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1 Journal of Parkinson s Disease 4 (2014) DOI /JPD IOS Press Research Report 97 Dopamine Replacement Therapy and Deep Brain Stimulation of the Subthalamic Nuclei Induce Modulation of Emotional Processes at Different Spatial Frequencies in Parkinson s Disease Martial Mermillod a,b,, Laurie Mondillon c, Isabelle Rieu d, Damien Devaux c, Patrick Chambres c, Catherine Auxiette c,hélène Dalens e, Louise Marie Coulangeon e, Isabelle Jalenques f and Franck Durif d a Université Grenoble Alpes, LPNC, F-38040, Grenoble & CNRS, LPNC UMR 5105, F-38040, Grenoble, France b Institut Universitaire de France c Laboratoire de Psychologie Sociale et Cognitive, CNRS UMR 6024, Clermont Université, Université Blaise Pascal, France d CHU Clermont-Ferrand, Service de Neurologie A, F Clermont-Ferrand, France e CHU Clermont-Ferrand, Service d Ophtalmologie, F Clermont-Ferrand, France f CHU Clermont-Ferrand, Service de Psychiatrie de l Adulte A, F Clermont-Ferrand, France Abstract. Background: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is an effective treatment for the most severe forms of Parkinson s disease (PD) and is intended to suppress these patients motor symptoms. However, be it in association with Dopamine Replacement Therapy (DRT) or not, STN-DBS may in some cases induce addictive or emotional disorders. Objective: In the current study, we suggest that PD patients suffer from emotional deficits that have not been revealed in previous studies because in those experiments the stimuli were displayed for a time long enough to allow patients to have recourse to perceptual strategies in order to recognize the emotional facial expressions (EFE). Methods: The aim of the current article is to demonstrate the existence of emotional disorders in PD by using a rapid presentation of the visual stimuli (200-ms display time) which curtails their perceptual analysis, and to determine whether STN-DBS, either associated or not associated with DRT, has an impact on the recognition of emotions. Results: The results show that EFE recognition performance depends on both STN-DBS ( on vs. off ) and medication ( on vs. off ), but also that these variables have an interactive influence on EFE recognition performance. Moreover, we also reveal how these EFE impairments depend on different spatial frequencies perceptual channels (related to different cortical vs. subcortical neural structures). Conclusions: The effect of PD without therapy seems to be particularly acute for LSF emotional faces, possibly due to a subcortical dysfunction. However, our results indicate that the joint action of STN-DBS and DRT could also disrupt recognition of emotional expressions at the level of occipito-temporal cortical areas (processing HSF visual information) inducing broad global impairment of EFE at the level of HSF visual channels. Keywords: Parkinson s disease, emotions, dopamine replacement therapy, deep brain stimulation, spatial frequency information Correspondence to: Martial Mermillod, Université Pierre Mendès France, Laboratoire de Psychologie et NeuroCognition, BP 47, Grenoble Cedex 9, France. Martial.Mermillod@ upmf-grenoble.fr. ISSN /14/$ IOS Press and the authors. All rights reserved

2 98 M. Mermillod et al. / Emotional Disorders INTRODUCTION The effect of STN-DBS on emotional processes Bilateral deep brain stimulation of the subthalamic nuclei (STN-DBS) is a well-documented and efficient treatment for severely disabled Parkinson s disease (hereafter, PD) patients with intractable motor complications. Although there is compelling evidence for the clinical efficiency of STN-DBS on motor symptoms [1, 2], the debate concerning the effects of STN- DBS on behavioral and emotional manifestations is still unresolved. On the one hand, [3] and [4] showed that STN-DBS may produce a significant emotional impairment, which is observed most particularly in the recognition of fear. On the other hand, however, [5] reported a more extensive impact of STN-DBS on the recognition of emotional expressions in PD patients. In this latter study, the participants had to recognize different emotional facial expressions (EFE) (sadness, anger, disgust) and quantify their intensity on seven-point scales. The intensity of each presented EFE varied from 30% to 70%. Using this very sensitive measure of less intense EFE (compared to previous studies), the authors were able to reveal significant impairments on each EFE (sadness, anger and disgust) after surgery compared to patients own pre-operative performance or matched control participants. These results are supported by data showing that negative EFE like fear and sadness were recognized less well by participants in an STN-DBS on condition [6]. Firstly, these results suggest that the use of STN-DBS in PD patients may result in a more widespread emotional impairment than has been reported previously. Secondly, they indicate that the commonly employed experimental tasks may not be sufficiently sensitive and may therefore have failed to reveal the full range of emotional impairment in PD. Potential interaction between STN-DBS and DRT The role of dopamine in the recognition of facial expressions seems to be well established. Indeed, [7] reported results showing that PD patients who were receiving no treatment exhibited a significant EFE impairment (more specifically relating to disgust) compared to healthy controls, but that this difference was no longer observed in patients with more severe PD who were receiving DRT. Similarly, [8] reported a selective impairment in PD patients recognition of the facial expression of anger after acute withdrawal of DRT compared to a matched control population. Taken together, these results suggest that DRT must be taken into account in the assessment of the effect of STN-DBS on emotional processes. However, to our knowledge, no study to date has simultaneously combined the effect of DRT ( on vs. off conditions) with the effect of STN-DBS ( on vs. off conditions) on recognition of emotions. In our opinion, this is a significant weakness since this STN-DBS is administered in combination with DRT and it would be valuable to observe the effect of the interaction between the two therapies on emotional processes. The study conducted by [3] compared the effect of STN-DBS in different stimulation conditions to a control population, whereas in the studies reported by [4] and [5], patients receiving DRT were compared before and after undergoing surgery with STN-DBS switched on but without any examination of the effect of reducing the DRT. Different spatial frequency channels for different emotional processes The impairment of facial recognition induced by STN-DBS suggests that a modulation of STN activity may disturb the functioning of associative and limbic circuits. Neuroanatomical studies in animals have already demonstrated that the STN can be divided into sensory-motor (dorsolateral), limbic (medial) and cognitive-associative (ventromedial) areas [9, 10]. The STN is thus closely connected to the limbic areas of the basal ganglia, such as the ventral pallidum and ventral striatum, as well as to limbic cortical areas such as the anterior cingulate cortex and the orbitofrontal cortex [11]. Furthermore, a neuroimaging study [4] has shown a positive correlation between the impairment of fear in patients after STN-DBS and changes in glucose metabolism, especially in the right OFC, and a negative correlation with amygdala activity. As part of a large cerebral network underlying emotional processing, the anterior cingulate cortex, orbitofrontal cortex and amygdala are known to play a major role in several aspects of emotional processing [12] including the recognition of emotions based on faces and voices [13, 14]. The negative correlation between STN-DBS and amygdala activity proposed by [15] suggests new hypotheses on the possible involvement of different spatial frequency channels in the emotional modulations reported above. At a perceptual level, the magnocellular layers of the lateral geniculate nucleus act as a high-pass temporal frequency filter and a low-pass spatial frequency filter, whereas the parvocellular layers correspond to a low-pass temporal filter but process high spatial frequency information. In fact, different neuroimaging [16, 17], behavioral [18, 19] and neurocomputational results [20, 21] suggest a preferential link between low spatial frequency (hereafter,

3 M. Mermillod et al. / Emotional Disorders 99 LSF) information and fast and automatic emotional processes. Hypotheses At a theoretical level, given our knowledge of this preferential link between LSF information and the amygdala, in relationship with related subcortical structures [16, 22], we assume that STN-DBS may produce a specific impairment of EFEs presented on LSF faces, and especially concerning fearful faces. Such results would be supported by neuroimaging data showing a relationship between LSF fearful faces and the amygdala [16] but also potentially by clinical data suggesting a possible relationship between STN-DBS and the amygdala [3, 4, 15]. Moreover, because of the large impact of STN-DBS on STN but also on adjacent fiber tracts surrounding or running through the stimulated site including nigrostriatal (increasing release of dopamine), pallidothalamic, cerebellothalamic, and pallidonigral fiber tracts [23], we suspect that HSF faces may also be modulated by STN-DBS. This hypothesis would be supported by new neurophysiological evidence firstly reported for pro-active vision [24] but subsequently extended to affective processing [22, 25] that leads us to assume that high spatial frequency (hereafter, HSF) faces are processed more specifically by occipito-temporal cortical areas [26] but subject to a modulation by the orbito-frontal cortex (OFC). In other words, the primary modulation of OFC, based on LSF information might induce subsequent modulation of temporal cortical areas processing of more slowly processed HSF information [24]. Therefore, given the high level of neural connectivity between OFC and the basal ganglia, we assume that STN-DBS and DRT might also produce significant modulation in the recognition of LSF EFE through direct (concerning DRT) and indirect (through modulation of the activity of the STN and related adjacent fiber tracts surrounding or running through the stimulated site concerning STN-DBS) effects on the OFC as well as on HSF EFE due to top-down processes operating from OFC through to temporal cortical areas [22, 25]. To assess the impairment of the recognition of facial expressions after STN-DBS while also taking into account the role of DRT, we carried out a study that tested the effect of STN-DBS (STN-DBS off vs. STN-DBS on ) and dopaminergic medication (DRT off vs. DRT on ) in postoperative PD patients, compared to matched healthy controls (hereafter, MHC). At a methodological level, it has been shown that patients may use perceptual details to recognize the emotion present in an EFE when they have no clear emotional feeling arising from the different EFEs [27]. In support of this view, [28] have shown that a simple perceptual model of vision is able to perform the task of categorizing the six basic EFE at a level of accuracy similar to that of human participants. In order to reduce the possibility that participants use perceptual strategies, we opted for a very rapid presentation procedure of the emotional stimuli, with a 200-ms display time. We believe that deficits in the recognition of EFE may have passed unnoticed in previous studies using broad spatial frequency (BSF) faces (i.e., all coming, not filtered EFE images) and long EFE presentation times. MATERIALS AND METHODS Participants Eighteen patients with Parkinson s disease, aged 62.2 ± 6.3 years, were recruited for the study. All the patients were suffering from idiopathic Parkinson s disease according to the criteria of the Parkinson s Disease Society Brain Bank [29]. All the participants had been admitted for surgery according to the inclusion criteria defined by the French consensus conference of treatment of Parkinson s disease (Consensus Conference Proceedings, 2000). The patients for this study were selected at least 6 months after surgery. The main inclusion criterion was an excellent response (>50%) to acute STN-DBS, which, in concrete terms, corresponds to a correct location of effective electrode contacts in the STN area (Tables 1 and 2). Concerning other possible cognitive or perceptual troubles not related to Parkinson s disease, we made every effort to minimize the biases that might impair EFE processing. None of the patients suffered either from depression, or any significant dysexecutive syndrome, conditions that are also associated with an impaired EFE recognition [30 32]. The absence of most of the cognitive impairments was ensured by exclusion criteria. Inclusion criteria were an absence of dementia: MMS (Mini-Mental State [33]) 24, MAT- TIS scale (Mattis Dementia Rating Scale [34]) >130, and no moderate or severe depression (MADRS <15). As shown in Table 3, the PD patients who were retained had no cognitive impairment (MMS = (0.51), MATTIS = (1.43)). MATTIS was used as a measure of general cognitive abilities and lack of dementia, in line with recent studies, in order to assess the impact of DBS on cognitive flexibility, neuropsychological and psychiatric changes [35], but also the effect of DRT on reward

4 100 M. Mermillod et al. / Emotional Disorders Table 1 Motor assessment scores for each PD patient, and levodopa treatment dose (LEDD, levodopa equivalent daily dose, calculated as the dose of dopamine agonists in addition to levodopa medication: Thobois et al., 2006): UPDRS I = scores on the Unified Parkinson s Disease Rating Scale I collected when PD patients were in their best on state; UPDRS II = scores on the Unified Parkinson s Disease Rating Scale II collected when PD patients were in their best on vs. off state; UPDRS III = scores on the Unified Parkinson s Disease Rating Scale motor score in the 4 experimental conditions (DRT on = under medication; DRT off = without medication; STN-DBS on = with stimulation; STN-DBS off = without stimulation) UPDRS I UPDRS II UPDRS III LEDD L-Dopa Dopa-agonist (mg/d) (mg/d) (mg/d) DRT on DRT off On Off STN-DBS on STN-DBS off STN-DBS on STN-DBS off P P P P P P P P P P P P P P Mean SD Table 2 Deep brain stimulation parameters for each PD patient Stimulation parameters Left Right Participant plot V Hz s plot V Hz s P1 6 2, P2 5 3, , P , P4 STN-DBS Off 2+ et P P6 5 2, , P7 7 1, , P , P9 6 3, , P10 6 2, , P11 5 3, , P12 6 3, P13 5 et 6 3, , P motivation [5, 31]. Among the neuropsychological tests involved in the process of inclusion, we have distinguished two kinds of test measuring, on the one hand, general cognitive abilities and absence of dementia (MATTIS and MMS), and, on the other hand, executive functions on the basis of the Frontal Assessment Battery (FAB [36]) and Wisconsin Card Sorting Test (WCST [37]). The dysexecutive syndrome (impairment in conceptualization, inhibition, flexibility, and deduction) was assessed using 1) the FAB (score 15 [36]), and 2) the correctly sorted categories, the number of errors and perseverative responses on the WCST (Tscore 45 or percentile >16 [38]). Based on the results to these tests we can warrant that no patient included in our study had a significant cognitive impairment. We also assessed the ability of the PD patients to perform a face recognition task correctly (Benton facial recognition test >39) [39], and normal visual contrast and sensitivity to spatial frequency, as assessed by a VISTECH test (VCTS 6500) (Vistech Contrast Sensitivity Test. Manual. Dayton, OH. Vistech Consultants, Inc., 1988). These criteria led us to exclude

5 M. Mermillod et al. / Emotional Disorders 101 Table 3 Neuropsychological assessment results for each PD patient. All evaluations were collected while PD patients were in their best on state. MMS (Mini-Mental State), MATTIS (Mattis Dementia Rating Scale), FAB (Frontal Assessment Battery), BFRT (Benton Facial Recognition Test), WCST (Wisconsin Card Sorting Test; mean score on the WCST (a t-score >45 represents a normal performance; Heaton et al. (1993)), and MADRS (Montgomery and Asberg Depression Rating Scale) MMS MATTIS FAB BFRT WSCT MADRS /30 /144 /18 /54 Correctly sorted Perseveration Errors /60 categories percentile percentile t-score percentile t-score P > P > P > P > P > P > P > P > P > P nd > P > P > P > P > Mean SE patients due to abnormal results in ophthalmologic assessments (Table 4). The final sample therefore consisted of 14 patients (9 men, 5 women) aged 60.6 ± 1.6 years with a mean duration of disease of ± 0.71 years. These patients were studied postoperatively on average 3.5 ± 0.5 years after surgery. Patients L-Dopa dose at the time of the testing was expressed as the levodopa equivalent daily dose (LEDD, Table 1), calculated as the dose of dopamine agonists plus levodopa medication [40]. Fourteen matched healthy control (MHC) subjects (9 men, 5 women) aged 59.9 ± 1.6 years were also recruited to match the patients on age, gender, age at the end of their education and academic level (based on the 5-point French Academic Levels). They did not differ on age, F(1, 26) = 0.1, MSE = 36.1, p = 0.76, gender (all MHC had the same gender as their corresponding patient), age at the end of their education, F(1, 26) = 0.26, MSE = 3.45, p = 0.61, and academic level, F(1, 26) = 0.28, MSE = 0.51, p = 0.6. The study protocol was approved by the regional Medical School Ethics Committee (AU700) and was performed in accordance with the principles set out in the Declaration of Helsinki and French legislation (Huriet law). The nature and potential risks of the study were fully explained and written informed consent was obtained from each participant. The study was also registered with the clinical trial-specific website (NCT: ). Surgery The surgical procedure was based on the precise location of the STN using stereotactic NMR and electrophysiological mapping (recording and stimulation of the STN area) as detailed elsewhere [41]. A stereotactic frame (Lekesll G frame, Elekta, Sweden) was fitted with its repositioning kit (Elekta, Sweden) under local anesthesia, without withdrawal of the antiparkinsonian drug therapy. A stereotactic 1.5 Tesla MRI (Sonata, Siemens, Germany) was then performed with a voxel of mm 3 (field of view = 270 mm; matrix = , slice thickness = 2 mm). To visualize both the stereotactic markers of the repositioning kit and the subthalamic anatomy of the nuclei and bundles, a T2-weighted sequence was performed: Turbo Spin Echo (TSE) sequence, TR = 8000 ms, TE = 10 ms, 24 images in the coronal plan, acquisition 10 min. During the planning phase (Iplan, BrainLab, Germany), the frame was removed for patient comfort. The main structures of the subthalamic region were manually identified: the substantia nigra (SN), the subthalamic nucleus (STN), the zona incerta (ZI) and the red nucleus (RN) with the help of anatomic and stereotactic handbooks and in-house 3D anatomy 4.7 T MRI software. On the following day, the frame was repositioned under local anesthesia and without antiparkinsonian therapy. Pre-operative X-ray controls were carried out during

6 102 M. Mermillod et al. / Emotional Disorders Table 4 Ophthalmologic assessment results for of each PD patient Distant visual acuity Near visual acuity Visual contrast sensitivity 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 Ophthalmologic assessments were carried out using the Moneyer Scale (distant visual acuity) and Parinaud test (near visual acuity). Visual contrast sensitivity was assessed using the VISTECH test (VCTS 6500) (normal values were comprised between and 24.44). Four patients (P15, P16, P17, P18) were excluded due to their abnormal visual contrast sensitivity. the procedure to check that the coordinates and the tracts respected the planning. The two quadripolar electrodes (DBS Medtronic 3389, Medtronic, Minneapolis, USA) were positioned during the same procedure. On each side, the electrode was implanted after electro-physiological mapping using two exploration electrodes (Alpha Omega, Israel) introduced with guide tubes: one on the planned tract and a second one on a parallel tract located 2 mm anterior to it. The electro-physiological analysis consisted of micro-recordings of neuronal activity with 500 mm step checkpoints followed by monopolar acute stimulation tests with 1 mm step checkpoints. A neurologist (PD, MU) assessed the effect of acute stimulation for 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. A few days later, the electrodes were connected to a pulse generator (Kinetra, Medtronic, Minneapolis, USA). Stimulation settings and the antiparkinsonian therapy were adapted postoperatively according to the efficacy of chronic stimulation. Assessment of parkinsonian symptoms The efficacy of acute STN-DBS was assessed in accordance with part III of the Unified Parkinson s Disease Rating Scale (UPDRS, a standardized evaluation of all the motor signs of the disease, with a score range of 0 to 108), under four conditions: (1) Stimulation off and drug therapy off, after a 10-hour withdrawal of antiparkinsonian medication and after stimulation had been switched off for at least 1 h; (2) stimulation on and drug therapy off, after stimulation had been switched on for at least half an hour; (3) stimulation on and drug therapy 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) stimulation off and drug therapy on, after stimulation had been switched off for at least 1 h. Each session was video-recorded. The other tests included UPDRS part I (mental state, with a score range of 0 to 16), part II (activities of daily life, with a score range of 0 to 52), part IV (L-Dopa complications), Hoehn and Yahr stage classification and the Schwab and England scale (which also measures activities of daily life, with a score range from 0 to 100%). During the follow-up, neuropsychological tests were performed, including the Wisconsin card sorting test, the Gröber and Buschke memory test, and a memory span measurement test. Stimuli and material The images were taken from Ekman and Friesen s series [42]. Faces of 10 different individuals (5 female and 5 male) were depicted as black-and-white pictures displaying EFE corresponding to the 6 basic emotions (Anger, Disgust, Fear, Happiness, Sadness, Surprise)

7 M. Mermillod et al. / Emotional Disorders 103 D-1 10 p.m. D 7 a.m. 9 a.m. 10 a.m. 11 a.m. L-dopa stopped DBS stopped Phase 1 / Block 1 STN-DBS off DBS run Phase 2 / Block 2 STN-DBS on DRT off A B D+1 8 a.m. L-dopa administered 9 a.m. Phase 1 / Block 2 STN-DBS on C D+2 7 a.m. DBS stopped 8 a.m. L-dopa administered 9 a.m. Phase 2 / Block 1 STN-DBS off DRT on Fig. 1. Example of experimental procedure as a function of DRT and STN-DBS conditions. A: patients were on DRT off the first day; B and C: patients were on DRT on the second and third day, respectively. The protocol took place on four consecutive days. The timeline from left to right represents the time of the day when we changed therapeutic status. together with a neutral expression. Original blackand-white non-filtered images, which constituted the BSF stimuli, were filtered using Matlab software (The MathWorks Inc., Natick, MA, USA) in 2 spatial frequency (SF) resolutions: High Spatial Frequency band (HSF, >24 cycles/image) and Low Spatial Frequency band (LSF, <8 cycles/image) [43] [44 46]. All the images were normalized at the same luminance and do not differ statistically in contrast across the experimental conditions. There was therefore a total of 210 stimuli (10 Individuals x (6 EFEs + neutral expression) 3 SFs), all of which were displayed in 256 grayscale levels at a pixel resolution on a 19-inch computer screen. These stimuli were divided into 2 blocks of 105 stimuli each for use in the 2 STN-DBS conditions (STN-DBS on vs. STN-DBS off ) and the 2 medication conditions (DRT on vs. DRT off ) (see Fig. 1). The experiment was run using E-prime 1.2 software (PST, Pittsburgh, PA, USA) on an Intel Pentium IV (1,3GHz/512 Mb RAM) PC connected to a 85-Hz, 19 CRT screen. The experimenter used the keyboard keys 1 to 7 on the keyboard to enter patients responses. Experimental design The participants were tested individually. They sat at a distance of 90 cm from the computer screen. The experiment was conducted as follows. Immediately after a fixation cross had been displayed at the center of the screen for 5 seconds, a face image appeared for 200 ms. We had already undertaken a pilot study on healthy subjects and checked that a 100-ms display time was sufficient to detect emotional expressions on the stimuli of this database at different spatial frequencies [47]. We then had to adapt the exposure time to PD patients by increasing the exposure time to 200 ms in order to ensure that PD patients actually perceived each EFE. The EFE was followed by 30-ms mask displayed at the same location in order to cancel out retinal persistence. The patient s task was to categorize the presented EFE correctly and to give a response orally. Participants were given the option of not answering had they not perceived the image. After a 12-trial training phase that was used to assess whether the participant had correctly understood the purpose of the task, the experimental phase was run. In order to avoid learning effects, we split the original 210 stimuli into two blocks of 105 stimuli and counterbalanced the test condition across participants such that half the participants (PD patients and MHC) started the first phase with Block 1 while the others started with Block 2 (Fig. 1). Then, the block assignment was reversed in the second phase. Thus, EFEs were displayed in random order within each block, with blocks chosen on the basis of the DRT/STN-DBS variables so that each participant viewed each block twice. Medication and stimulation conditions over the four consecutive days of the protocol are displayed in Fig. 1. Effect of DRT ( on vs. off ) was tested in the morning during two separate days after withdrawal of all antiparkinsonian medication for at least 10 hours in the STN-DBS on condition. Half of the PD patients were assessed first in the off DRT condition (Fig. 1), the other half began the protocol in their best on DRT medication state 1 h after the patients had received 1.5 times their usual morning L-Dopa dose, in the form of dispersible L-Dopa (Modopar dispersible, Roche). For the participants assessed first in the off DRT condition (Fig. 1A), the performance was tested after a deprivation of all

8 104 M. Mermillod et al. / Emotional Disorders antiparkinsonian medication for at least 10 hours, first with STN-DBS off ( 9 a.m. ) and then with STN- DBS on ( 11 a.m. ) (Fig. 1B and 1C). Conversely, for the PD patients initially assessed in their best on DRT medication state, the EFE recognition task was first run in the STN-DBS on condition at 9 a.m. and then one day later in the STN-DBS off condition (after stimulation had been turned off for at least 1 h), at 9 a.m. The MHC participants underwent the 4 blocks of EFE in the same order as the patients they were paired with. Each MHC participant was paired with his or her corresponding PD patient not only on the variables age, gender, age at the end of their education and academic level, but also with the Block variable (Block 1 vs. Block 2 stimuli). For instance, a MHC paired with a PD patient who started the protocol off DRT (i.e., with part A first, see Fig. 1) was first run on Block 1 stimuli, then on Block 2 stimuli, and later again on Block 2 stimuli, then on Block 1 stimuli, while a MHC paired with a PD patient who started the protocol with part B (see Fig. 1) was first run on Block 2 stimuli, then on Block 1 stimuli, and later again on Block 1 stimuli, then on Block 2 stimuli. RESULTS Surgical outcomes The effects of medication and DBS on motor disorders are reported in Table 1. The acute efficacy of STN-DBS, assessed using UPDRS part III, was ± 3.27% despite the fact that the patients had been operated on average 3.5 years before assessment. The stimulation parameters are reported for each individual patient in Table 2. The treatment, calculated as the dose of dopamine agonists plus levodopa medication, was ± mg/d. In order to make sure that both therapies had an effect at the level of motor symptoms, we conducted a statistical analysis by means of a repeated-measures ANOVA with STN-DBS (STN-DBS on ; STN-DBS off ) and DRT conditions (DRT on ; DRT off ) and with UPDRS score as dependent variable. Results revealed a main effect of DRT, F(1, 13) = 87.8, MSE = 40.2, p < 0.001, with better motor abilities being observed for the DRT on (M = 7.82, SE = 1.38) than for the DRT off (M = 23.65, SE = 2.43) condition. They also revealed a main effect of STN-DBS, with better motor abilities being observed in the STN-DBS on (M = 11.13, SE = 1.48) than in the STN-DBS off (M = 20.35, SE = 2.34) condition, F(1, 13) = 89.7, MSE = 13.2, p < 0.001, as well as a significant interaction effect between the two factors, F(1, 13) = 59.9, MSE = 17.7, p < Pairwise comparisons corrected by a Tukey-Kramer for post-hoc multiple comparisons revealed a significant difference between all STN-DBS and DRT conditions except for STN- DBS on /DRT on (M = 7.57, SE = 1.25) compared to STN-DBS off /DRT on (M = 8.07, SE = 1.54). The neuropsychological results are summarized in Table 3 and revealed no significant cognitive impairment. Furthermore, none of the patients presented any depressive syndrome at the time of the study (Montgomery and Asberg Depression Rating Scale (MADRS) <15 for all patients). Statistical analyses The data we consider for the analyses are the average ratio of EFE recognition accuracy, expressed as the mean ± MSE, for both the PD and MHC groups. We chose not to analyze reaction times because PD patients may suffer from motor impairments that may vary greatly from one patient to another and would entail highly variable reaction times, a bias that would compromise the statistical comparison of their results to those of MHC. The accuracy measure is a valid one, as we can warrant that the PD patients perceived and processed EFEs. Indeed, though they were offered the possibility of not responding (e.g., if they did not perceive the stimulus), the participants virtually never took this option, thanks to the fact that it was always the patient who pressed the keyboard SPACE bar to initiate the presentation of a stimulus. Moreover, the patients exhibited a better level of accuracy regarding the neutral faces (as compared to the EFEs), a difference that would not exist if the accuracy measure were not a sound one. Finally, not only was the facial emotion recognition task meaningful to the PD patients, as the accuracy of the data shows, but under some experimental conditions the PD patients even outperformed the MHC (see Table 5). Average accuracy was analyzed using a mixedmeasures ANOVA with EFE (angry/disgusted/fearful/happy/neutral/sad/surprise), Spatial Frequency (BSF; HSF; LSF), STN-DBS (STN-DBS on ; STN- DBS off ) and DRT conditions (DRT on ; DRT off ) as within-subjects variables, and Experimental Group (PD patients vs. MHC participants) as a between-subjects variable. It is important to note that each MHC participant was also matched on the Block variable (see Experimental design section for details). This experimental design makes it possible to compare each of the four PD groups resulting from the complete

9 M. Mermillod et al. / Emotional Disorders 105 Table 5 Average facial expression recognition rate (mean (S.D.) and [Hedges g] for effect size) for PD patients for each of the four experimental conditions resulting from the manipulation of STN-DBS ( on vs. off ) and DRT ( on vs. off ), and average facial expressions recognition rate for (mean (S.D.)) MHC participants, and results of the statistical comparison of the two, as a function of the facial expression (rows) and the spatial frequency channel (columns). BSF = broad spatial frequency; HSF = high spatial frequency; LSF = low spatial frequency (see text for details) BSF faces HSF faces LSF faces PD patients MHC PD patients MHC PD patients MHC STN-DBS off DRT off Anger 0.7(0.17)**[1.15] 0.50(0.17) 0.51(0.2) [ 0.59] 0.63(0.2) 0.24(0.18) [ 0.76] 0.40(0.23) Disgust 0.54(0.18) [ 0.11] 0.56(0.18) 0.51(0.29) [ 0.47] 0.63(0.2) 0.15(0.14)** [ 1.31] 0.39(0.21) Fear 0.34(0.26) [ 0.08] 0.36(0.24) 0.27(0.2) [ 0.43] 0.37(0.25) 0.14(0.16) [ 0.7] 0.33(0.34) Happy 0.96(0.08) [0.24] 0.94(0.08) 0.96(0.08) [ 0.44] 0.99(0.05) 0.94(0.09) [0.26] 0.91(0.13) Neutral 0.64(0.27) [0.22] 0.58(0.26) 0.87(0.22)* [0.76] 0.67(0.29) 0.8(0.25)** [1.54] 0.33(0.34) Sad 0.59(0.3) [0.08] 0.57(0.16) 0.46(0.33) [ 0.62] 0.63(0.19) 0.2(0.27)** [1.14] 0.51(0.26) Surprise 0.83(0.17) [0.38] 0.77(0.14) 0.59(0.34) [ 0.5] 0.74(0.24) 0.66(0.18) [ 0.15] 0.69(0.2) STN-DBS off DRT on Anger 0.69(0.13) [0.43] 0.61(0.22) 0.46(0.24)* [ 0.8] 0.63(0.17) 0.27(0.18)** [1.2] 0.53(0.24) Disgust 0.53(0.24) [ 0.3] 0.60(0.22) 0.43(0.31) [ 0.62] 0.61(0.25) 0.34(0.22) [ 0.55] 0.47(0.24) Fear 0.31(0.22) [ 0.16] 0.35(0.27) 0.17(0.2)* [ 1.02] 0.43(0.29) 0.14(0.12) [ 0.71] 0.31(0.31) Happy 0.96(0.08) [ 0.14] 0.97(0.06) 0.90(0.17) [ 0.53] 0.97(0.07) 0.86(0.18) [ 0.17] 0.96(0.8) Neutral 0.59(0.26) [ 0.23] 0.65(0.25) 0.73(0.27) [0.00] 0.73(0.35) 0.74(0.23) [0.75] 0.53(0.31) Sad 0.47(0.33) [ 0.6] 0.63(0.18) 0.41(0.23) [ 0.64] 0.54(0.16) 0.24(0.26)** [ 1.13] 0.53(0.24) Surprise 0.73(0.23) [0.08] 0.71(0.25) 0.69(0.35) [0.29] 0.60(0.25) 0.59(0.16) [ 0.67] 0.71(0.19) STN-DBS on DRT off Anger 0.63(0.2) [0.00] 0.63(0.16) 0.49(0.2) [ 0.71] 0.64(0.21) 0.2(0.17)** [ 1.41] 0.50(0.24) Disgust 0.59(0.15) [ 0.06] 0.60(0.18) 0.36(0.27)** [ 1.1] 0.64(0.21) 0.26(0.23)* [ 0.8] 0.47(0.28) Fear 0.27(0.2) [ 0.68] 0.42(0.23) 0.11(0.15)** [ 1.9] 0.51(0.24) 0.2(0.25)* [ 0.81] 0.43(0.3) Happy 0.99(0.05) [0.88] 0.93(0.08) 0.93(0.13) [ 0.27] 0.96(0.08) 0.89(0.13) [ 0.15] 0.91(0.13) Neutral 0.61(0.31) [0.03] 0.60(0.32) 0.79(0.26) [0.47] 0.64(0.36) 0.71(0.29) [0.72] 0.47(0.36) Sad 0.59(0.26) [0.07] 0.57(0.26) 0.34(0.32)* [ 0.82] 0.56(0.18) 0.40(0.26) [ 0.11] 0.43(0.26) Surprise 0.74(0.14) [ 0.52] 0.81(0.12) 0.59(0.24) [ 0.44] 0.71(0.29) 0.53(0.32) [ 0.62] 0.71(0.24) STN-DBS on DRT on Anger 0.67(0.17) [0.41] 0.59(0.21) 0.43(0.19)** [ 1.2] 0.70(0.23) 0.23(0.17)* [ 0.91] 0.43(0.25) Disgust 0.53(0.23) [ 0.27] 0.66(0.2) 0.41(0.28)** [ 1.2] 0.70(0.17) 0.29(0.24)* [ 0.85] 0.47(0.17) Fear 0.30(0.28) [ 0.49] 0.44(0.28) 0.21(0.21)* [ 0.76] 0.43(0.34) 0.04(0.8)** [ 0.5] 0.34(0.26) Happy 0.93(0.1) [ 0.09] 0.94(0.11) 0.91(0.1) [ 0.5] 0.97(0.13) 0.94(0.09) [0.3] 0.91(0.1) Neutral 0.77(0.19) [0.7] 0.60(0.28) 0.89(0.19) [0.64] 0.71(0.34) 0.8(0.27)** [1.08] 0.46(0.34) Sad 0.63(0.23) [0.42] 0.53(0.23) 0.41(0.3) [56] 0.56(0.22) 0.33(0.23) [ 0.3] 0.40(0.23) Surprise 0.73(0.18) [0.29] 0.66(0.28) 0.43(0.28)** [ 1.4] 0.77(0.2) 0.56(0.26) [0.07] 0.54(0.33) p < 0.08, *p < 0.05, **p < 0.01 crossing of the two levels of STN-DBS and DRT variables to MHC participants, as the PD patients and their MHC experienced the same Block (1 and 2). Pairwise comparisons between PD patients and MHC participants were realized with respect to the Block sessions. The statistical analyses were performed under Statistica 7.0 (SYSTAT, Chicago, IL). Recognition of emotional expressions We observed a marginally significant effect of Experimental Group, F(1, 26) = 3.85, MSE = 0.71, p = 0.06, toward a lower recognition of EFE by PD patients (M = 0.54, SE = 0.02) compared to MHC (M = 0.61, SE = 0.02). We observed a significant interaction between Experimental Group and EFE, F(6, 156) = 7.16, MSE = 0.16, p < 0.001, which is evidence for the fact that the impaired EFE recognition ability of PD patients is limited to specific emotional expressions. We also observed a significant interaction between Experimental Group and Spatial Frequency, F(2, 52) = 15.31, MSE = 0.05, p < 0.001, which shows that PD patients were less accurate than MHC for HSF and LSF information but not for BSF information (Table 5). Moreover, we observed a significant 3- way Experimental Group EFE Spatial Frequency interaction, F(12, 312) = 6.05, MSE = 0.04, p < 0.001, suggesting that the effect of Spatial Frequency is related to specific EFE for PD patients compared to MHC. More specifically, and with respect to our initial hypotheses, we conducted a specific analysis of the global effect in PD patients of each therapy on EFE categorization for the different SF channels. Concerning

10 106 M. Mermillod et al. / Emotional Disorders the effect of STN-DBS, we did not find a global effect of STN-DBS on recognition of either BSF or LSF faces. However, the STN-DBS on condition produced a lower overall recognition rate for HSF EFE than the STN-DBS off condition, F(1, 26) = 3.99, MSE = 0.05, p < The effect of DRT did not produce any global effect on EFE for BSF, LSF or HSF EFE. However, we observed a significant 5-way interaction effect among Experimental Group EFE Spatial Frequency STN-DBS DRT, F(12, 312) = 2.63, MSE = 0.03, p < 0.01, suggesting that the effect of each therapy should be specified for each EFE and SF channel. In other words, the main effects and lower order interaction effects reported above should be specified for each modality of the experimental design. For instance, it will be meaningless to describe the 2-way interaction Experimental Group EFE since this interaction have to be specified for each spatial frequency, but also STN-DBS and DRT factors, as revealed by the significant 5-way interaction Experimental Group EFE Spatial Frequency STN-DBS DRT. In order to understand this 5-way interaction, we reported an exhaustive presentation of the results of PD patients compared to their respective MHC for each spatial frequency, EFE, STN-DBS and DRT conditions (Table 5). More precisely, to assess whether STN-DBS and DRT have a more deleterious impact on emotional processing for HSF and LSF compared to BSF EFE, we tested the effect of each of the four therapy conditions (STN-DBS on vs. off DRT on vs. off ) by comparing the performance of the PD patients to that of MHC for each EFE and SF channel. In order to prevent any post-hoc bias related to multiple comparisons, as well as due to the fact that the assumption of homogeneity of covariance necessary to perform an ANOVA was violated for different specific local comparisons, local contrasts between PD patients and MHC were performed using a non parametric two-tailed Mann- Whitney U test. The results, displayed in Table 5, revealed no recognition impairment on emotional expressions for BSF faces. Compared to the MHC participants, PD patients even had a better recognition of anger under STN-DBS off and DRT off condition, and a marginally significant better recognition of happiness, accompanied by a marginally significant lower recognition of fear under STN-DBS on and DRT off condition. However, and in line with our initial hypotheses, this normal-level performance of PD patients on BSF faces contrasts sharply with the impaired performance on LSF and HSF faces. PD patients emotion recognition impairment largely reduced the recognition of LSF and HSF EFEs and is often of quite a high magnitude (Table 5) with a noteworthy exception for neutral expressions (PD patients produced a significant over-representation of the neutral faces). These impairments of PD compared to MHC on LSF emotional faces (but not HSF or BSF faces) were particularly acute in the STN-DBS off and DRT off condition. Moreover, similar emotional impairments were also found on LSF faces in the active STN-DBS and DRT conditions (see Table 5). Results show that DRT alone (STN-DBS off and DRT on condition) not only reduced the negative effect of PD for LSF EFE but also induced new impairments relating to fearful and angry HSF EFE. More problematic is that this negative effect of DRT on HSF angry and fearful faces was still present and even extended to new emotional expressions including disgust and sad expressions under the STN-DBS on and DRT off condition, or disgust and surprise expressions under the STN-DBS on and DRT on condition. It should be noted that the negative effect of STN-DBS on fearful expressions reported in the literature (Biseul et al. 2005) was very weak for BSF EFE but was particularly intense for LSF and HSF EFE in the STN-DBS on conditions (see bottom part of Table 5 for details). DISCUSSION This study was designed to investigate the effect of Parkinson s disease on emotional processes at different spatial frequencies (i.e. at the level of different brain structures) in severely affected PD patients in different STN-DBS and DRT conditions by comparing their performance to that of MHC participants and by using an original experimental design aimed at precluding the use of perceptual strategies at the time of judging an emotional facial expression. Our results contrast with those reported in studies in which patients were assessed postoperatively in a condition of chronic STN-DBS stimulation coupled with DRT administration and when their performance was compared to their preoperative state and that of healthy participants [3, 5]. In our study, in the experimental condition where the PD patients were deprived of both STN-DBS and DRT we didn t find an impairment in the recognition of the facial expression of fear in our patients compared to healthy volunteers when non-filtered images were used. As far as the effect of L-Dopa is concerned, some results reported in the literature indicate that dopamine

11 M. Mermillod et al. / Emotional Disorders 107 plays a role in EFE recognition in both healthy participants and PD patients [8]. However, the absence of an effect of DRT on BSF faces is consistent with a meta-analysis conducted by [48], who found that the effect of dopaminergic medication on EFE recognition in Parkinson s disease is not systematic, and is often based on moderate effect sizes. Therefore, we assume that the controversy reported by [48] concerning a possible difference between DRT conditions and MHC in previous studies, based on BSF faces and long EFE presentation times, could result not from emotional deficits but from the difficulty experienced by patients in mobilizing perceptual strategies. In other words, we suggest here that a task that is more closely related to emotional processes (by means of fast presentations of the EFE at different spatial frequencies) is probably more suitable than the extended presentation of BSF faces in revealing the impact of DRT and STN-DBS on PD patients compared to MHC. However, the main finding of this study is that, behind an apparent correct recognition performance relating to normal BSF EFEs (except for a marginally significant effect on fearful faces under STN-DBS on and DRT off condition), large and widespread impairments are revealed by a manipulation of the spatial frequencies of the emotional faces. It should be noted that, according to the main models of spatial frequency processing [22, 44, 49], the result of the dynamic integration of the HSF in the LSF information for BSF stimuli is more than the simple sum of the LSF and HSF information. Therefore, a deficit in the processing of each visual pathway could be hidden at the level of BSF faces because of the powerful interaction between the two visual pathways. Different neuro-anatomical routes could account for these results. Therefore, we provide here different possible theoretical models published in this field, with regards to the main functional-anatomical models of spatial frequency information applied to emotional processes. However, we have to mention that these models only constitute a non extensive set of a posteriori explanations for these results and that new behavioral and neuroimaging experiments will be required to test these (or other) theoretical alternatives. First, recognition of LSF EFEs (but not HSF EFEs) was largely impaired in the PD patients from the STN-DBS off and DRT off condition. Moreover, and more surprisingly, the administration of STN-DBS and DRT therapies separately are not only insufficient to reduce these LSF impairments obtained in STN-DBS off and DRT off condition, but also produces new impairments on HSF faces. This effect was particularly acute in the case of STN-DBS, which induced a significant global decrease in recognition of EFE for HSF faces. This effect was surprising but might be consistent with a recent study by [50], which suggests that STN-DBS and DRT might results in fronto-striatal abnormalities that would entail an impairment in the recognition of facial expressions. Since HSF parvocellular information is processed by temporal cortical areas, this effect seems to imply that STN-DBS and DRT have indirect consequences on these neural structures. In terms of the effect of L-Dopa, this result would be consistent with animal studies [51] suggesting that the function relating cognitive performance (more specifically learning and attention flexibility) to dopamine level has an inverted U shape. These studies suggest that L-Dopa doses required for an appropriate processing within the subcortical structures such as the putamen might be detrimental to the neural structures in the cortical areas [51, 52]. The current study suggests that such processes could occur at the level of the temporal cortical areas and proposes the use of HSF stimuli in order to test this hypothesis. Given our knowledge of the neural routes dedicated to LSF and HSF visual information, especially concerning emotional processing [16, 22], and our knowledge of the dopaminergic depletion in PD, further evidence in support of this finding comes from a possible disruption in the processing of LSF faces induced by Parkinson s disease. This type of disruption could be due to a direct subcortical LSF route from the thalamus to the amygdala [49]. However, here we do not make any definite assumptions concerning the neuroanatomical pathway from the LSF visual layers to the basal ganglia since recent evidence suggests that alternative neural pathways might exist, either from the extra-striate cortex to the amygdala [53, 54]. Nevertheless, aside these bottom-up view of emotional perception, the theoretical model proposed by Bar [22] could constitute an alternative hypothesis. Under this theoretical framework, the effect could be produced by the loss of the synchronization between the LSF information provided by top-down fronto-cortical areas, and more specifically the OFC [55] toward the bottom-up HSF information provided by the ventral stream. To our opinion, this neurofunctional model could provide a better theoretical account of the current results, compared to a purely bottom-up approach, especially concerning HSF-EFE. Of course, these a posteriori hypotheses have to be tested and a combination of behavioral studies, in combination with fmri (for spatial resolution) and EEG or MEG (for temporal resolution) studies will be necessary in order to address this hypothesis.

12 108 M. Mermillod et al. / Emotional Disorders Finally, the general deficit regarding emotional expressions that is reported in this study and the improvement observed for the neutral expressions by PD patients compared to MHC are consistent with the hypothesis proposed within the general framework of embodiment theory [56 58], which holds that motor disorders have a direct influence on emotional processes [27, 59]. This result cannot be due to a default response since participants were able to not respond if they did not recognize an EFE. Interestingly, we obtained opposite results (i.e. an under-estimation of neutral expressions) when using exactly the same experimental design with Tourette s Syndrome (TS) patients [45]. According to the embodiment theory, this would suggest that facial movements (facial amimia in PD patients vs. facial TICs in TS patients) may be involved in these modulations of categorization of EFEs. Recent behavioral evidence suggests that this type of emotional modulation could occur in response to the fast and automatic sensory-motor embodiment of the perceived emotion [59]. Important effects consistent with the embodiment theory were already reported in the literature for PD patients at the level of cognitive processes [60] and we suggest that similar impairments might occur for emotional faces, but not for neutral faces, precisely because the latter do not require from the PD patients the motor activation of their facial muscles at the time when they have to recognize emotional expressions. Therefore, these results suggest that motor disorders in PD probably have major consequences on how PD patients experience an emotion. This hypothesis is currently being examined in order to determine whether there is a direct link between facial amimia in PD (measured by facial EMG) and the reduction of magnitude in the experience of an emotion. To conclude, this experiment confirms the presence of slight and rare emotional deficits, as reported in previous studies examining normal BSF faces [3, 5, 7, 61]. More importantly however, our study clearly shows that when PD patients are in a situation that reduces the use of perceptual strategies allowing the specific investigation of different perceptual routes (by means of spatial frequency processing), they achieve a significantly lower recognition rate than MHC participants on a wide range of emotions. The effect of PD without therapy seems to be particularly acute for LSF emotional faces, possibly due to a subcortical dysfunction, and appears to be accompanied by an over-representation of the neutral face answer as predicted by the embodiment theory. In addition, this article provides novel data about the interactive effect of DRT and STN-DBS on emotional processes. Our current results equally suggest that the joint action of STN-DBS and DRT could also disrupt emotional integration at the level of occipito-temporal cortical areas, as the reduced recognition accuracy on HSF EFEs in the STN-DBS on and DRT on, as well as in the STN-DBS on and DRT off conditions, indicates. More specifically, we have shown in this study that STN-DBS produces a broad global impairment of EFE at the level of HSF visual channels. This surprising result suggests that STN-DBS could have an unexpected effect during the integration of HSF information at the level of temporal cortical areas. This hypothesis will have to be carefully investigated by combining behavioral experiments and neuroimaging studies applied to emotional processing [22]. ACKNOWLEDGMENTS This work was supported by the French National Center for Scientific Research as well as by grant No. ANR-06-BLAN from the French National Research Agency (ANR) and the Institut Universitaire de France to Martial Mermillod and the Programme Hospitalier de Recherche Clinique from the University Hospital Center of Clermont-Ferrand to Franck Durif and Isabelle Jalenques. CONFLICT OF INTEREST The authors have no conflict of interest to report. CONCLUSION REFERENCES [1] Derost P, Ouchchane L, Morand D, Ulla M, Llorca PM, Barget M, Debilly B, Lemaire JJ, & Durif F (2007) Is DBS-STN appropriate to manage severe Parkinson s disease in an elderly population? Neurology, 68, [2] Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, & Benabid A-L (1998) Electrical stimulation of the subthalamic nucleus in advanced Parkinson s disease. New Engl J Med, 339, [3] Biseul I, Sauleau P, Haegelen C, Trebon P, Drapier D, Raoul S, Drapier S, Lallement F, Rivier I, Lajat Y, & Verin M (2005) Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson s disease. Neuropsychologia, 43, [4] Le Jeune FL, Péron J, Biseul I, Fournier S, Sauleau P, Drapier S, Heagelen C, Drapier D, Millet B, Garin E, Herry JY, Malbert CH, & Vérin M (2008) Subthalamic nucleus stimulation