity Test-VCTS 6500; Dayton, OH. Vistech Consultants. Inc., 1988) or who were unable to recognize faces (Benton facial recognition test 439) (Benton, Hamsher, Varney, & Spreen, 1983) (Table 1). As far as cognitive abilities are concerned (Tables 2 and 3), the following inclusion criteria were adopted: no dementia and a normal general cognitive functioning, as determined by the Mattis dementia rating scale MATTIS (score Z130 2 )(Mattis, 1988; Schmidt et al., 1994), and the Mini Mental State Examination Status MMSE (score Z26) (Folstein, Folstein, & McHugh, 1975); an absence of dysexecutive syndrome, as determined by the frontal assessment battery FAB (score Z15; Dubois, Slachevsky, Litvan, & Pillon, 2000), and by the correctly sorted categories, the number of errors and perseverative responses on the Wisconsin card sorting test (WCST; Grant & Berg, 1948) (t-score Z45 i.e., percentile 416; Heaton, Chelune, Talley, Kay, & Curtiss, 1993); no moderate or severe depression (depression rating scale MADRS o15; Montgomery & Asberg, 1979) (Tables 2 and 3), since depression has been associated with EFE impairment (Dujardin, Sockeel, Delliaux, Destée, & Defebvre, 2009; Butterfield, Cimino, Oelke, Hauser, & Sanchez-Ramos, 2010). Finally, we excluded 4 patients due to their abnormal ophthalmic evaluations (Table 1), thus the final population consisted of 14 patients (9 men, 5 women, aged years) with a mean history of PD of years. To reduce the variability of the results, we chose to test the patients at least 6 months after surgery ( years after surgery), a period that warrants patients stimulation and medication are stabilized. The interruption of stimulation lead to the immediate reemergence of tremors (within seconds), followed by bradykinesia and rigidity a few minutes later. It has been demonstrated (Temperli 2 A 130 cut-off on the Mattis was also used as inclusion criteria in recent studies, aiming at examining the impact of PD therapies on several cognitive functions (Czernecki et al., 2002; Witt et al., 2004; Witt et al., 2008) and also EFE recognition (Dujardin et al., 2004). We thank an anonymous reviewer for suggesting us to clarify this point. Table 1 Ophthalmic assessments of each patient. Distant visual Near visual Visual contrast sensitivity Acuity Acuity Right eye Left eye Right eye Left eye Right eye Left eye P P2 P P P2 P P P2 P P P2 P P P2 P P P2 P P P2 P P P2 P P P2 P P P14 P P P2 P P P2 P P P2 P P P2 P P P2 P P P3 P P P2 P P P2 P Ophthalmic assessments were performed using the moneyer scale (distant visual acuity) and Parinaud test (near visual acuity); Visual contrast sensitivity was assessed using the VISTECH test (VCTS 6500) (31.18onormal valueso24.44). Four patients (P15, P16, P17, P18) were excluded due to abnormal visual contrast sensitivity. et al., 2003) that 1 h after DBS is turned off around 90% of motor symptoms reappear (compared to a basal condition). In addition, 14 matched healthy control (MHC) subjects (9 men, 5 women, aged years) were chosen to match PD patients with respect to age, gender and education level (based on the 5-points French Academic Levels scale). The protocol used in the present work was approved by the Regional Medical School Ethics Committee (AU700) and was implemented according to the principles set out in the Declaration of Helsinki and in compliance with French legislation (law on biomedical research). The nature and potential risks of the study were fully explained and a written informed consent was obtained from each participant. The study was also registered with the clinical trial specific website (NCT: ) Surgical procedure and electrodes location Quadripolar electrodes (Model 3387, Medtronic, Minneapolis) were implanted bilaterally under local anesthesia. The target (STN area) was localized using preoperative magnetic resonance imaging (MRI), intra-operative electrophysiological recording and macrostimulation (Derost et al., 2007; Lemaire et al., 2007; Coste et al., 2009). A neurologist assessed the effect of acute stimulation on contralateral rest tremor, rigidity (wrist, elbow and ankle) and bradykinesia (thumb index tapping). One contact of the DBS electrode was placed at the location where acute stimulation was found to be most effective. Post-operative MRI or CT scan was performed to verify the correct placement of the leads around the STN area. The electrodes were then connected to a pulse generator (Kinetra, Medtronic, Minneapolis) few days later under general anesthesia. Stimulation settings and antiparkinsonian therapy were adapted post-operatively according to the efficacy of chronic stimulation. Doses of antiparkinsonian medication are expressed as levodopa equivalent daily dose (LEDD) (Thobois, 2006) Assessment of the symptoms of Parkinson s disease The efficacy of acute DBS was assessed using part III of the UPDRS, a standardized evaluation of the range of all motor signs in PD (with a score range of 0 108), including tremor, akinesia, rigidity, but also axial signs such as posture, dysarthria, amimia and postural instability. These ratings were conducted under the four following conditions: (1) L-dopa off /DBS off, after a 12 h withdrawal of antiparkinsonian medication and after stimulation had been switched off for at least 1 h 3 ; (2) L-dopa off /DBS on, after stimulation had been switched on for at least 1 h; (3) L-dopa on /DBS on, 1 h after the intake of 1.5 times the usual morning L-dopa dose, using a dispersible L-dopa formulation (Modopar Dispersible, Roche) (4) L-dopa on /DBS off, after stimulation had been switched off for at least 1 h. The other tests included UPDRS part I (mental state, score range: 0 16), part II (activities of daily life, score range: 0 52), and part IV (L-dopa complications). Each session was video-recorded. The 3 Actually, for all stimulation off conditions, stimulation was turned off at least 1 h and 20 min before testing, with values varying randomly between 80 min and 2 h.

4 2872 L. Mondillon et al. / Neuropsychologia 50 (2012) Table 2 Neuropsychological assessment for each patient. MMS /30 MATTIS /140 FAB /18 Benton Wisconsin MADRS /60 Correctly sorted categories Perseveration Errors Percentile Percentile t-score Percentile t-score P P P P P P P P P P nd P P P P Mean SE Values correspond to PD patients mean scores. All evaluations were collected while PD patients were in their best on state; nd¼not done. MMS¼Mini mental state score; MATTIS¼MATTIS score; FAB¼mean score on the frontal assessment battery; Benton¼mean score on the Benton facial recognition test; Wisconsin¼mean score on the Wisconsin card sorting test (a t-score Z45 represents a normal performance; Heaton et al. (1993)); MADRS¼Montgomery and Asberg depression rating scale. Table 3 Age, history of PD, medication, and motor assessment for each PD patient. Age (y) History of PD (y) LEDD (mg/d) UPDRS I UPDRS II UPDRS III on off L-dopa on L-dopa off DBS on DBS off DBS on DBS off P P P P P P P P P P P P P P Mean 60,57 12, n 8.07 n n SE 1,64 0, Values correspond to PD patients scores. Some of their data are presented here to correspond to the four therapy conditions: L-dopa on ¼under medication; L-dopa off ¼without medication; DBS on ¼with stimulation; DBS off ¼without stimulation. LEDD¼levodopa equivalent daily dose, calculated as the dose of dopamine agonists plus levodopa medication (Thobois, 2006); UPDRS I¼scores on the Unified Parkinson s disease rating scale I collected when PD patients were in their best on state; UPDRS II¼scores on the Unified Parkinson s disease rating scale II collected when PD patients were in their best on vs. off state; UPDRS III¼scores on the Unified Parkinson s disease rating scale motor score in the 4 therapy conditions. n po.05 vs. L-dopa off /DBS off (repeated-measures ANOVA followed by Tuckey Krammer pairwise comparisons). resident neurologists and neuropsychologists responsible for carrying out the neuropsychological post-operative assessments were blind as to the experimental condition patients were assigned to Material and design Emotional facial expressions extracted from The Karolinska directed emotional faces database (Lundqvist, Flykt, & Öhman, 1998) were used. We selected color pictures of 16 different individuals (8 women and 8 men), each displaying 7 different emotional expressions (EFE), namely the 6 basic emotions (anger, disgust, fear, happiness, sadness, and surprise; 100% emotional intensity) and a neutral expression (0% emotional intensity). There were therefore a total of 112 stimuli (16 Individuals 7 EFEs), all of which were displayed at a resolution of pixels. Two matched blocks of 56 stimuli were then constructed in order to avoid learning effects throughout the 4 therapy conditions (see Fig. 1). Half the participants (PD patients and MHC) started the first phase (Time 1) with Block 1 while the others started with Block 2, the block assignment being reversed in the second phase (Time 2). The stimuli were presented using PsyScope (Cohen, MacWhinney, Flatt, & Provost, 1993) in a cm window centered on a 19 in. CRT screen connected to a MacBookPro computer Procedure Within each of the 2 blocks, EFEs were displayed in random order. Blocks (1 vs. 2) were also randomly selected on the basis of the L-dopa/DBS variables, so that each participant viewed each block twice (Time 1 vs. Time 2). Medication and

5 L. Mondillon et al. / Neuropsychologia 50 (2012) Fig. 1. Example of experimental phases for the L-dopa and DBS conditions as a function of the Time variable (d¼day), with the patients in the conditions (A) L-dopa off / DBS on and off, (B) L-dopa on /DBS on, and (C) L-dopa on /DBS off. The timeline from left to right represents the time of the day when we changed therapeutic status. stimulation conditions were counter-balanced across participants (Fig. 1). Effect of medication ( on vs. off ) was tested during two separate sessions, over a period of three consecutive days. Half the participants began the protocol in their best on medication state, while the other half began in the off condition. For each L-dopa condition, patients were randomly assigned to the two DBS conditions ( on vs. off ). Half the patients were tested first in the DBS on condition (in the morning), and then in the DBS off condition, at least 1 h after stimulation had been switched off. This order was reversed for the other half of the participants. MHCs performed the experiments in these 4 conditions (Block 1 vs. Block 2, and Time 1 vs. Time 2) in the same order as their matched patients. Participants were tested individually in a quiet room, where they sat at approximately 90 cm from the screen. The experimenter provided the instructions and placed in front of the participants a notepad where the emotional categories were printed in a large font to ensure participants could easily read. Once the aim of the task was correctly understood, the test phase began. Each trial started with a 500-ms display of a fixation cross centered on the screen, immediately followed by the target, also displayed for 500 ms. The trial number was displayed with each EFE in order to avoid patient discouragement. The participants had to categorize each EFE by giving their response orally to the experimenter. The experimenter entered participants answers via the keyboard (one key was assigned to each EFE), then pressed the spacebar to move on to the next trial. It was thus possible to interrupt the experiment between two trials if the experimenter felt the patient was tired and/or inattentive. The experimenter was blind to the experimental condition. 3. Results 3.1. Surgical outcomes The effects of medication and DBS on motor disorders are reported in Table 3. The acute efficiency of DBS, assessed using UPDRS part III, was % despite the fact that the patients had been operated on average 3.5 years before the assessment. Stimulation settings were and V (right and left sides, respectively), Hz and ms. Medication, calculated as the dose of DA agonists plus levodopa medication, was mg/d. The neuropsychological results are summarized in Table 2 and did not reveal any cognitive impairment. Moreover, the patients had no dysexecutive syndrome (no pathological performance on the WSCT or FAB). Furthermore, no patients exhibited depressive syndromes at the time of the study (MADRSo15 for all patients) Effect of Parkinson s disease on EFE recognition 2.4. Statistical analyses With regard to the WCST data, patients performance was compared to the reference norms for this test (Heaton et al., 1993). A t-score computed by considering each patient s age and education level was used to define each patient s performance level within the following classification: 20rt-score r24¼very severely impaired performance; 25rt-scorer29¼severely impaired performance; 30rt-scorer34¼moderately impaired performance; 35rt-score r39¼mildly to moderately impaired performance; 40rt-scorer44¼very mildly impaired performance; 45rt-scorer54¼normal performance; t-score Z55¼above-average performance. Since the participants gender did not modify the explained variance in the EFE recognition task, this variable was removed from the analyses. As far as motor assessment in PD patients is concerned (Table 3), the statistical analyses consisted of a repeated-measures ANOVA including the four therapy conditions, followed by Tuckey Krammer pairwise comparisons. All the following statistical analyses were performed on the EFE average recognition accuracy ratio. In order to assess possible emotion recognition impairment in PD patients compared to MHC, we first conducted a between-group repeated-measures ANOVA with EFE (Anger vs. Disgust vs. Fear vs. Happy vs. Neutral vs. Sad vs. Surprise) as a within-subjects variable and Group (PD patients vs. MHC) as a between-subjects variable. It is important to note that, as mentioned in Section 2.3, each control participant was also matched on the Time and Block variables. Consequently, because the PD patients and their corresponding MHC experienced the same Block (1 and 2) and Time (1 and 2) conditions, we were able to compare Groups for each of the 4 therapy conditions. A repeated-measures ANOVA with EFE (Anger vs. Disgust vs. Fear vs. Happy vs. Neutral vs. Sad vs. Surprise), L-dopa ( on vs. off ) and DBS ( on vs. off ) as within-subjects factors was performed to test the effect of the two therapies on PD patients EFE recognition. Given the restricted sample size, homogeneity of variances assumption was not met, so we used non-parametric pairwise comparisons (Mann Whitney U for comparisons of independent groups). The significance level was chosen as usual at.05. We first report the effect of PD compared to MHC participants regardless of stimulation and medication conditions. As frequently reported in the literature, we observed a main effect of EFE (F(6, 156)¼93, MSE¼.08, po.001). More importantly, we observed a significant Group EFE interaction effect (F(6, 156)¼2.75, MSE¼.08, po.05) which would indicate an emotion-specific recognition impairment in PD patients (Fig. 2). Non-parametric pairwise comparisons revealed that compared to the control participants PD patients yielded a lower recognition rate for disgust (U¼56.5, p¼.054), but a higher one for neutral (U¼54.5, po.05) faces. No impairment was observed on the other EFEs. In view of our hypothesis concerning the effects of DBS and L- dopa on EFE recognition in PD patients compared to MHC, in order to focus on the effect of Group (PD vs. MHC) and Emotions in each of the 4 therapy within-conditions the following analyses used pairwise comparisons of means. As Table 4 indicates, significant differences were observed between PD patients and MHC when the patients were no longer receiving L-dopa. First, we observed a significant decrease in recognition of disgust in the DBS on condition (U¼27.5, po.001). Second, when the patients were off both therapies, we observed a tendency toward an impaired recognition of fear (U¼62, p¼.089). Finally, no specific EFE impairment was found in the L-dopa on /DBS on and L-dopa on /DBS off conditions. To sum up, DBS on (with L-dopa off ) induced an impairment of fear recognition, L-dopa by itself did not produce a decrease in EFE recognition, and when participants received both therapies (i.e., L-dopa and DBS) no EFE recognition impairment was observed either.

6 2874 L. Mondillon et al. / Neuropsychologia 50 (2012) Fig. 2. EFE recognition for MHC and PD patients, regardless of L-dopa and DBS status. EFE recognition was computed as a mean recognition accuracy ratio for each EFE. Error bars represent SD. Table 4 EFE recognition for PD patients compared to MHC, for each emotion according to DBS status ( on vs. off ) with L-dopa off. L-dopa off DBS on DBS off PD patients MHC PD patients MHC Fear y Anger Disgust nnn Happiness Neutral Sadness Surprise EFE recognition was computed as a mean recognition accuracy ratio, for each EFE. This ratio was measured for PD patients and MHC in the four experimental conditions. Although MHC did not receive any therapy during the experimental session, they shared the same Block (1 and 2) and Time (1 and 2) conditions as their corresponding PD patients. This allowed us to compare the groups in the four conditions. Their data are therefore presented to correspond to the L-dopa and DBS conditions of the PD patient with whom they were matched. Data are expressed as means7sd. y po.08. nnn po.001 (Mann Whitney U pairwise comparisons) DBS and L-dopa effects on EFE recognition in PD patients To describe the differential effects of DBS and L-dopa on the processing of emotional information, we report the effect of the two therapies for the PD patients only. Unsurprisingly, we found a main effect of EFE which suggests that, all other things being equal, some emotions are recognized better than others (F(6, 78)¼63.88, MSE¼.06, po.001). No main effect of therapies was found (L-dopa: p¼0.59 and DBS: p¼0.84). However, the most interesting result concerns their interaction. Indeed, L-dopa DBS interaction was significant (F(1, 13)¼9.65, MSE¼.01, po.01), a finding that suggests at least one of the therapies has a differential effect depending on the status of the other ( on vs. off ). To further elaborate on this analysis, we examined the simple effects Fig. 3. EFE recognition in PD patients as a function of L-dopa and DBS status. EFE recognition is computed as a mean recognition accuracy ratio across EFEs. Data were collected in the four therapy conditions (L-dopa on /DBS on, L-dopa on /DBS off, L-dopa off /DBS on, and L-dopa off /DBS off ). þpo.06, npo.05 of both therapies. In other words, we evaluated the impact of DBS status with medication off and the impact of medication status with DBS off. As shown in Fig. 3, pairwise comparisons revealed that with medication off, DBS off produced a better recognition than DBS on (t(13)¼2.23, po.05). Interestingly, this effect was not obtained for L-dopa, whose status did not modify EFE recognition with DBS off (t(13)¼1.21, p¼0.25). These results confirm previous analyses, which indicated a simple effect of DBS when L-dopa was off. However, the corresponding effect was not found for L-dopa. Complementary analyses confirmed and completed the previous results by indicating that with medication on, patients exhibited greater recognition abilities with DBS on than with DBS off (t(13)¼2.48, po.05). The L-dopa status only produced a slight modification of EFE recognition when the patients were in

7 L. Mondillon et al. / Neuropsychologia 50 (2012) the DBS on condition (t(13)¼2.08, p¼.057). Finally, no differences were observed between the L-dopa on /DBS on and L-dopa off /DBS off (p¼0.65) or between the L-dopa on /DBS off and L- dopa off /DBS on (p¼0.55) conditions. Taken together, these results suggest that a greater benefit, mainly due to stimulation, was observed when the two therapies were both administered at the same time, and that administering only one therapy yielded worse EFE recognition results than no therapy at all. 4. Discussion The current research, using a transversal approach, reveals the differential effect on EFE recognition of the two therapies that are commonly used to treat PD, namely STN DBS and L-dopa medication. A comparison of EFE categorization performance by MHC and PD patients regardless of stimulation and medication conditions revealed group (PD vs. MHC) differences for specific emotions. First, PD patients identified neutral faces better than the controls. We further discuss the implications of this finding later in the present section. Second, PD patients were impaired in their recognition of disgust. This finding is consistent with much of the literature on this issue. For instance, Suzuki, Hoshino, Shigemasu, and Kawamura (2006) used a more refined assessment method than usually employed to clarify whether EFE processing deficits observed in individuals with PD are emotionspecific. As in our study, they controlled for task difficulty and eliminated other methodological problems such as ceiling effects. Their results revealed lower scores for disgust recognition, whereas the conventional methods used in previous studies failed to identify this specific impairment. We did not find an EFE recognition deficit for pleasant stimuli (i.e., happy EFE), while Kühn et al. (2005), in STN intra-cerebral recordings studies, found that PD patients showed a reduced processing of mood-incongruent pleasant stimuli. We see two causes to this contradiction. First, only non-depressed patients took part in the present study, so it would not be clear why happiness EFEs would necessarily be mood-incongruent stimuli not to mention that the negativity bias in depressive patients is still a matter of debate as to its causes (reduced attention toward positive events or enhanced response to negative ones; Huebl et al., 2011). Second, Kühn et al. (2005) used IAPS pictures (Lang, Bradley, & Cuthbert, 2008) that include very few EFEs. The few IAPS images that depict faces do not match the validation standards of EFE batteries (e.g., one EFE at a time, same background, centered), and this makes the comparison with our results difficult. Another explanation to this specific impairment is that, already mentioned, of a categorization bias, a bias often encountered in forced-choice identification tasks. In support of this view, Gray and Ticke-Degnen (2010) recently showed a greater deficit in EFE recognition than in EFE rating tasks. We believe that further free-response tasks are required to fully understand the EFE recognition impairment. Focusing on a comparison of MHC and PD patients in the four therapy conditions, our analyses revealed an impaired recognition of disgust in the patients receiving stimulation with L-dopa off. This result contradicts those of previous studies that found specific impairments in the recognition of fear (e.g., Biseul et al., 2005), but is fairly consistent with those pointing to disparate results depending on the type of experimental design used (Drapier et al., 2008; Dujardin et al., 2004; Schroeder et al., 2004). Conversely, in the L-dopa on /DBS off condition, no EFE recognition impairment was found, thus indicating that there is no recognition impairment when medication is well-controlled, a finding consistent with recent studies. Indeed, in their metaanalysis, which was designed to calculate the magnitude of the reported deficit in emotion recognition and its changes as a function of potentially critical variables, Gray and Ticke-Degnen (2010) examined whether medication status modulated the emotion recognition deficit in PD. This comparison of 22 studies, including dopamine-replete vs. hypodopaminergic states compared to healthy controls, revealed that the difference between the two experimental designs was not significant, despite the fact that the size effect in the latter seemed to be higher than that found for participants receiving L-dopa. In the light of the results of this meta-analysis we suggest that discrepancies between previous studies might be due to an effect of medication that would be too weak to always manifest itself irrespective of the experimental protocol. Concerning the differential effect of the two therapies in PD patients, a simple effect of DBS with L-dopa off was obtained. It is congruent with findings of recent studies showing that DBS decreases the overall recognition ratio (Biseul et al., 2005; Drapier et al., 2008; Dujardin et al., 2004; Péron et al., 2010; Schroeder et al., 2004). The reverse effect of L-dopa (L-dopa change with DBS off ) did not reach the level of significance despite the apparent change visible in the graph. As mentioned above, the absence of a significant effect of dopaminergic medication is consistent with the results reported concerning comparisons between PD patients and MHC participants, as well as with the recent work conducted by Gray and Ticke-Degnen (2010). Little is known about emotional processing in PD patients who are receiving both DBS and dopamine replacement therapy. We obtained new and particularly interesting results in the field of emotion recognition in PD, which indicate that L-dopa-induced dopaminergic modulations may produce subtle effects, especially in interaction with the modulation of the subcortical networks induced by DBS. More specifically, it seems that the combined effect of the two therapies, also found in comparisons between patients and controls, is much more beneficial than that of each therapy administered separately. One possible explanation for this result lies in the activity of the baso-cortico-striatal circuitry, which is modulated differently in PD patients treated with DBS vs. L-dopa (Funkiewiez et al., 2006). The basal ganglia share several connections with other brain structures which are of importance for facial emotion recognition, including the right orbitofrontal cortex (OFC) and, indirectly via the nucleus accumbens (Alheid, 2003; Floresco, 2007; Goto & Grace, 2008; Humphries & Prescott, 2010; Parent & Hazrati, 1995), the amygdala (Adolphs, 2002a; Adolphs, 2002b; Adolphs, 2006; Le Jeune et al., 2008). Moreover, many studies have lent support to the idea that the right OFC is activated in the recognition of fear (Vuilleumier et al., 2001) and angry faces, but not in response to happy and sad faces (Blair, Morris, Frith, Perrett, & Dolan, 1999; for a review, see Murphy, Nimmo-Smith, & Lawrence, 2003), especially when the task requires explicit identification of the emotion (Narumoto et al., 2000). Consequently, interfering with the right OFC can result in impaired EFE recognition (Adolphs, 2002a; Hornak, Rolls, & Wade 1996), as evidenced in transcranial magnetic stimulation (Harmer, Thilo, Rothwell, & Goodwin, 2001), PFC depth electrode stimulation, or surgical removal (Marinkovic, Trebon, Chauvel, & Halgren, 2000). Since the OFC and the amygdala are known to share several functional connections involved in emotional processing (Bar, 2003; Bar, 2004; Kveraga, Ghuman, & Bar, 2007; Mega & Cummings, 2001), the OFC has been recently supposed to constitute an indirect pathway between the amygdala and basal ganglia (Le Jeune et al., 2008). Its dysfunctions in response to DBS may thus be responsible for a functional de-synchronization of the fronto-limbic projections (Brücke et al., 2007; Geday et al., 2006; Schroeder et al., 2003, 2004; Temel, Blokland, Steinbusch, & Visser-Vandewalle, 2005). Within this perspective, Le Jeune et al.

8 2876 L. Mondillon et al. / Neuropsychologia 50 (2012) (2008) showed a direct link between DBS and OFC functioning during emotion recognition. Controlling stimulation effects in a pre- and post-surgery (3 months after implantation) PET study, they found a decrease in glucose metabolism of the right OFC that was positively correlated with modified performances in an EFE recognition task, especially in the case of negative expressions such as fear. L-dopa medication, which primarily affects levels of DA in the nigrostriatal and mesocorticolimbic systems (Maruyama, Naoi, & Narabayashi, 1996), improves motor symptoms but its side effects on cognitive functions may result from its prejudicial effects on frontal areas. Some of the most important studies in this domain suggest an inverted U curve function, which can lead to both excessive and insufficient DA-D1 receptor stimulation in the prefrontal cortex (PFC) (Arnsten, 1998; Cools et al., 2001). Indeed, while DA depletion in the dorsal prefrontal cortex is related to subtle cognitive impairments (Cools et al., 2007; Owen et al., 1995), L-dopa doses required to rectify the DA deficiency in the putamen and dorsal striatum may have a detrimental effect by overdosing in DA other areas, including those in which the DA system remained intact, and more specifically the broad ventral striato-frontal circuitry projecting to the OFC (Cools et al., 2001; 2003; 2007; Gotham et al., 1988; McDonald et al., 2011). Delaveau et al. (2005, 2009) consistently found that L-dopa not only incidentally overdoses the mesolimbic projections toward the amygdala in nondemented and nondepressed PD patients, but also in control volunteers, and leads to decreased amygdala activation in response to emotion perception. Taken together, these results suggest that DBS and L-dopa medication may bring about modifications to the non-motor basal ganglia-thalamo-cortical circuitry (Schroeder et al., 2002) and consequently impair the emotional functions of the OFC, but do so in different ways. We speculate that stimulation may impair OFC by inducing deactivation, while L-dopa would produce an almost identical effect on the OFC by saturating it in DA. In both cases, this would result in a dysfunction of the OFC amygdala projections. As far as the present results are concerned, although medication did not produce a significant deficit in EFE processing probably because the L-dopa doses were relatively wellcontrolled we presume the significant amount of DA (induced through L-dopa intake) present in the ventral stream of the PFC, and more specifically the thalamo-cortical circuitry projecting to the OFC, may partly rectify the stimulation-induced impairment by neutralizing the inactivation of the OFC. This outcome contrasts with previous findings from pre- vs. post-surgery studies (Biseul et al., 2005; Dujardin et al., 2004; Drapier et al., 2008; Le Jeune et al., 2008; Péron et al., 2010). As mentioned by Schneider et al. (2003), serious emotional symptoms appear mostly during the first post-operative week, when the extensive dopaminergic reduction is implemented. Nevertheless, Schneider et al. (2003), Dujardin et al. (2004) and Péron et al. (2010) are the only ones to have mentioned and/or described controls for classical post-surgery modifications in L-dopa doses. This type of modification may be a variable that introduces a significant amount of confusion. In the present study, patients were systematically evaluated post-surgery, that is to say without profound dopaminergic modifications throughout the DBS experimental conditions ( on vs. off ). As mentioned earlier, a compensation of the DBS impairment effect by L-dopa doses via their respective effects on the OFC may explain the EFE recognition improvement when on of both therapies. In their pre- vs. post-surgery study, Péron et al. (2010) found an effect of DBS unrelated to medication modifications. Nevertheless, this was a statistical post-hoc control performed under parametric analyses and not an a priori control under a post-surgery on vs. off design. Concerning post-operative studies (Schroeder et al., 2004; Geday et al., 2006, for assessments of emotional prosody see Brück et al., 2011), the assessments were performed off levodopa, so the discrepancy between their results and ours could again be explained as we propose, that is, the lack of levodopa medication did not allow to compensate the deleterious effects of DBS. Another, more recent, study (Serranova et al., 2011) evaluated emotional processing post-operatively, but cannot be directly compared to the present one since it dealt with visual perception of emotional stimuli other than EFE, and 10% of all patients were free of dopaminergic medication. As mentioned above, we believe that the only way to adequately assess the effect of both therapies is to perform a fully-factorial design (i.e., crossing both on vs. off modalities for both therapies), while keeping all other things equal. A related consideration about the differential effects of L-dopa and DBS on emotion recognition concerns the somatosensory cortices and their involvement in the process of embodiment. These structures are well known to play a role in EFE recognition (Adolphs, Damasio, Tranel, Cooper, & Damasio, 2000; Heberlein, Adolphs, Pennebaker, & Tranel, 2003) by generating internal somatosensory representations of perceived faces and thereby constituting a simulation of socially relevant information (Adolphs, Tranel, & Damasio, 2003; Adolphs, 2006; Costa, Valls- Solé, Valldeoriola, & Rumia, 2008; Heberlein & Adolphs, 2007). Given that a recent study has revealed differential effects of DBS and L-dopa on somatosensory temporal discrimination (Conte et al., 2010), we believe that further studies should consider simulation-based models, including both the use of ambiguous and dynamic facial expressions and measures of somatosensory cortex activity, in order to identify all the parallel processes responsible for the decline in EFE recognition in PD patients. PD patients recognized neutral expressions better than the MHC participants, a result that agrees with the above-mentioned facial simulation models (see also Niedenthal et al., 2010). Indeed, as suggested by Gray and Ticke-Degnen (2010) (see also Smith, Smith, & Ellgring, 1996), PD patients amimia could have made them adopt a relatively neutral expression during the task (without any notable facial simulation). Embodiment-based accounts would then predict that patients would recognize the corresponding neutral faces better than MHCs. It should be noted that there is an alternative explanation for this result, namely that neutral answers given by the PD patients are a default-response they give when faced with the difficult EFE recognition task. We believe it is important to be able to choose between these explanations, which we cannot here, and suggest to study through an objective method such as electromyography whether amimia affects EFE recognition in the way we suggest here. The present study has some limitations, which we delineate below,andweencourageacautiousinterpretation of its results in the light of these limitations. In the DBS off condition, the time between DBS shutdown and the beginning of the task corresponds to the time required for the majority of motor symptoms to reappear (Temperli et al., 2003), but there is no guarantee that DBS emotional effects washed away completely after this time interval. Yet it is difficult to stop the stimulation longer for ethical reasons, and this delay is similar to those reported in previous postoperative studies (e.g., Biseul et al., 2005; Schneider et al., 2003; Serranova et al., 2011). What more, in the L-dopa off conditions, if extending the DBS off delay before testing suppressed entirely the long-lasting effect of stimulation this would boost the emotional improvement effect when off L-dopa (as compared to on DBS), rather than making it disappear. The same reasoning applies to a potential long-lasting medication effect after 12 h of withdrawal. Furthermore, this delay has also been used in previous studies (e.g., Geday et al., 2006; Lawrence, Goerendt, & Brooksn, 2007; Schneider et al., 2003; Schroeder et al., 2004), and L-dopa has a half-life of 1 2 h (Gancher, Nutt, & Woodward, 1987).