Philippe Voruz

Florence Le Jeune

Claire Haegelen

Karim N'diaye

Jean-François Houvenaghel

Paul Sauleau

Sophie Drapier

Dominique Drapier

Didier Grandjean

Marc Vérin

Dr Julie Péron
email: julie.peron@unige.ch

Running head: Vocal emotion and STN DBS in PD Motor symptom asymmetry in Parkinson's disease predicts emotional outcome following subthalamic nucleus deep brain stimulation

Keywords: emotional prosody, Parkinson's disease, asymmetry, striatum, 18 FDG-PET, subthalamic nucleus, deep brain stimulation

The objective of this study was to explore the brain modifications associated with vocal emotion (i.e., emotional prosody) processing deficits in patients with Parkinson's disease after deep brain stimulation of the subthalamic nucleus, and the impact of motor asymmetry on these deficits. We therefore conducted 18-fluorodeoxyglucose positron emission tomography scans of 29 patients with left-or right-sided motor symptoms of Parkinson's disease before and after surgery, and correlated changes in their glucose metabolism with modified performances on the recognition of emotional prosody. Results were also compared with those of a matched healthy control group. Patients with more left-sided motor symptoms exhibited a deficit in vocal emotion recognition for neutral, anger, happiness and sadness in the preoperative condition that was normalized postoperatively. Patients with more right-sided motor symptoms performed comparably to controls in the preoperative condition, but differed significantly on fear postoperatively. At the metabolic level, the improvement observed among patients with left-sided motor symptoms was correlated with metabolic modifications in a right-lateralized network known to be involved in emotional prosody, while the behavioral worsening observed among patients with right-sided motor symptoms was correlated with metabolic modifications in the left parahippocampal gyrus and right cerebellum. We suggest that surgery has a differential impact on emotional processing according to motor symptom lateralization, and interpret these results as reflecting the (de)synchronization of the limbic loop in the postoperative condition.

INTRODUCTION

Over the past decade, research on the emotional effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson's disease (PD) or obsessive-compulsive disorder, coupled with intracranial recordings or metabolic functional imaging, has enabled researchers to explore the STN's functional specialization and integration in emotion [START_REF] Le Jeune | Subthalamic nucleus stimulation affects limbic and associative circuits: a PET study[END_REF][START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF]Péron, Le Jeune, et al., 2010). On the basis of this corpus of findings, an integrative model has been developed [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF], according to which the STN forms part of a distributed neural network underlying emotion processing in humans.

More specifically, rather than playing a specific function in a given emotional process, the STN, together with other basal ganglia, coordinates neural patterns, either synchronizing or desynchronizing the activity of the different neuronal populations involved in specific emotion components. For the recognition of vocal expressions of emotion (i.e., emotional prosody), for instance, the basal ganglia recruit and synchronize the activity of the structures involved in the different steps of emotional prosody processing, while competing neuronal patterns are inhibited [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF]. This mechanistic process subtends the ensuing function. In line with [START_REF] Graybiel | Habits, rituals, and the evaluative brain[END_REF]'s propositions concerning the motor and cognitive domains, the basal ganglia iteratively assess contexts and select actions in order to form (or control the expression of) coordinated emotional sequences. If these emotional sequences become recurrent or repetitive, the basal ganglia combine their representations into units (also called chunks). In other words, the basal ganglia code for the neuronal co-activation of the different cortical and subcortical structures needed for specific emotion components, in order to chunk information into manageable quanta. This information chunking provides a mechanism for acquiring and expressing emotional repertoires which, without such information compression, would be biologically unwieldy or difficult to implement. This model has given rise to several postulates that have already been partially tested and validated.

First, it suggests that, in functional terms, the STN is a constituent part of all the distributed networks that subtend specific emotional subprocesses. This hypothesis was confirmed in a high-resolution functional magnetic resonance imaging (fMRI) study of healthy individuals [START_REF] Péron | Structural and Functional Connectivity of the Subthalamic Nucleus During Vocal Emotion Decoding[END_REF] that explored the structural and functional connectivity of the STN with other brain regions related to vocal emotion, by combining diffusion tensor imaging and psychophysiological interaction analysis.

Second, it suggests that the basal ganglia, and more specifically the STN, are sensitive to rhythm, owing to their intrinsic functional role of rhythm organizer, or coordinator of neural patterns. In a more operational way, the model hypothesizes that the STN is involved in i) all stages of emotion processing, and ii) all emotion processing irrespective of stimulus valence (positive or negative) and sensory modality (e.g., visual or auditory). This has been confirmed by intracranial local field potential recordings in patients with PD undergoing DBS [START_REF] Kühn | Activation of the subthalamic region during emotional processing in Parkinson disease[END_REF][START_REF] Péron | Vocal emotion decoding in the subthalamic nucleus: An intracranial ERP study in Parkinson's disease[END_REF].

Third and last, the model suggests that although STN DBS restores motor functions, the surgery impairs nonmotor functions such as emotion processing. More specifically, STN DBS restores the functional synchronization of the motor loop while at the same time desynchronizing the limbic one [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF]. The model further suggests that the metabolic modifications correlating with emotional disturbances following surgery are both task dependent and sensory input dependent [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF]. This hypothesis has been tested and validated for most emotional components, including the recognition of facial emotions [START_REF] Le Jeune | Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study[END_REF], the affective component of theory of mind (Péron, Le Jeune, et al., 2010), subjective emotional experiences or feelings [START_REF] Ory | Pre-frontalinsular-cerebellar modifications correlate with disgust feeling blunting after subthalamic stimulation: A positron emission tomography study in Parkinson's disease[END_REF], and action tendencies [START_REF] Le Jeune | Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study[END_REF]. However, it has yet to be tested for the recognition of vocal emotions (i.e., emotional prosody), defined as suprasegmental changes in the course of a spoken utterance, encompassing intonation, amplitude, envelope, tempo, rhythm, and voice quality [START_REF] Grandjean | Intonation as an interface between language and affect[END_REF].

Finally, a recent study in the field of emotion recognition in PD indicated that the asymmetry of motor symptoms is an important clinical factor, in that it may influence the presence or severity of affective disorders in PD . In this study, results indicated that patients with left-sided motor symptoms (LPD) displayed vocal emotion deficits. These correlated with the asymmetry of these motor symptoms, as well as with glucose metabolism modifications in the right brain network subtending higher-order processes of vocal emotion recognition. This inferred differential impact of PD motor symptom asymmetry on the recognition of emotional prosody was recently corroborated by a meta-analysis [START_REF] Coundouris | Social perceptual function in parkinson's disease: A meta-analysis[END_REF]. However, the interaction of this variable with the effects of STN DBS has yet to be explored.

Aim of the study

In this context, the purpose of the present study was twofold. The first aim was to test the notion that the STN is a functional component of the brain network subtending the recognition of emotional prosody at the metabolic level. The second aim was to test the impact of motor asymmetry on emotional performances before and after DBS. We therefore combined and correlated the emotional prosody performances of 29 consecutive patients with PD who underwent STN DBS in pre-versus postoperative conditions with modifications in cerebral glucose metabolism, as assessed with 18-fluorodeoxyglucose positron emission tomography ( 18 FDG-PET), and according to the precise anatomical positions of the 8 stimulation contacts within the target structure. The patients were carefully selected to create two clinically homogeneous subgroups of patients that could be differentiated by the lateralization of their motor symptoms, as attested by the calculation of an asymmetry index.

Predictions

Regarding behavioral results, on the strength of previous results concerning the effects of STN DBS on emotional prosody recognition in patients with PD [START_REF] Péron | Sensory contribution to vocal emotion deficit in Parkinson's disease after subthalamic stimulation[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF], we expected to observe a significant modulation of emotional prosody recognition scores in the postoperative condition, but no difference in the preoperative condition between the PD group and a group of healthy controls (HC). Given the results reported by [START_REF] Stirnimann | Hemispheric specialization of the basal ganglia during vocal emotion decoding: Evidence from asymmetric Parkinson's disease and (18)FDG PET[END_REF], we predicted that these effects would be driven by the LPD subgoup (i.e., patients with greater right hemispheric brain dysfunction).

Regarding cognitive-metabolic results, on the basis of Péron et al.'s model (2013), we expected to find significant correlations between modifications in emotion recognition performances in the postoperative condition and glucose metabolism modifications in the brain network subtending emotional prosody recognition, namely the orbitofrontal and auditory cortices (i.e., voice-sensitive areas), amygdala, basal ganglia (notably the striatum), and posterior cerebellum [START_REF] Ethofer | Impact of voice on emotional judgment of faces: An eventrelated fMRI study[END_REF][START_REF] Ethofer | Cerebral pathways in processing of affective prosody: a dynamic causal modeling study[END_REF][START_REF] Ethofer | Emotional Voice Areas: Anatomic Location, Functional Properties, and Structural Connections Revealed by Combined fMRI/DTI[END_REF]Frühholz, Ceravolo, & Grandjean, in press;[START_REF] Grandjean | The voices of wrath: brain responses to angry prosody in meaningless speech[END_REF][START_REF] Sander | Emotion and attention interactions in social cognition: brain regions involved in processing anger prosody[END_REF][START_REF] Schirmer | Beyond the right hemisphere: brain mechanisms mediating vocal emotional processing[END_REF][START_REF] Wildgruber | A cerebral network model of speech prosody comprehension[END_REF].

PARTICIPANTS AND METHODS

Participants

One group of patients with PD and one HC group took part in the study. All the patients met the clinical criteria of the Parkinson's UK Brain Bank for idiopathic PD [START_REF] Hughes | Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases[END_REF].

Patients with Parkinson's disease (Table 1)

The patient group consisted of a series of 29 consecutive patients with medically intractable PD who underwent bilateral STN DBS at Rennes University Hospital (France).

Standard selection and exclusion criteria for surgery were applied to all patients [START_REF] Welter | Clinical predictive factors of subthalamic stimulation in Parkinson's disease[END_REF]. In particular, patients with brain atrophy were excluded on the basis of the preoperative MRI. There were 16 men and 13 women in the patient group. Their mean age at surgery was 56.5 years (SD = 7.98, range = 36-68), and their mean education level (in years of school completed) was 11.30 (SD = 3.60,. According to the criteria of the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: the Edinburgh inventory[END_REF], 27 patients were right-handed, and two were left-handed. Their mean disease duration at surgery was 11.20 years (SD = 4.20,. The total levodopa-equivalent daily dose (LEDD) was calculated on the basis of [START_REF] Lozano | Effect of GPi pallidotomy on motor function in Parkinson's disease[END_REF]: M = 1280.76 mg (SD = 588.50, range = 360-2520) before STN DBS and M = 717.21 mg (SD = 562.47, range = 0-2020) after STN DBS.

The patients with PD were divided into two subgroups, based on side of symptom onset: primarily left-affected (LPD; n = 13) versus primarily right-affected (RPD; n = 16). We then calculated an asymmetry index based on the lateralized items (Items 20-26) of Part III of the Unified Parkinson's Disease Rating Scale (UPDRS III; [START_REF] Fahn | UPDRS Development committee. unified Parkinson's disease Rating Scale[END_REF], by subtracting the item scores related to the left side of the body from the item scores related to the right side of the body, in order to use the patients' current asymmetry status to corroborate our distinction. T tests for independent groups revealed a significant difference between the 10 two subgroups on the asymmetry index in both the on-dopa (t = -4.72, p < .001) and off-dopa (t = -3.25, p = .003) conditions. In the preoperative condition, the two patient subgroups were otherwise similar, in terms of sex ratio (8 women and 8 men in the RPD group; 6 women and 7 men in the LPD group), age, education level, age at motor symptom onset, disease duration, and stage of the disease (Table 1). Note. T test for independent groups. SD: standard deviation; LPD: patients with PD exhibiting predominantly left-sided motor symptoms; RPD: patients with Parkinson's disease exhibiting predominantly right-sided motor symptoms.

Matched healthy controls

The HC group consisted of 29 healthy matched individuals who had no history of neurological disease, head injury or alcohol abuse, and displayed no signs of dementia, as attested by their scores on the Mattis Dementia Rating Scale [START_REF] Mattis | Dementia rating scale[END_REF] (mean score = 141.70, SD = 1.70). There were 16 men and 13 women in this group. Their mean age was 54.35 years (SD = 8.50, range = 35-66), and their mean education level was 12.40 years (SD = 11 2.50, range = 9-15). According to the criteria of the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: the Edinburgh inventory[END_REF], 27 HC participants were right-handed and two were left-handed.

The two groups (whole PD vs. HC) were comparable for handedness and sex ratio.

Furthermore, there was no statistical difference between the two groups on either age (t = -1.274, p = .2) or education level (t = 1.594, p = .1).

After receiving a full description of the study, all participants gave their written informed consent, and the study was conducted in accordance with the Declaration of Helsinki.

General procedure

All patients were assessed 3 months before and 3 months after surgery with motor, PET, and neuropsychological tests. These evaluations were all performed in the same week.

All patients had stimulation turned on and were on levodopa when they underwent the PET and neuropsychological assessments.

Motor assessments

All patients were evaluated according to the Core Assessment Program for Intracerebral Transplantation [START_REF] Langston | Core assessment program for intracerebral transplantations (CAPIT)[END_REF] and scored on the UPDRS I-IV [START_REF] Fahn | UPDRS Development committee. unified Parkinson's disease Rating Scale[END_REF], Hoehn and Yahr scale (H&Y, [START_REF] Hoehn | Parkinsonism: onset, progression and mortality[END_REF], and Schwab and England scale (S&E, [START_REF] Schwab | Projection techniques for evaluating surgery in Parkinson's Disease[END_REF] 3 months before and 3 months after surgery. Patients were assessed on and off levodopa before and after surgery. Stimulation remained on after surgery.

Neurosurgery and electrode location (SI 1)

Quadripolar (from 0 for the most ventral contact to 3 for the most dorsal) 3389 DBS electrodes (Medtronic, Minneapolis, MN, USA) were implanted bilaterally in the STN in a single operating session. The overall methodology was similar to that previously described by Benabib and colleagues (2000). A brain MRI was performed at the onset of the surgical 12 procedure, to calculate the stereotactic coordinates for positioning the two selected electrode contacts (one on the left and one on the right). The intended coordinates at the tip of Contact 0 were 10-12 mm from the midline, 0-3 mm behind the midcommissural point, and 3-5 mm below the anterior commissure-posterior commissure line. During the operation, the final course and depth of the electrodes was determined by the best effect obtained on rigidity with no side effects and at the lowest voltage. A three-dimensional computed tomography brain scan performed a few days later confirmed the position of the electrodes. The exact contact locations for each patient and for each of the right and left electrodes are available in Supplementary Material SI 1.

In all patients, chronic stimulation was monopolar, using a single contact of the quadripolar electrode chosen for the best motor improvement. The stimulation characteristics were as follows: mean pulse width 60 µs for the right side (SD = 0) and 60 µs (SD = 0) for the left side, mean frequency 133 Hz (SD = 8.2) for the right side and 131 Hz (SD = 6.1) for the left side, and mean voltage 2.2 V (SD = 0.6) for the right side and 2.2 V (SD = 0.6) for the left side.

Neuropsychological and psychiatric assessment

A short neuropsychological and psychiatric battery was administered to participants prior to the vocal emotion recognition sessions [START_REF] Péron | Major depressive disorder skews the recognition of emotional prosody[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF]. This battery included the MDRS [START_REF] Mattis | Dementia rating scale[END_REF] and a series of tests to assess frontal executive functions: Nelson modified Wisconsin Card Sorting Test (MCST, [START_REF] Nelson | A modified card sorting test sensitive to frontal lobe defects[END_REF],

Trail Making Test (TMT, [START_REF] Reitan | Validity of the trail making test as an indication of organic brain damage[END_REF], Categorical and Literal Fluency Test [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level[END_REF], Action (Verb) Fluency Task [START_REF] Woods | Action (verb) fluency: test-retest reliability, normative standards, and construct validity[END_REF], and Stroop test [START_REF] Stroop | Studies of interference in serial verbal reactions[END_REF]. Depression was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS, [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF]. This scale was chosen because of the predominance of psychic items over somatic ones, thus limiting interference with the PD symptoms. Finally, the State-Trait Anxiety Inventory (STAI, [START_REF] Spielberger | Manuel de l'inventaire d'anxiété état-trait forme Y (STAI-Y) [Inventory of state-trait anxiety manual[END_REF] was used to assess anxiety, and the Apathy Evaluation Scale (clinician version; [START_REF] Marin | Reliability and validity of the Apathy Evaluation Scale[END_REF] to assess apathy.

Vocal emotion recognition assessment

Stimuli

All participants were exposed to a set of vocal stimuli [START_REF] Péron | Major depressive disorder skews the recognition of emotional prosody[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF]. These stimuli, extracted from the database developed and validated by Banse and Scherer (1996), consisted of short segments of meaningless speech (pseudoword 1: fɪ goet laiʃ ʃɑ ̃ kil gɔs tɛʀ, pseudo-word 2: h'ɛt s'ɒ dik pr'ɒ g nj'y v'ɛntzi), obtained by concatenating different syllables found in Indo-European languages so that they would be perceived of as natural utterances, with emotional intonation (across different cultures) but no semantic content. Four categories of emotional prosody (anger, fear, happiness, and sadness), together with a neutral condition, were used in the present study. We selected utterances produced by 12 different actors (6 women and 6 men), each expressed with five different prosodies (anger, fear, happiness, neutral, and sadness). The set of vocal stimuli (pseudowords) comprised 60 stimuli (12 actors × 5 emotion conditions) and is extensively described elsewhere [START_REF] Péron | Sensory contribution to vocal emotion deficit in Parkinson's disease after subthalamic stimulation[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF].

Vocal emotion recognition procedure

All stimuli were presented bilaterally via stereo headphones with an Authorware program designed especially for this study. Participants sat comfortably in a quiet room in front of the computer and looked at a fixation cross while listening to the stimuli. They were told that they would hear meaningless speech uttered by male/female actors and that these actors would express emotions through their utterances. Participants were required to listen to 14 each stimulus, after which they were asked to rate its emotional content on a set of visual analogue scales ranging from Not at all to Very much, which were simultaneously displayed on the computer screen (see Appendix). More specifically, participants rated each stimulus on six scales: one scale for each featured emotion (anger, fear, happiness, and sadness), one for neutral, and one for the surprise emotion, so that we could determine whether the fear emotion expressed by the human voice was confused with surprise, as is the case with facial expressions [START_REF] Ekman | Emotions revealed[END_REF][START_REF] Scherer | Multimodal expression of emotion: affect programs or componential appraisal patterns?[END_REF]. Participants were told that they could listen again to each stimulus as many as six times, by clicking on a button on the computer interface (click counter). Participants were given two examples to familiarize themselves with the task.

Audiometric screening procedure

To ensure that all participants had normal hearing, we carried out a standard audiometric screening procedure (AT-II-B audiometric test) to measure tonal and vocal sensitivity. This was done in the Ear, Nose and Throat Department of Rennes University Hospital. None of the patients included in the study wore hearing aids or had a history of tinnitus or a hearing impairment.

As described elsewhere [START_REF] Le Jeune | Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study[END_REF][START_REF] Péron | Subthalamic nucleus stimulation affects fear and sadness recognition in Parkinson's disease[END_REF][START_REF] Péron | Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease[END_REF][START_REF] Péron | Are dopaminergic pathways involved in theory of mind? A study in Parkinson's disease[END_REF], Versions A and B of the emotional recognition task were counterbalanced, to avoid a list effect between the pre-and postoperative conditions in the PD group. The protocol was completed in a single 90-minute session.

PET imaging

Acquisition

All patients underwent the 18 FDG-PET scans in a resting state with their eyes open.

They underwent two scans while on their antiparkinsonian medication: the first was performed 3 months before surgery, and the second 3 months after surgery, with the stimulator switched on. PET measurements were performed with a dedicated Discovery ST PET scanner (GEMS, Milwaukee, WI, USA) in 2D mode with an axial field of view of 15.2 cm. A 222-296 MBq injection of 18 FDG was administered intravenously under standardized conditions (in a quiet, dimly lit room with the patient's eyes and ears open), with normal fasting blood glucose < 1.4 g/l before injection. During acquisition, the patient's head was immobilized with a head holder. A cross-laser system was used to achieve stable and reproducible positioning. A 20-minute 2D emission scan was performed 30 minutes postinjection and after X-ray-based attenuation correction. The patient was positioned at the center of the field of view. Following scatter, dead time, and random corrections, the PET images were reconstructed by 2D filtered back projection, yielding 47 contiguous transaxial 3.75-mm thick slices.

PET image transformation

Using a method described elsewhere (Le Jeune et al.

Statistical analysis

Analyses testing predictions about behavioral results

Sociodemographic, neuropsychological, and psychiatric data. Intergroup comparisons were performed using t tests for two independent groups. Intragroup comparisons were performed using t tests for two dependent groups, to evaluate the effect of experimental condition.

Vocal emotion recognition data. We calculated three generalized linear mixed models (GLMMs) with participant as the random factor. This type of statistical model allows random effects such as interindividual variability to be controlled, in addition to fixed effects. Using R software, we calculated a first GLMM with three within-participants factors: emotion (five levels), scale (six levels), and condition (pre-vs. postoperative; two levels). A second GLMM was run with emotion (five levels) and scale (six levels) as within-participants factors, and group (PD preoperative vs. HC; two levels) as a between-participants factor. A third GLMM was calculated with emotion (five levels) and scale (six levels) as within-participants factors, and group (PD postoperative vs. HC; two levels) as a between-participants factor. To investigate the effects in greater detail, for each model, we used the phia package in R and performed contrasts between the groups (or conditions) for each prosodic category and each rating scale. Each p value yielded by the contrasts was false discovery rate (FDR) corrected.

Relationship between vocal emotion recognition performances and secondary variables.

To assess the relationships between the psychiatric, clinical, neuropsychological and sociodemographic variables and the recognition of emotional prosody variables, we entered these variables in multiple regression models. More specifically, the postoperativepreoperative deltas for emotional prosody ratings were entered as dependent variables and the postoperative -preoperative deltas for the sociodemographic, psychiatric, clinical, and neuropsychological variables, as well as the contact locations, were entered as independent variables. In addition, relative to our operational hypotheses, we included the preoperative ondopa motor asymmetry index. The regression analyses were performed with experimental emotional conditions and secondary variables of interest (i.e., those reported to be significant between the pre-and postoperative conditions), in order to avoid Type I errors. The results of forward, backward, and stepwise regressions were all consistent.

Analyses testing predictions about cognitive-metabolic results

The SPM software established correlations between pre-versus postoperative changes in recognition of emotional prosody data and pre-versus postoperative changes in brain FDG uptake. To identify those regions that correlated significantly with the recognition of emotional prosody, we tested a general linear "single subject, covariates only" model for every voxel, with emotional prosody as a covariant: one model for each of the emotional prosody recognition-dependent variables that were found to be significantly different in the postoperative condition compared with the preoperative one, between the RPD and LPD subgroups, or between the PD patient group and HC. As levodopa medication can influence neural metabolism, we included LEDD as a nuisance variable. Relative to our operational hypotheses, and as with the cognitive-emotional regressions, we included the preoperative ondopa motor asymmetry index as a second nuisance variable. This yielded a regression coefficient that was then converted into a t value. Two t tests were performed, one intended to reveal correlations between modifications in emotional scores and decreased cerebral glucose metabolism, the other to reveal correlations between these modifications and increased cerebral FDG uptake. Next, t statistic parametric maps were calculated for each covariate.

Clusters of a minimum of 70 contiguous voxels with a threshold of p < 0.001 (corrected for multiple comparisons) were deemed to be significant for cortical structures, while clusters of a minimum of 25 contiguous voxels with a threshold of p < 0.001 (corrected for multiple comparisons) were deemed to be significant for smaller structures such as the basal ganglia, thalamus and amygdala, as well as for cerebellar structures.

RESULTS

Clinical and motor results (Table 2)

Intergroup comparisons

Apart from the motor asymmetry index (see Methods), no significant difference between the LPD and RPD patients was observed in either the pre-or postoperative condition (all ps > .08).

Intragroup comparisons

For both patient subgroups, we observed a significant motor improvement 3 months after surgery. For the RPD subgroup, the effects were significant for the motor UPDRS III score in both the off-dopa (t = 4.79, p < .001) and on-dopa (t = 4.16, p = .008) conditions, the off-dopa S&E score (t = 2.08, p = .046), and the off-dopa H&Y score (t = -2.18, p = .04). For the LPD subgroup, the effects were only significant for the motor UPDRS III score in the offdopa condition (t = 4.1, p = .001). LEDD decreased significantly after surgery for both subgroups (RPD: t = -3.41, p < .001; LPD: t = -2.09, p = .047). All the data, other effects, p and statistical values are available in full in Table 2.

Neuropsychological background and psychiatric results (Table 3)

Intergroup comparisons

RPD versus HC. In the preoperative condition, there were significant differences between the RPD and HC groups on the TMT B-A (t = -2.92, p = .01), the numbers of criteria (t = 2.49, p = .02) and errors (t = -2.56, p = .01) in the MCST, the Action (Verb) Fluency Task (t = -2.13, p = .04), MADRS (t = -3.95, p < .01), and STAI A (t = -2.13, p = .04). In the postoperative condition, there were significant differences between the RPD and HC groups on the TMT B-A (t = -2.99, p =.01) and MDRS (t = -2.8, p = .01). The RPD subgroup therefore had poorer cognitive performances than HC and were more depressed.

LPD versus HC. In the preoperative condition, no significant differences were found for neuropsychological background and psychiatric tests. In the postoperative condition however, there were significant differences on the number of criteria (t = 2.15, p = .04) in the MCST and on the Action (Verb) Fluency Task (t = 2.19, p = .03). The LPD subgroup therefore had poorer cognitive performances than HC.

LPD versus RPD. Interestingly, the RPD and LPD subgroups differed significantly in the preoperative condition on STAI A (t = 2.69, p = .01) and B (t = 2.17, p = .01), with RPD patients scoring higher on anxiety than LPD patients. In the postoperative condition, no significant difference was found between the RPD and LPD subgroups on any of the neuropsychological background or psychiatric tests.

Intragroup comparisons

Within RPD. No significant difference was found between the pre-and postoperative conditions for neuropsychological background and psychiatric tests, except for phonemic verbal fluency (t = -3.19, p = .009), on which RPD patients performed more poorly in the postoperative condition than in the preoperative one.

Within LPD. No significant difference was found between the preoperative and postoperative conditions for neuropsychological background and psychiatric tests, except for phonemic verbal fluency (t = -3.05, p = .01) and the MDRS (t = -2.53, p = .03), on which LPD patients performed more poorly in the postoperative condition than in the preoperative one. 4 &5)

Vocal emotion recognition results (Tables

Interestingly, analysis revealed the following significant interaction effects: Emotion × To investigate these effects in greater detail, we ran Condition × Side of symptom onset × Scale interaction analyses for each separate emotion. Contrasts (FDR corrected) were then performed between the groups for each prosodic category and ratings on (a) the target scale, that is, the scale (e.g., Anger) corresponding to the stimulus emotion (e.g., anger), and (b) the nontarget scales, that is, the scales that did not correspond to the stimulus emotion (e.g.

Fear scale for anger stimulus). Contrasts were performed for the nontarget scales in order to investigate the patterns of confusion between the different emotions. Means and standard deviations are available in Table 4, and summarized results in Table 5.

In the preoperative condition, compared with both the RPD subgroup and HC, the LPD subgroup exhibited emotional deficits for ratings on the target scales when they listened to neutral (Fig. 1) and happiness stimuli. Moreover, compared with HC, the LPD subgroup exhibited emotional deficits for ratings on the target scale when they listened to sadness stimuli. These significant differences were no longer present in the postoperative condition. By contrast, for ratings on the Fear scale when participants listened to fear stimuli, the RPD subgroup did not differ significantly from either the HC or LPD in the preoperative condition. However, they provided a significantly higher number of emotional misattributions in the postoperative condition, compared with HC (Fig. 2). All the effects are summarized in Table 5.

Relationships between vocal emotion recognition performances and secondary variables

When the stimuli were neutral and the scale was Neutral, the best fit was achieved using LEDD (R 2 = .29, p = .008).

When the stimuli were neutral and the scale was Surprise, the best fit was achieved using the on-dopa off-stim UPDRS III score (R 2 = .27, p = .007) and x coordinate of the right DBS electrode (R 2 = .22, p = .005).

When the stimuli were happiness and the scale Happiness, the best fit was achieved using the y coordinate of the right DBS electrode (R 2 = .12, p = .048), x coordinate of the left DBS electrode (R 2 = .08 p = .02), preoperative on-dopa motor asymmetry index (R 2 = .08, p = .003), and Action (Verb) Fluency Task score (R 2 = .03, p = .02).

When the stimuli were happiness and the scale was Surprise, the best fit was achieved using the on-dopa off-stim UPDRS III score (R 2 = .22, p = .02), off-dopa on-stim UPDRS III score (R 2 = .16, p = .03), and Action (Verb) Fluency Task score (R 2 = .09, p = .04).

When the stimuli were fear and the scale was Fear, the best fit was achieved using the MDRS score (R 2 = .22, p = .02), on-dopa S&E score (R 2 = .22, p = .008), x coordinate of the right DBS electrode (R 2 = .11, p = .04), on-dopa off-stim UPDRS III score (R 2 = .03, p = .02), number of categories in the MCST (R 2 = .06, p = .02), and Action (Verb) Fluency Task score (R 2 = .03, p = .02).

When the stimuli were sadness and the scale Sadness, no significant results were observed. k > 25* for subcortical and cerebellar structures.

Relationship between recognition of emotional prosody and cerebral metabolic results (Table 6 and Figs 3-6)

Model 1: Ratings on Neutral scale for neutral stimuli (Fig. 3)

Correlations between decreased cerebral glucose metabolism and increased ratings after STN DBS (negative correlations) were observed in the right middle frontal gyrus (Brodmann area,BA 6). Correlations between increased cerebral glucose metabolism and increased ratings after STN DBS (positive correlations) were observed in the right posterior lobe of the cerebellum (Lobules VIII and VIIb).

Model 2: Ratings on Surprise scale for neutral stimuli

No significant correlations were observed.

Model 3: Ratings on Sadness scale for sadness stimuli (Fig. 4)

Correlations between decreased cerebral glucose metabolism and increased ratings after STN DBS (negative correlations) were observed in the right superior temporal gyrus (BA 41) and right inferior frontal gyrus (IFG) (BA 45). No significant correlations were observed between increased cerebral glucose metabolism and increased ratings after STN DBS (positive correlations). IFG: inferior frontal gyrus; L: left hemisphere; R: right hemisphere; STG: superior temporal gyrus.

Model 4: Ratings on Happiness scale for happiness stimuli (Fig. 5)

No significant correlations were observed between decreased cerebral glucose metabolism and increased ratings after STN DBS (negative correlations). Correlations between increased cerebral glucose metabolism and increased ratings after STN DBS (positive correlations) were observed in the right insula (BA 38).

Model 5: Ratings on Surprise scale for happiness stimuli

No significant correlations were observed.

Model 6: Ratings on

DISCUSSION

The aim of the present study was twofold: first, to investigate the effects of STN DBS on the ability of patients with PD to recognize emotional prosody, and to correlate these emotional prosody modifications with changes in cerebral glucose metabolism; second, to test the impact of motor asymmetry on emotional prosody performances before and after DBS.

We therefore correlated the emotional prosody performances of 29 consecutive patients with left-or right-sided PD motor symptoms who underwent STN DBS in pre-versus postoperative conditions with modifications in cerebral glucose metabolism, as assessed with 18 FDG-PET.

Based on [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF]'s model, we expected to observe impaired emotional prosody recognition in the postoperative condition. These emotional modifications following STN DBS would be correlated with glucose metabolism modifications in the cerebral network that subtends emotional prosody, namely, the orbitofrontal cortex (OFC), IFG, auditory cortex, basal ganglia, amygdala, and posterior cerebellum. In the light of Stirnimann et al.

(2018)'s results, we predicted that these emotional effects would be driven by a specific subgroup of patients characterized by more left-sided motor symptoms (i.e., with greater right hemispheric brain dysfunction). Results partially confirmed these hypotheses, but also revealed patterns of effects that were more complex than expected. An interaction between STN DBS and motor lateralization had a differential impact on the performances of LPD and RPD patients, resulting in two main patterns of effects.

Dichotomization of effects

The behavioral results could be grouped into two patterns of effect.

The first pattern was characterized by performances that seemed to normalize postoperatively. This was the case for ratings on the target scales when participants listened to neutral, happiness or anger stimuli, as well as on the nontarget Surprise scale when participants listened to happiness stimuli. These effects were driven by the performances of the LPD subgroup.

The second pattern was characterized by a postoperative deterioration in the ability to recognize emotional vocal expressions, characterized by comparable performances across the control and PD groups in the preoperative condition, but significantly different performances in the postoperative condition for ratings on the Fear scale when participants listened to fear stimuli. This effect was driven by the performances of the RPD subgroup.

As far as cognitive-metabolic correlations are concerned, interesting and partly predicted results emerged. We found predicted correlations between modifications in emotional prosody recognition and metabolic modifications in the right IFG, superior temporal gyrus, insula and posterior cerebellum. However, the involvement of the left perirhinal cortex (BA 35) and right middle frontal gyrus (BA 6) had not been predicted.

Differential impact of STN DBS according to motor symptom asymmetry

Overall, we observed that patients in the LPD subgroup exhibited a vocal emotional impairment in the preoperative condition for neutral, sadness and happiness stimuli that STN DBS seemed to normalize. By contrast, the surgery seemed to have a deleterious effect on fear recognition abilities in the RPD subgroup of patients.

From our point of view, this pattern of results, while partly unexpected, can still be interpreted in the context of [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF]'s model, and even seems to reinforce it.

Accordingly, RPD patients, who did not show any emotional impairment prior to surgery, owing to the right hemispheric specialization of the basal ganglia during vocal emotion processing [START_REF] Stirnimann | Hemispheric specialization of the basal ganglia during vocal emotion decoding: Evidence from asymmetric Parkinson's disease and (18)FDG PET[END_REF], developed emotional impairment in the wake of DBS.

Just as dopatherapy can create an overdose effect on functionally intact circuits, so STN DBS can desynchronize the limbic loop while at the same time re-synchronizing the activity of the motor loop, as predicted by [START_REF] Péron | Subthalamic nucleus: A key structure for emotional component synchronization in humans[END_REF] The present results corroborate the notion of hemispheric specialization of the STN during vocal emotion decoding, suggesting that the right STN plays a role in emotional prosody processing. This is in line with three studies in patients with PD [START_REF] Garrido-Vasquez | An ERP study of vocal emotion processing in asymmetric Parkinson's disease[END_REF][START_REF] Stirnimann | Hemispheric specialization of the basal ganglia during vocal emotion decoding: Evidence from asymmetric Parkinson's disease and (18)FDG PET[END_REF][START_REF] Ventura | Hemispheric asymmetries and prosodic emotion recognition deficits in Parkinson's disease[END_REF] that demonstrated an emotional prosody processing impairment in LPD but not in RPD, compared with HC. It is also congruent with a neuroimaging study in HC [START_REF] Kotz | On the lateralization of emotional prosody: an event-related functional MR investigation[END_REF] that reported right but not left basal ganglia activation by emotional prosody. Finally, our results are in line with two intracranial event-related potential studies among patients with PD who had undergone DBS that revealed heightened neural activity at the spike [START_REF] Eitan | Asymmetric right/left encoding of emotions in the human subthalamic nucleus[END_REF] and local field potential [START_REF] Péron | Vocal emotion decoding in the subthalamic nucleus: An intracranial ERP study in Parkinson's disease[END_REF] levels in the right ventral STN, in response to emotional versus neutral auditory material. STN DBS appears to have a differential impact, depending on the lateralization of patients' motor symptoms and their baseline emotion perception abilities. The metabolic results seem to go in the same direction, as we observed that the pattern of effects primarily involving modifications in the RPD subgroup's performances (worsening) correlated with metabolic modifications in the left hemisphere (i.e., parahipppocampal gyrus), while the pattern of results mainly involving modifications in the LPD subgroup's performances (improvement) correlated with metabolic modifications solely in the right hemisphere.

Accordingly, we believe that the literature in this domain should be reread in the light of these new findings, and it may be that the divergent results that have sometimes been reported, and which have fueled virulent debates in the scientific community [START_REF] Péron | Does STN-DBS really not change emotion recognition in Parkinson's disease?[END_REF], can be attributed to the fact that analyses are generally conducted for the whole group, even though the patients in question are actually quite heterogeneous. We observed an effect of DBS on emotional prosody recognition at the subgroup level, and we can assume that studies suggesting that there is no post-DBS effect are those that fail to take motor lateralization at disease onset into account, thereby inducing a noneffect. For instance, a recent study concluded that after STN DBS, the ability to recognize emotional prosody remains intact, and only fear production is impaired [START_REF] Jin | Altered emotional prosody processing in patients with Parkinson's disease after subthalamic nucleus stimulation[END_REF]. It is interesting to note that its results at the whole group level were almost the same as ours (compare Supplementary Material Fig. SI 2 in this article with Fig. 1b in [START_REF] Jin | Altered emotional prosody processing in patients with Parkinson's disease after subthalamic nucleus stimulation[END_REF]. Had these authors analyzed their data separately according to motor lateralization, we can speculate that the patterns of results would have been different. Future studies should distinguish between patients on the basis of their motor lateralization.

Specificity of the emotions affected and potential STN involvement in embodiment processes

The question of the specificity of the emotions affected remains to be addressed. Why does the recognition of some emotions deteriorate (here, fear) and that of others improve (here, anger, happiness, neutral and sadness)? Our study was not designed to answer this question, but previous results can shed light on it, notably regarding neutral emotion.

The case of neutral is very interesting. Our results replicated [START_REF] Mondillon | The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease[END_REF]'s results for the recognition of neutral, but unfortunately this study did not distinguish between LPD and RPD patients. When [START_REF] Mondillon | The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease[END_REF] explored the recognition of facial emotions in patients with PD following STN DBS, they found that the patients in the postoperative condition recognized neutral expressions better than the matched HC group did.

The authors interpreted their results in the context of simulation models [START_REF] Niedenthal | Embodying emotion[END_REF][START_REF] Niedenthal | The Simulation of Smiles (SIMS) model: Embodied simulation and the meaning of facial expression[END_REF]. The patients' amimia may have led them to adopt a relatively neutral expression during the task. As a consequence, they recognized the corresponding neutral faces better than HC did. We believe that the same hypothesis could reasonably apply in the vocal modality, thus explaining the present results. Although it remains to be demonstrated, we can hypothesize that vocal emotion recognition deficits in PD should be interpreted in the context of impaired audio autofeedback. Dysarthrophonic disorders in PD can affect the speech production subsystem (e.g., glottal-supraglottal articulation system), but may also affect the laryngeal phonatory system and/or the pulmonary system. Thus, we can also assume that minute movements in the larynx and other muscles involved in speech articulation (inner speech processes or related processes; i.e., subvocalization processes) are affected, leading to increased misattribution in the recognition of vocal emotions. Interestingly, previous studies have reported modifications in velopharyngeal control and speech respiration following STN DBS [START_REF] Hammer | Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson's disease[END_REF], 2011). In their discussion, [START_REF] Mondillon | The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease[END_REF] could not rule out an alternative explanation, whereby the answers given by patients with PD are default responses that they give when they experience difficulty in an emotion recognition task. Interestingly, our methodology featuring nontarget scales and continuous ratings (in contrast to the categorical choices used in Mondillon et al.'s study), enabled us to exclude this alternative explanation. The embodiment explanation was also corroborated by our metabolic results. At the neural level, lesions in the right ventral primary and secondary somatosensory areas, temporoparietal junction [START_REF] Arzy | Neural basis of embodiment: distinct contributions of temporoparietal junction and extrastriate body area[END_REF] and, to a lesser extent, the insula and anterior supramarginal gyrus, have repeatedly been found to compromise emotion recognition [START_REF] Adolphs | Neural systems for recognizing emotion[END_REF]. One interpretation of these findings is that viewing expressions of emotion triggers an emotional response in the perceiver that mirrors the emotion depicted in the stimulus [START_REF] Wild | Are emotions contagious? Evoked emotions while viewing emotionally expressive faces: quality, quantity, time course and gender differences[END_REF], and representing this emotional response in somatosensory cortices in turn provides information about the emotion.

According to embodiment theories, by generating internal somatosensory representations of perceived emotional stimuli, and thereby simulating socially relevant information, the somatosensory cortices play a role in emotion recognition. To sum up, and in line with Mondillon et al.'s propositions, we suggest that for the LPD subgroup of patients, whereas L-DOPA overdoses the ventral stream of the OFC with dopamine in the preoperative condition, DBS compensates for this overactivation by decreasing OFC activity, thereby restoring the necessary OFC-amygdala interaction needed to preserve vocal emotion processing. This is reinforced by the fact that their patterns of performances were correlated with LEDD, and is corroborated by a previous report demonstrating the presence of dopaminergic overdose effects in the context of vocal emotion recognition in PD [START_REF] Péron | Effect of dopamine therapy on nonverbal affect burst recognition in Parkinson's disease[END_REF]. At the metabolic level, we were surprised not to observe correlations with a network involving the OFC-amygdala pair. We only found significant effects in the right middle frontal gyrus (BA 6) and right posterior lobe of the cerebellum (Lobules VIII and VIIb) (Fig. 3 and Table 6). This is, however, a very interesting result. First, regarding the right premotor cortex, it is in line with the simulation hypothesis. Second, recent propositions have been made regarding the cerebellum's involvement in the network that subtends embodied cognition [START_REF] Guell | Embodied cognition and the cerebellum: Perspectives from the Dysmetria of Thought and the Universal Cerebellar Transform theories[END_REF] and in the affective domain. It has been suggested that increased volumes in Crus 1 in persons with high alexithymic traits are related to an altered embodiment process, leading to emotions that are not cognitively interpreted [START_REF] Laricchiuta | The embodied emotion in cerebellum: a neuroimaging study of alexithymia[END_REF]. [START_REF] Thomasson | Cerebellar contribution to vocal emotion decoding: Insights from stroke and neuroimaging[END_REF] recently demonstrated that patients with chronic cerebellar ischemic stroke display vocal emotion deficits, compared with matched HC, and these emotional misattributions are correlated with lesions in right Lobules VIIb, VIIIa,b and IX, corroborating the effects we observed for Lobules VIIb and VIII.

Regarding fear, it is interesting to note that studies reporting a significant deficit in emotion recognition following STN DBS have often highlighted impairments for this particular emotion. As mentioned previously, these effects may have been driven by RPD patients [START_REF] Biseul | Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease[END_REF][START_REF] Le Jeune | Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study[END_REF]. Unfortunately, this information is rarely documented, and analyses would therefore need to be rerun on the raw data to take account of this factor, which seems to be critical in the results.

SUMMARY AND CONCLUSION

Taken together, patients with predominantly left-sided motor symptoms (i.e., with greater right hemispheric brain dysfunction; LPD) presented impaired vocal emotion recognition in the preoperative condition for neutral, sadness and happiness stimuli that STN DBS seemed to normalize. By contrast, surgery seemed to have a deleterious effect on fear recognition abilities in the subgroup of patients with predominantly right-sided motor symptoms (i.e., with greater left hemispheric brain dysfunction; RPD). The behavioral improvement observed in LPD patients was correlated with metabolic modifications in a right-lateralized network known to be involved in emotional prosody recognition (i.e., right IFG, superior temporal gyrus, insula, and posterior cerebellum), while the behavioral worsening effect among RPD patients was correlated with metabolic modifications in the left parahippocampal gyrus and right cerebellum.

The present results corroborate the notion of hemispheric specialization of the STN during vocal emotion decoding and the differential impact of STN DBS according to PD motor symptom asymmetry, and raise the question of the potential involvement of this basal ganglion in embodiment processes.

Abbreviations:

  Abbreviations: ANOVA, analysis of variance; BA, Brodmann area; DBS, deep brain stimulation; 18 FDG-PET, 18-fluorodeoxyglucose positron emission tomography; FDR, false

  , 2008), we analyzed the data with statistical parametric mapping (SPM) software (Wellcome Department of Cognitive Neurology, London, UK) implemented in MATLAB Version 8 (Mathworks Inc., Sherborn, MA, USA). All the patients' images were first realigned and normalized to MNI space.

  Scale × Condition × Side of symptom onset, F(20, 20733) = 1.8, p = .01; Emotion × Scale × Side of symptom onset, F(20, 20733) = 4.4, p < .001; Scale × Condition × Side of symptom onset, F(5, 20733) = 5.28, p < .001; Condition × Emotion × Scale, F(20, 20733) = 2.1, p < .001; Emotion × Scale, F(20, 20733) = 376.44, p < 0.001; Scale × Side of symptom onset, F(20, 20733) = 8.42, p < .001; and Scale x Condition, F(5, 20733) = 3.76, p = .002. There were also main effects of emotion, F(4, 20733) = 13.67, p < .001, and scale, F(5, 20733) = 37.1, p < .001. There was no significant effect of either Condition × Emotion × Side of symptom onset, F < 1, Emotion x Side of symptom onset, F < 1, Emotion × Condition, F < 1, or Condition x Side of symptom onset, F(4, 20733) = 2.43, p = .12. Nor was there a significant main effect of either condition, F(1, 20733) = 3.25, p = .07, or side of symptom onset, F < 1.

Figure 1 .

 1 Figure 1. Mean ratings (and standard deviations) across all three groups (RPD,

Figure 2 .

 2 Figure 2. Mean ratings (and standard deviations) for all three groups (RPD, LPD and

Figure 3 .

 3 Figure 3. Statistical parametric maps displaying correlations between decreased

Figure 4 .

 4 Figure 4. Statistical parametric maps displaying correlations between decreased

Figure 5 .

 5 Figure 5. Statistical parametric maps displaying correlations between increased cerebral

  Fear scale for fear stimuli (Fig.6) No significant correlations were observed between decreased cerebral glucose metabolism and increased ratings after STN DBS (negative correlations). Correlations between increased cerebral glucose metabolism and increased ratings after STN DBS (positive correlations) were observed in the right anterior cerebellum (Lobules IV and V) and left parahippocampal gyrus (BA 35).

Figure 6 .

 6 Figure 6. Statistical parametric maps displaying correlations between increased cerebral

Table 1 . Sociodemographic data before STN DBS for the two patient subgroups (RPD and LPD) (n = 29)

 1

	RPD group	LPD group	T value and
	Mean ± SD	Mean ± SD	p value

Table 2 . Motor scores before (preoperative condition, baseline) and after (postoperative condition, M+3) STN DBS for patients with PD (n = 29), according to subgroup (LPD or RPD).

 2

		RPD Off-dopa		RPD On-dopa		LPD Off-dopa		LPD On-dopa
		Pre	Post	Pre	Post	Pre	Post	Pre	Post
		Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
	UPDRS III 35.34 ±	14.83 ± 8.38 **	8.16 ± 5.32	4.90 ± 3.66 *	31.12 ± 9.01	15.46 ± 9.98 *	8.27 ± 6.39	4.81 ± 3.82
		15.87
	S&E (%)	56.54 ±	74.38 ±	81.43 ± 24.13	93.75 ± 6.19	70.77 ± 15.49	76.92 ± 15.49	87.69 ± 12.56	94.62 ± 10.32
		23.00	23.00 **
	H&Y	2.60 ± 1.05	1.72 ± 1.17 *	1.1 ± 0.99	0.91 ± 1.07	2.19 ± 0.75	2.04 ± 0.77	1.03 ± 0.83	0.81 ± 0.99
	LEDD	NA	NA	1306.69 ±	685.47 ±	NA	NA	1248.75 ±	753.85 ±
				593.18	544.12 **			605.23	603.07

* Note. T test for dependent groups. STN DBS: subthalamic nucleus deep brain stimulation; LPD: patients with Parkinson's disease exhibiting predominantly left-sided motor symptoms; RPD: patients with Parkinson's disease exhibiting predominantly right-sided motor symptoms; UPDRS: Unified Parkinson's Disease Rating Scale; SD: standard deviation; S&E: Schwab & England scale; H&Y: Hoehn & Yahr scale; LEDD: levodopa-equivalent daily dose; NA: not applicable. * p < 0.05. ** p < 0.001.

Table 3 . Performances of patients with PD before (preoperative condition, M-3, n = 29) and after (postoperative condition, M+3, n = 29) STN DBS, according to subgroup (LPD or RPD), and HC (n = 29) on neuropsychological tests

 3

		RPD Preoperative	RPD Postoperative	LPD Preoperative	LPD Postoperative	HC
		Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
	MDRS (/144)	140.31 ± 2.94	141.00 ± 2.22	140.92 ± 1.89	138.08 ± 4.36 #	141.68 ± 1.70
	Stroop Test -Interference	1.73 ± 8.17	2.48 ± 7.55	3.60 ± 6.39	5.21 ± 7.52	3.09 ± 6.83
	TMT B-A (s)	75.06 ± 47.08 *	95.93 ± 84.64 *	64.54 ± 79.16	75.69 ± 76.2	42.56 ± 23.87
	Categorical verbal fluency (2	30.38 ± 9.49	28.94 ± 9.24	27.69 ± 13.30	29.38 ± 12.37	32.64 ± 7.52
	min)
	Phonemic verbal fluency (2 min)	22.69 ± 6.07	19.63 ± 5.29 #	20.92 ± 7.43	17.00 ± 6.38 #	20.96 ± 6.29
	Action (Verb) Fluency (1 min)	13.06 ± 6.21 *	13.56 ± 5.12	14.38 ± 6.59	13.31 ± 5.95 *	16.24 ± 4.85
	MCST -Number of categories	5.54 ± 0.82 *	5.82 ± 0.35	5.75 ± 0.62	5.21 ± 1.75 *	5.96 ± 0.20
	(/6)
	MCST -Number of errors	5.50 ± 4.56 *	3.63 ± 3.59	3.58 ± 4.68	4.67 ± 6.84	2.80 ± 2.10
	MCST -Number of	1.44 ± 1.82	1.13 ± 1.67	1.08 ± 2.07	1.83 ± 3.33	0.56 ± 0.77
	perseverative errors
	MADRS	5.60 ± 4.39 *	4.73 ± 4.61 *	3.15 ± 3.48	3.38 ± 4.46	1.29 ± 2.07
	STAI-A State	40.62 ± 11.84 *	34.54 ± 7.78	29.64 ± 5.37 @	32.36 ± 11.25	31.06 ± 10.70
	STAI-B Trait	44.79 ± 8.62	41.86 ± 9.87	36.64 ± 11.20 @	38.64 ± 11.25	39.82 ± 9.16
	AES Total	32.40 ± 5.45	34.73 ± 9.66	30.08 ± 7.54	30.69 ± 7.06	-
					0.05
	compared with HC group (t test for independent samples). # p < 0.05 compared with
	preoperative condition (t test for dependent samples). @ p < 0.05 compared with RPD group (t
	test for independent samples).

Note. STN DBS: subthalamic nucleus deep brain stimulation; LPD: patients with Parkinson's disease exhibiting predominantly left-sided motor symptoms; RPD: patients with Parkinson's disease exhibiting predominantly right-sided motor symptoms; HC: healthy controls; MDRS: Mattis Dementia Rating Scale; TMT: Trail Making Test; MCST: Modified Wisconsin Card Sorting Test; MADRS: Montgomery-Åsberg Depression Rating Scale; STAI: State-Trait Anxiety Inventory; AES, Apathy Evaluation Scale; SD: standard deviation. * p <

Table 4 . Mean ratings (standard deviations) of pseudoword stimuli in emotional prosody task for patients with PD (preoperative vs. postoperative condition), according to subgroup (LPD; n = 13 vs. RPD; n = 16), and for HC RPD Preoperative condition (baseline) (n = 16)

 4

	Emotion	Anger scale	Happiness scale	Neutral scale	Fear scale	Surprise scale	Sadness scale
	Anger	46.20 (± 11.91)	1.76 (± 2.50)	5.03 (± 5.88)	4.57 (± 5.27)	7.72 (± 6.66)	0.66 (± 1.97)
	Fear	7.34 (± 7.26)	3.16 (± 2.58)	4.23 (± 3.83)	38.61 (± 14.65)	8.68 (± 10.29)	10.03 (±12.94)
	Happiness	5.36 (± 4.92)	34.07 (± 11.99)	1.77 (± 3.06)	6.95 (± 6.73)	13.81 (± 10.57)	5.87 (± 6.19)
	Neutral	0.15 (± 0.08)	6.41 (± 5.90)	34.40 (± 18.54)	0.67 (± 0.97) *	11.36 (± 8.32)	1.34 (± 1.69)
	Sadness	0.98 (± 2.17)	1.06 (± 2.75)	18.93 (± 10.42)	8.91 (± 8.13)	3.52 (± 5.42)	33.58 (± 17.96)
	RPD Postoperative condition (M+3) (n = 16)
	Emotion	Anger scale	Happiness scale	Neutral scale	Fear scale	Surprise scale	Sadness scale
	Anger	48.39 (± 11.98)	0.71 (± 1.46)	6.51 (± 6.72)	5.18 (± 7.11)	9.08 (± 6.34)	1.13 (± 1.81)
	Fear	6.74 (± 5.34)	3.38 (± 3.41)	5.67 (± 7.20)	34.88 (± 13.30) *	12.99 (± 9.91)	9.47 (± 8.48)
	Happiness	3.85 (± 4.59)	30.45 (± 13.93)	4.61 (± 6.47)	6.12 (± 6.09)	19.70 (± 10.11)	6.50 (± 8.26)
	Neutral	0.43 (± 0.54)	6.67 (± 6.60)	36.04 (± 15.29)	1.68 (± 1.83) *	11.83 (± 9.75)	1.63 (± 2.01)
	Sadness	2.65 (± 4.08)	1.17 (± 2.20)	14.34 (± 12.09)	9.33 (± 7.44)	4.65 (± 5.87)	36.14 (± 17.23)
	Emotion	Anger scale	Happiness scale	Neutral scale	Fear scale	Surprise scale	Sadness scale
	Anger	46.01 (± 13.67)	1.92 (± 4.95)	5.75 (± 3.97)	6.62 (± 11.14)	11.91 (± 10.91)	6.05 (± 12.14)
	Fear	11.33 (± 14.70)	3.42 (± 7.14)	5.76 (± 7.51)	37.46 (± 21.02)	14.68 (± 12.56)	14.35 (± 15.37)
	Happiness	9.39 (± 11.67)	23.29 (± 10.27) *@	2.52 (± 4.02)	10.41 (± 10.71)	24.03 (± 14.46) @	12.39 (± 12.12)
	Neutral	5.69 (± 11.61)	7.22 (± 8.80)	22.67 (± 8.71)	4.94 (± 10.34) *@	17.69 (± 14.25) @	7.03 (± 12.44)
	Sadness 30.65 (± 10.96) Emotion 5.07 (± 11.53) 2.01 (± 4.85) 19.12 (± 8.52) 11.94 (± 11.40) 6.82 (± 13.99) Anger scale Happiness scale Neutral scale Fear scale Surprise scale Sadness scale
	Anger	48.31 (± 13.51)	3.56 (± 10.13)	9.34 (± 10.71)	6.68 (± 11.11)	12.86 (± 12.72)	4.36 (± 12.31)
	Fear	7.95 (± 11.37)	4.21 (± 12.32)	8.78 (± 11.98)	38.93 (± 17.64)	14.15 (± 14.57)	12.08 (± 11.06)
	Happiness	8.66 (± 11.73)	24.66 (± 11.88)	7.73 (± 12.24)	14.06 (± 12.74)	19.83 (± 15.13)	13.29 (± 12.07)
	Neutral	3.77 (± 11.56)	4.97 (± 8.81)	38.95 (± 18.24) #	3.93 (± 10.72)	18.61 (± 14.66) @	5.64 (± 13.03)
	Sadness	4.13 (± 11.32)	3.41 (± 9.85)	21.14 (± 12.61)	9.11 (± 10.54)	5.6 (± 12.2)	36.58 (± 9.19)

LPD Preoperative condition (baseline) (n = 13) *

LPD Postoperative condition (M+3) (n = 13) * p < .05 compared with HC group (intergroup comparisons). # p < 0.05 compared with preoperative condition (intragroup comparisons). @ p < 0.05 compared with RPD group (intergroup comparisons).

Table 5 . Table summarizing vocal emotion recognition results (FDR corrected)

 5

	Note. LPD: patients with Parkinson's disease exhibiting predominantly left-sided motor
	symptoms; RPD: patients with Parkinson's disease exhibiting predominantly right-sided
	motor symptoms; HC: healthy controls; pre: preoperative condition; post: postoperative
	condition; ns: Not statistically significant.

Table 6 . Regions with decreased or increased glucose metabolism following STN DBS in the patient group (n = 29), for each significant result

 6

	Emotion /	Regions	MNI	MNI	MNI z	z	Voxel
	Scale		X coordinates	Y coordinates	coordinates	value	number
		Negative correlations:
		Right cerebrum, frontal	36	6	54	3.75	91
		lobe, middle frontal gyrus
	neutral /	(BA 6)
	Neutral
		Positive correlations:	36	-44	-50	3.61	29*
		Right cerebellum, posterior
		lobe, Lobules VIII and VIIb
		Negative correlations:
		Right temporal lobe,	54	-24	6	3.90	167
		superior temporal gyrus
	sadness /	(BA 41)
	Sadness	Right frontal lobe, inferior	40	20	16	3.76	108
		frontal gyrus (BA 45)
		Positive correlations:
	happiness / Happiness	Right temporal lobe, superior temporal gyrus,	44	8	-16	3.58	30*
		insula (BA 38)
		Negative correlations:
		Left limbic lobe,
		parahippocampal gyrus (BA	-16	-10	-24	3.82	29*
	fear / Fear	35)
		Right cerebellum, anterior
		lobe of cerebellum, culmen,	26	-34	-26	3.79	36*
		Lobules IV and V
	Note. Results for each emotion/Scale are ordered according to z score values. MNI: Montreal
	Neurological Institute; BA: Brodmann area. p < .001 corrected. k > 70 for cortical structures.

  's model. By contrast, LPD patients did display vocal emotional impairment prior to surgery (in line with[START_REF] Stirnimann | Hemispheric specialization of the basal ganglia during vocal emotion decoding: Evidence from asymmetric Parkinson's disease and (18)FDG PET[END_REF], but STN DBS seemed to normalize this deficit, through the functional re-synchronization of the limbic loop, thereby restoring the necessary cerebral and cerebellar interactions needed for intact vocal emotion processing.

Acknowledgements

The present study was performed at the Neurology Department of Rennes University Hospital, France (Prof. Vérin), and the design and acquisition part of the study was funded by the France Parkinson association. The first author was funded by Swiss National Foundation grant no. 105314_182221 (PI: Dr Julie Péron). The funders had no role in data collection, discussion of content, preparation of the manuscript, or decision to publish. We would like to thank the patients and healthy controls for contributing their time to this study. We are also grateful to the Ear, Nose, and Throat Department of Rennes University Hospital for conducting the hearing tests.

Conflict of interest

The authors report no conflicts of interest.