Gabriel Arnold

Jacques Pesnot-Lerousseau

Malika Auvray
email: malika@malika-auvray.com

Individual Differences in Sensory Substitution

Keywords: Sensory substitution, individual differences, rehabilitation technologies, multisensory processes, blindness, sensory modalities

Sensory substitution devices were developed in the context of perceptual rehabilitation and they aim at compensating one or several functions of a deficient sensory modality by converting stimuli that are normally accessed through this deficient sensory modality into stimuli accessible by another sensory modality. For instance, they can convert visual information into sounds or tactile stimuli. In this article, we review those studies that investigated the individual differences at the behavioural, neural, and phenomenological levels when using a sensory substitution device. We highlight how taking into account individual differences has consequences for the optimization and learning of sensory substitution devices. We also discuss the extent to which these studies allow a better understanding of the experience with sensory substitution devices, and in particular how the resulting experience is not akin to a single sensory modality. Rather, it should be conceived as a multisensory experience, involving both perceptual and cognitive processes, and emerging on each user's pre-existing sensory and cognitive capacities.

Introduction

Sensory substitution devices convert stimuli that are normally accessed through one sensory modality (e.g., vision) into stimuli accessible through another sensory modality (e.g., touch or audition). These devices have broad applications such as sensory rehabilitation and perceptual augmentation. For instance, visual-to-tactile (e.g., [START_REF] Bach-Y-Rita | Vision substitution by tactile image projection[END_REF][START_REF] White | Seeing with the skin[END_REF] and visual-to-auditory (e.g., [START_REF] Hanneton | The vibe: a versatile vision-to-audition sensory substitution device[END_REF][START_REF] Meijer | An experimental system for auditory image representations[END_REF] conversion systems were designed in order to assist blind and visually impaired people (see Auvray and Myin, 2009, for a review). For visual-to-tactile devices, the translation code can be analogical; for instance, a visual circle can be translated into a circular pattern of tactile stimuli. Non-analogical codes have also been used, for instance by converting distance into vibrations (e.g., [START_REF] Farcy | Electronic travel aids and electronic orientation aids for blind people: technical, rehabilitation and everyday life points of view[END_REF][START_REF] Maidenbaum | The "EyeCane", a new electronic travel aid for the blind: technology, behavior and Swift learning[END_REF]. The code used in visual-to-auditory devices translates several dimensions of the visual signal into dimensions of the auditory signal. For instance, the vOICe [START_REF] Meijer | An experimental system for auditory image representations[END_REF] translates vertical position into frequency, horizontal position into time scanning, and visual brightness into auditory loudness. Other visual-to-auditory devices convert colour information into musical notes (e.g., the EyeMusic; [START_REF] Levy-Tzedek | Color improves "visual" acuity via sound[END_REF] or using different orchestral instruments (the See ColOr; [START_REF] Bologna | On the use of the auditory pathway to represent image scenes in real-time[END_REF]. Numerous devices were designed to compensate other deficits (such as proprioceptive deficits, e.g., see [START_REF] Danilov | Efficacy of electrotactile vestibular substitution in patients with peripheral and central vestibular loss[END_REF][START_REF] Diot | Sensory substitution for balance control using a vestibular-to-tactile device[END_REF]. However, in this article, we will focus on those devices that were designed to compensate for visual impairments. In the field of perceptual augmentation, these devices were developed in order to gain access to visual information, either under degraded conditions of perception (such as firefighting or military operations, e.g., see [START_REF] Jones | Vibrotactile pattern recognition on the arm and back[END_REF] or when the amount of visual information is thought to be too important (such as in car driving; e.g., [START_REF] Ho | The Multisensory Driver: Implications for Ergonomic Car Interface Design[END_REF].

Studies conducted on sensory substitution devices have revealed an important structural and functional plasticity of the central nervous system. As will be seen in detail in this article, the structural and functional plasticity resulting from the use of these devices is highly subject to individual differences. The main findings regarding structural plasticity have shown that the use and practice of visual-to-tactile [START_REF] Ptito | Cross-modal plasticity revealed by electrotactile stimulation of the tongue in the congenitally blind[END_REF] and visual-to-auditory (e.g., Striem-Amit and Amedi, 2014; for reviews, see [START_REF] Proulx | Multisensory perceptual learning and sensory substitution[END_REF]Stiles and Shimojo, 2015) devices result in increased activation in the blind participants' visual cortex. Regarding functional plasticity, users of such devices can build a perceptual space that possesses visual characteristics although the sensory inputs come from another sensory modality (e.g., [START_REF] Renier | The Ponzo illusion using auditory substitution of vision in sighted and early blind subjects[END_REF]. Note, however, that the degree to which the use of a substitution device involves visual processes varies from one user to another (e.g., [START_REF] Auvray | Learning to perceive with a visuo-auditory substitution system: localization and object recognition with the voice[END_REF]. The possibility that the associated subjective experience becomes visual for some users, while remaining tactile or auditory for others, remains insufficiently investigated.

From an applied point of view, the challenge faced by designers consists of finding the best way to provide users with more accurate information usually allowed by vision, such as colour, shape, or distance. This challenge also involves designing devices that are ergonomically adapted to their users [START_REF] Elli | Is there a future for sensory substitution outside academic laboratories?[END_REF]. Improving the design of sensory substitution devices, as will be further described, will benefit from the identification of individual differences, either between different target populations (e.g., sighted, early-blind, and lateblind people) or within each population, in the different perceptual and spatial processes that are required to learn and acquire a new way of interpreting external information. This will allow the devices to be better adapted to people's specificities in use and learning.

From a theoretical point of view, one of the main goals is to understand what underlies the acquisition of new recognition and localization skills that are usually characteristic of a given sensory modality by means of another. In particular, one important question raised is to which sensory modality does the perception with a sensory substitution device belong? Two opposite theses were, at first, put forward: The dominance thesis (e.g., [START_REF] Block | Tactile sensation via spatial perception[END_REF][START_REF] Humphrey | A History of the Mind[END_REF][START_REF] Prinz | Putting the brakes on enactive perception[END_REF] according to which perception with a sensory substitution device remains in the substituting modality (touch or audition), and the deference thesis (e.g., [START_REF] Hurley | Neural plasticity and consciousness[END_REF][START_REF] Noë | Action in Perception[END_REF][START_REF] O'regan | Why Red Doesn't Sound Like a Bell. Understanding the Feel of Consciousness[END_REF] according to which perception switches to the substituted modality (vision). The deference thesis opened the door to over-optimistic claims, involving the idea that users of visual-to-tactile substitution devices would become able to 'see with the skin' [START_REF] White | Seeing with the skin[END_REF] or to 'see with the brain' (Bachy-Rita et al., 2003). [START_REF] Auvray | Perception with compensatory devices. From sensory substitution to sensorimotor extension[END_REF], followed by Deroy andAuvray (2012, 2014; see also [START_REF] Farina | Neither touch nor vision: sensory substitution as artificial synaesthesia?[END_REF] suggested that it is time to go beyond the dominance versus deference debate, and that perception with a sensory substitution device goes beyond assimilation to either the substituting or the substituted modality. According to this view sensory substitution should be understood as being vertically integrated on pre-existing capacities that involve, among other processes, both the substituting and the substituted sensory modalities. In addition, sensory substitution should be treated as involving both perceptual and cognitive processes, which take into account integration of the novel information with the existing perceptual-semantic route.

The proposed alternative view has important consequences to understand the use of sensory substitution devices as being dependent on individual capacities (see Fig. 1). First, it involves the idea that, at the perceptual level, performance and experience with the device will depend on each person's abilities. Second, if the use of sensory substitution devices is both perceptual and cognitive, then this leaves room for perceptual strategies that will differ as a function of people's specificities and cognitive style. In other words, performance and experience with the device will then be done with different weights attributed to each of the sensory modalities. These weights will depend on people's individual capacities, perceptual strategies, and cognitive styles. Note that these weights might subsequently vary as a function of expertise, appropriation of the device, and type of task. To give an example, it might be the case that a musician will be able to perform auditory analyses that non-musicians could not, consequently giving more weights to auditory processes, and possibly having a predominant auditory experience when using the device.

In this article we will review the individual differences that have been reported regarding the perceptual and spatial processes involved when using sensory substitution devices aiming at compensating visual deficits. Using a sensory substitution device requires learning to extract perceptual information that arrives in the brain via an unnatural way and to correctly interpret it. It also requires correctly organizing this perceptual information spatially, in order to reconstruct the external environment that the device allows one to explore. Regarding perceptual processes, we will first focus on the role of individual abilities in the different sensory modalities, both in the substituted deficient modality (e.g., vision) and in the substituting preserved modality (e.g., audition and touch). Second, we will focus on multisensory processes, particularly on the natural associations that exist between the senses and their implications for optimally converting visual into auditory or tactile stimuli. Regarding spatial processes, we will focus in particular on the reference frames that are involved when integrating multisensory information and when performing navigation tasks with a sensory substitution device. Note that, in this article, we will not discuss more central processes such as learning, attention, or executive function that are also important when using sensory substitution devices. The individual differences reviewed here concern both differences between different populations of users (e.g., sighted and blind people, musicians and non-musicians) and within the same population, taking into account individual perceptual and spatial abilities. We will address individual differences at the behavioural, neural, and phenomenological levels. Finally, we will highlight the implications of individual differences, both for theoretical and applied research.

Individual Differences in Perceptual Processes

Modality-Specific Processes

The theoretical debate opposing the deference and dominance theses has led researchers to investigate whether the use of a sensory substitution device relies on individual abilities both in the substituted and in the substituting sensory modalities. For the substituted modality (i.e., vision), an interesting question is whether perceptual performance with a sensory substitution device is influenced by visual or visuo-spatial abilities. [START_REF] Brown | Seeing with sound? Exploring different characteristics of a visual-to-auditory sensory substitution device[END_REF] found no influence of individual visual imagery abilities (measured with the Vividness of Visual Imagery Questionnaire, VVIQ; [START_REF] Marks | Visual imagery in the recall of pictures[END_REF] on the learning of the vOICe. On the other hand, in a study by [START_REF] Hanneton | Intermodal recoding of a video game: learning to process signals for motion perception in a pure auditory environment[END_REF], performance reached by the participants on a task based on the auditory conversion of a visual video game was found to be correlated to the scores the participants obtained in a visual mental rotation test [START_REF] Vandenberg | Mental Rotation Test[END_REF]. It thus seems that performance with sensory substitution devices is related to only some visuo-spatial abilities. More studies are therefore necessary to investigate the visuo-spatial abilities that are used and those that are not.

Regarding the substituting modality (i.e., audition or touch), differences in the use and appropriation of the devices were found as a function of auditory abilities. Brown et al.'s (2011) study revealed that participants with good musical abilities (in particular discrimination of tonal changes) did not reach better abilities with the device. However, they learned it faster than participants with low musical abilities. This result shows that the use of the device depends on pre-existing auditory abilities. Similar results were found in Pesnot-Lerousseau et al.'s (subm.) study. Participants with high auditory abilities (discrimination of intensity, pitch, and duration) were found to have better performance with the vOICe than those with low auditory abilities. Musicians were also found to have a better 'visual' acuity (tested with Snellen E) when using the vOICe than non-musicians [START_REF] Haigh | How well do you see what you hear? The acuity of visual-to-auditory sensory substitution[END_REF]. Regarding touch, while low-level tactile abilities (discrimination thresholds) have been expected to have an influence on the use of visual-to-tactile substitution devices (e.g., [START_REF] Loomis | Sensory substitution of vision: importance of perceptual and cognitive processing[END_REF], no studies have directly investigated this hypothesis. More studies on individual differences in tactile abilities are thus required to estimate the extent to which people differ and the extent to which these differences influence the use of sensory substitution devices.

Multisensory Processing

Individual differences exist at the level of multisensory processes. This has been illustrated, for instance, with cross-modal correspondences, which are associations people make between sensory dimensions across distinct sensory modalities. The existence of such natural associations is particularly relevant for sensory substitution as learning to use sensory substitution devices may be more optimal if the codes that are implemented correspond to these associations [START_REF] Deroy | Differentiated audio-tactile correspondences in sighted and blind individuals[END_REF][START_REF] Kristjánsson | Designing sensory-substitution devices: principles, pitfalls and potential[END_REF]Stiles and Shimojo, 2015). Cross-modal correspondences have been reported to involve individual differences existing both between blind and sighted people and among sighted people. For instance, [START_REF] Marks | On cross-modal similarity: the perceptual structure of pitch, loudness, and brightness[END_REF] found a cross-modal correspondence between loudness and brightness; however, when looking at individual profiles, this occurred only in around half of the participants. With respect to blind people, Stiles and Shimojo (2015) have reported that, similarly to sighted people but in a weaker way, they intuitively associated (i.e., without training) the vOICe's sounds to tactile textures. On the other hand, Deroy et al.'s (2016) study focused on the conversion of the vertical dimension (i.e., visual elevation) into auditory frequency. Their results revealed that sighted participants but not blind participants (neither early-blind, nor late-blind) naturally associate auditory frequency (high-pitched vs. low-pitched tone) with the direction of tactile motion (ascending vs. descending). One possibility to explain these discrepant results is that blind and sighted people differ in their natural associations only when spatial information is present (e.g., top vs. bottom, left vs. right). Investigating further the individual differences concerning the sensitivity to cross-modal correspondences between blind and sighted persons and within each population should therefore allow designing devices more optimally adapted to their target users.

More generally, perception is qualitatively different between blind and sighted people. Due to brain plasticity, the absence of vision allows the recruitment of visual brain areas for tactile tasks (see [START_REF] Sathian | Cross-modal plasticity of tactile perception in blindness[END_REF], for a review). Such recruitment of supplementary brain areas, combined with the fact that blind people have to rely more on touch, can partly explain why they have a higher tactile acuity than sighted people. Multisensory integration also differs between blind and sighted people. For instance, auditory and tactile stimuli are better integrated in sighted than in blind people (Hötting and Röder, 2004). In addition, blind people inhibit more easily stimuli presented in a task-irrelevant sensory modality (e.g., tactile stimuli for an auditory task) than sighted people (Hötting et al., 2004). The absence of vision, especially in congenitally blind people, has also been reported to have a global impact on spatial cognition, highlighting the important role of vision in the integration of the spatial information that is extracted from different sensory modalities (for a review, see [START_REF] Pasqualotto | The role of visual experience for the neural basis of spatial cognition[END_REF]. The next section will address those individual differences occurring in spatial processes.

Individual Differences in Spatial Processes

Multisensory Reference Frames

Spatial cognition is subject to inter-individual differences, which can influence the design of both visual-to-tactile sensory substitution devices and navigation aid devices. Individual differences arise both in the spatial reference frames that are adopted and in spatial navigation skills. With respect to the former, it should be noted that individual variability has to be investigated first for each sense, given that spatial reference frames are different from one sensory modality to another [START_REF] Cohen | A common reference frame for movement plans in the posterior parietal cortex[END_REF]. Indeed, visual information is initially coded in retinotopic coordinates, whereas tactile information is initially coded in somatotopic coordinates, and auditory information is initially coded according to a head-centred reference frame. Spatial diversity is also present within one sensory modality. For instance, the spatial coordinates of a tactile stimulation can be defined according to the stimulated body part, to the entire body, or to the external world [START_REF] Arnold | Taking someone else's spatial perspective: natural stance or effortful decentring?[END_REF]. These different reference frames can come into conflict, as revealed by the longer time needed to report which hand, the left or the right, has been stimulated first, when the arms are crossed as compared to uncrossed [START_REF] Shore | Confusing the mind by crossing the hands[END_REF]. The additional time it takes to localize touch in the crossed-hand condition has been interpreted as reflecting spatial transformation from a body-centred to an environment-centred reference frame [START_REF] Shore | Confusing the mind by crossing the hands[END_REF].

The diversity of spatial reference frames is even increased when it comes to planning an action, given that spatial information is also coded differently for sensors and action effectors [START_REF] Cohen | A common reference frame for movement plans in the posterior parietal cortex[END_REF]. However, spatial transformations allow integrating spatial information coming from the different senses into one common and unified reference frame with the goal of performing actions. This common reference frame is usually an eye-centred reference frame [START_REF] Cohen | A common reference frame for movement plans in the posterior parietal cortex[END_REF]. Spatial information coming from vision [START_REF] Boussaoud | Gaze effects in the cerebral cortex: reference frames for space coding and action[END_REF], audition [START_REF] Zwiers | Plasticity in human sound localization induced by compressed spatial vision[END_REF], and touch [START_REF] Harrar | Touch used to guide action is partially coded in a visual reference frame[END_REF] has indeed been reported to be coded according to the direction of the eyes. The spatial transformation of multisensory information into a common eye-centred reference frame may allow the perception of a unified external world rather than multiple worlds (Hartcher-O'Brien and Auvray, 2014).

Thus, when translating visual information into tactile or auditory information, as is the case with sensory substitution devices, the initial spatial information must be coded in a different reference frame. Interestingly, [START_REF] Levy-Tzedek | Cross-sensory transfer of sensory-motor information: visuomotor learning affects performance on an audiomotor task, using sensory-substitution[END_REF] reported that, after training with a visual-to-auditory device, spatial information from one sensory modality can inform movements guided by another sensory modality. However, the spatial transformation of sensory information is not performed in the same way by everyone, as there is an inter-individual variability in the reference frames that are used. For instance, in sighted people, different reference frames are adopted when interpreting letters -stimuli that are usually perceived visually -drawn on the body surface [START_REF] Arnold | Taking someone else's spatial perspective: natural stance or effortful decentring?[END_REF]. The reference frame that is adopted is egocentric, i.e., centred on the participant's body, for 80% of people, whereas 20% of people adopt a decentred reference frame, i.e., centred on a location external to the body. The individual variability is even stronger as, among egocentric people, some of them adopt a trunk-centred reference frame whereas others adopt a head-centred reference frame. Importantly, the reference frame that is adopted has been reported to be natural rather than a mere cognitive choice. It is worth mentioning here that other studies found differences in the reference frames that are adopted as a function of gender, age, and cultural background (e.g., [START_REF] Goeke | Cultural background shapes spatial reference frame proclivity[END_REF]. Overall, these results highlight that individual differences in the coding of spatial information have an impact on the way a sensory substitution device is used to explore environment and on the resulting sensory experiences.

Navigation Tasks

An important daily-life spatial task, for which individual differences are particularly salient, is navigation. Indeed, two well-contrasted frames of reference are differently adopted in navigation: an egocentric and an allocentric reference frame (e.g., [START_REF] Tversky | Structures on mental spaces: how people think about space[END_REF]. The egocentric reference frame represents the location of objects in space relative to the observer's body. On the other hand, the allocentric reference frame represents objects' locations relatively to other objects, and thereby, it involves knowledge of spatial relations that unite the various elements of the environment regardless of the observer's position. The way an itinerary is described orients the reference frame that is adopted (e.g., O' Keefe and Nadel, 1978). In particular, route descriptions are based on an egocentric reference frame. They consist of sequences of instructions specifying the changes in direction necessary to reach the final destination. They are characterized by a serial aspect whose consequence is that if people omit one instruction, they will be unable to reach their destination. By contrast, survey descriptions are based on an allocentric reference frame. They are characterized by a high level of flexibility and have certain superiority over the egocentric representations because they allow reorganization of itineraries such as finding alternative routes or taking shortcuts.

The construction of an allocentric representation requires full integration of the various paths in a geographic perspective using the cardinal directions [START_REF] Klatzky | Allocentric and egocentric spatial representations: definitions, distinctions, and interconnections[END_REF]. This construction is, in sighted people, greatly facilitated by the use of the visual modality, as it allows a multiple and simultaneous perception of spatial elements, even if they are distant. As a consequence, differences in the reference frame adopted between blind and sighted persons have been reported in many studies. For instance, [START_REF] Noordzij | The influence of visual experience on the ability to form spatial mental models based on route and survey descriptions[END_REF] used an environment that was verbally described either from a route description (egocentric frame of reference) or from a survey description (allocentric frame of reference). Their results revealed that blind people's mental representations share the same metric properties as those constructed by sighted people. However, blind people constructed a more robust spatial representation from a route description, whereas sighted people performed better with a survey description. Similarly, [START_REF] Rieser | Sensitivity to perspective structure while walking without vision[END_REF] found that when a navigation task requires a change of perspective or spatial inferences (that rely on allocentric reference frames) congenitally blind people do not perform as well as sighted and lateblind individuals. Visual experience also plays a role in the reference frame that is preferentially adopted when both egocentric and allocentric reference frames are possible to solve a spatial memory task [START_REF] Pasqualotto | Visual experience facilitates allocentric spatial representation[END_REF]. Sighted and late-blind participants prefer to adopt an allocentric reference frame, whereas congenitally blind participants, who never experienced vision, prefer to adopt an egocentric reference frame (see Gallay et al., 2013, for a review).

It should be noted that the use of an egocentric perspective is sufficient to succeed in some spatial tasks, for which sighted and blind people can thus obtain comparable performance. To give an example, [START_REF] Loomis | Nonvisual navigation by blind and sighted: assessment of path integration ability[END_REF] compared spatial memory performance in blind and sighted participants. The participants in this study were accompanied along a straight or curved path, and they were subsequently asked to reproduce it. No significant difference in performance was found between blind and sighted people. This result suggests that visual impairment does not entail the estimation of directions and distances between elements of an environment that has been physically explored. This can be due to the fact that the reproduction of a physically experienced itinerary is based on kinaesthetic and vestibular memory, which involves an egocentric frame of reference. However, when the tasks involve the encoding of spatial information that has not been physically explored, or when they involve spatial inferences or changes in perspective, differences appear between blind and sighted people (e.g., see [START_REF] Rieser | Sensitivity to perspective structure while walking without vision[END_REF].

As we have seen, there is an important inter-individual variability in the reference frames that are adopted when interpreting spatial information, and blind people, compared to sighted people, have a spontaneous tendency to adopt an egocentric perspective as opposed to an allocentric one. These individual differences are important to take into account when designing personalized navigation aid devices. In particular, two options are possible; the first one consists in implementing different reference frames so that people that have difficulties with the allocentric reference frame can use the egocentric one. The second one consists in favouring the development of allocentric reference frames in those persons that have difficulties with it. Regarding this option, [START_REF] Millar | Understanding and Representing Space: Theory and Evidence From Studies With Blind and Sighted Children[END_REF] hypothesised that it is the perception of distal elements that allows encoding spatial relations between elements of the environment, and therefore allows the construction of an allocentric reference frame. Thus, such access to distal cues, which can be converted into auditory or tactile information, could be implemented as an option in navigation aid devices. Relevant to this hypothesis, [START_REF] Pasqualotto | Sensory substitution: the spatial updating of auditory scenes "mimics" the spatial updating of visual scenes[END_REF] have shown that blindfolded sighted participants are able to elaborate an allocentric representation of a spatial scene when exploring the scene with the vOICe, in the same way as when the scene is explored visually. If similar results were to be found in blind participants, this would provide arguments for the hypothesis that sensory substitution devices can allow blind people to form allocentric spatial representations of their environment.

Finally, the effect of aging -one important source of individual differences in addition to being a cause of visual deficits -has scarcely been investigated. The only study conducted thus far investigating age-related differences when using a sensory-substitution device, found that older adults were less successful in completing a navigation task than younger adults [START_REF] Levy-Tzedek | Aging and sensory substitution in a virtual navigation task[END_REF]. This result may reflect a combination of perceptual and cognitive decline with age, and it suggests that older adults could use sensory substitution to compensate visual deficiency. However, significant efforts are necessary for older people to learn how to use the device.

Individual Differences at the Phenomenological Level

A few studies have investigated the phenomenology (or subjective experience) associated with the use of a sensory substitution device. Some of these studies highlighted the visual-like character of the experience with the device. For example, Guarniero, a blind philosophy student, who extensively used the Tactile Visual Substitution System, described: "very soon after I had learned how to scan, the sensations no longer felt as if they were on my back, and I became less and less aware that vibrating pins were making contact with my skin. By this time objects had come to have a top and a bottom; a right side and a left; but no depth -they existed in an ordered two-dimensional space" (Guarniero, 1974, p. 104). In a similar vein, a more recent study found a correlation between the recruitment of the occipital cortex and reports of new experiences of flashes in trained late-blind users of visual-to-tactile sensory substitution devices [START_REF] Ortiz | Recruitment of occipital cortex during sensory substitution training linked to subjective experience of seeing in people with blindness[END_REF]. However, such changes are not documented in congenitally blind individuals, and thus the visual character of these induced flashes or lights still remains to be investigated to better understand whether the experience is perceptually visual, due to imagination, or even due to residual vision.

Subjective changes have also been documented with visual-to-auditory devices. For instance, in a series of interviews, two blind users of the vOICe reported visual experiences, involving colour, but this phenomenology was limited to certain kinds of objects [START_REF] Ward | Visual experiences in the blind induced by an auditory sensory substitution device[END_REF]. According to these authors, training with the vOICe could lead to the occurrence of visual images, comparable to the synesthetic experiences enjoyed by coloured-hearing synaesthetes. However, these two users had an acquired blindness, and it cannot be ruled out that they associated the sounds to visual images from their memory. Thus, we remain unsure of whether the visual phenomenology is truly perceptual, or if it is just given by memory, or even by imagination, and then merely added to a set of non-visual qualities obtained when using the device (see [START_REF] Auvray | Patrolling the boundaries of synaethesia: a critical appraisal of transient and artificially-acquired forms of synaesthetic experiences, in: Sensory Blendings: New Essays on Synaesthesia[END_REF], for a discussion).

Subjective reports were also gathered in blindfolded sighted participants. In their study, [START_REF] Auvray | Learning to perceive with a visuo-auditory substitution system: localization and object recognition with the voice[END_REF] trained six persons with the vOICe for fifteen hours. The participants were given questionnaires about their qualitative experience while using the device. They were asked which sensory modality their experience most resembled for localization and recognition tasks. The replies varied inter-individually and as a function of the performed task. Localization tasks were more likely to be apprehended either as giving rise to visual experiences or as belonging to a new sense, whereas recognition tasks were judged as more closely resembling audition. Two participants mentioned a resemblance with the tactile modality. In addition, the participants often emphasised that they simply had the feeling of mastering a new tool. Thus, in this study, while the participants were able to perceive visual properties when they are converted into sound, they did not strictly speaking have a visual phenomenal experience or an auditory one. Rather, the participants' phenomenal experience was task-dependent and its tool-like nature was emphasized.

With the same device, the vOICe, in Pesnot-Lerousseau et al.'s (subm.) study, blindfolded sighted participants were trained at localization and recognition tasks. Prior to training, and after training in each of the tasks, they were questioned about their subjective experience by means of Likert scales. As in [START_REF] Auvray | Learning to perceive with a visuo-auditory substitution system: localization and object recognition with the voice[END_REF] study, participants had a different phenomenology as a function of the task. The overall phenomenology remained auditory, which is likely due to the fact that the stimuli consisted of sounds. However, in the object recognition task, participants additionally had an important visual experience, whereas in the object localization task they had an additional sonar-like experience, that is, an experience mainly based on spatial information of localization or distance from the body, without necessarily forming visual images of the object to localize. Another interesting result is that such differences in the phenomenologies as a function of the taskwhich probably result from the fact that several different processes are involved -are stronger in participants with good auditory capacities than in participants with low ones. It is likely that good auditory capacities allow the participants to identify those dimensions of the auditory signal that are the most relevant to the task while discarding the less relevant ones. Participants with low auditory capacities have a phenomenology that does not differ with the task, which suggests a lower plasticity in the involved processes. As their auditory inputs are poorer, it could be that they are less able to disentangle the different auditory dimensions and consequently to analyse them independently.

It is not straightforward to know what can be inferred exactly from these reports, as the evidence remains fragile. In blind persons, the reports are compatible with the resurgence of colour or texture memories for familiar objects. Similarly, it should be further investigated what type of visual imagery exactly is at stake, as it might correspond to a mere reminiscence of cross-modal imagery (e.g., [START_REF] Spence | Crossmodal mental imagery[END_REF], especially in blind people. This survey might also question participants' abilities to establish classes of similarities between their experiences. Nonetheless, what can be inferred from the results is that subjective experience with the device depends both on the task and on individual perceptual abilities.

Individual Differences at the Neural Level and Proposed Hypothesis of Two Different Processing Pathways

Individual differences at the neural level have been investigated both with visual-to-tactile and visual-to-auditory sensory substitution devices. Regarding visual-to-tactile devices, many studies revealed differences in the activation of the visual cortex in blind and sighted people after training (for reviews, see [START_REF] Poirier | What neuroimaging tells us about sensory substitution[END_REF][START_REF] Proulx | Other ways of seeing: from behavior to neural mechanisms in the online "visual" control of action with sensory substitution[END_REF]. For instance, [START_REF] Ptito | Cross-modal plasticity revealed by electrotactile stimulation of the tongue in the congenitally blind[END_REF] investigated changes in regional cerebral blood flow (rCBF) using positronemission tomography (PET) in congenitally blind people and sighted controls. The participants were required to learn to detect the orientation of visual stimuli presented through the device during one hour a day over one week. The blind and sighted participants reached an equal level of performance after training. No task-evoked rCBF increase was detected in the visual cortex of either group before training. After practice, whereas tongue stimulation significantly led to an increase in rCBF in the visual cortex of the blind participants, such activation was not found in the sighted controls. According to the authors, in the case of congenital blindness, training with a visual-to-tactile substitution device induces a rerouting of tactile information to the visual cortex. It should, however, be mentioned that increased activation in the visual cortex of blind participants does not necessarily mean that the corresponding perception is visual.

To test this hypothesis, [START_REF] Kupers | Transcranial magnetic stimulation of the visual cortex induces somatotopically organized qualia in blind subjects[END_REF] used transcranial magnetic stimulation (TMS) of blind and blindfolded sighted participants' visual cortex before and after training with a visual-to-tactile substitution device. Before training, when TMS was applied over their visual cortex, the participants did not report any subjective tactile sensation (only phosphenes were reported by sighted participants). After training, some of the blind participants (three out of eight early-blind participants and one out of five late-blind participants) reported tactile sensations when TMS was applied over the occipital cortex, whereas no such sensations were reported by sighted participants. The authors concluded that the subjective character of the percept would depend on the stimulated sensory channel and not on the activated cortex. In other words, the subjective experience associated with an activity in the visual cortex after training was tactile and not only visual.

Regarding visual-to-auditory devices, in a vast majority of cases, training participants results in an increased activation of their visual areas (for reviews, see [START_REF] Poirier | What neuroimaging tells us about sensory substitution[END_REF][START_REF] Proulx | Multisensory perceptual learning and sensory substitution[END_REF][START_REF] Proulx | Other ways of seeing: from behavior to neural mechanisms in the online "visual" control of action with sensory substitution[END_REF]. However, large inter-individual differences have been reported, in particular between earlyblind, late-blind, and sighted participants. Compared to late-blind and sighted participants, early-blind participants have stronger activations of their visual cortices [START_REF] Amedi | Shape conveyed by visual-to-auditory sensory substitution activates the lateral occipital complex[END_REF]. More precisely, their visual cortices are more modulated by training, and they show a stronger functional connectivity between visual and frontal areas [START_REF] Murphy | Topdown influence on the visual cortex of the blind during sensory substitution[END_REF]. In addition, early-blind people are better at using the device in orientation identification tasks (Stiles et al., 2015) and in 'visual' acuity tasks [START_REF] Striem-Amit | Visual' acuity of the congenitally blind using visual-to-auditory sensory substitution[END_REF]. To account for these differences, [START_REF] Poirier | What neuroimaging tells us about sensory substitution[END_REF] proposed a two-stream model. According to this model, early-blind participants would recruit a cross-modal pathway, consisting of a direct stream between auditory cortices and visual ones. On the other hand, late-blind and blindfolded sighted participants, due to their past or current possession of the visual sense, would activate a mentalimagery pathway. Sighted participants, even when blindfolded, would process the information in higher order multimodal cortices and then propagate the signal into visual cortices. This multimodal pathway corresponds to the transduction of the auditory signal not only into visual images, but also potentially into spatial images, that is, a multimodal signal. In this section, three hypotheses are proposed to explain how and why these two pathways can be observed (see Fig. 2).

First, before training, cross-modal connections between visual and auditory cortices may be stronger in early-blind than in late-blind and sighted people. This hypothesis makes sense in the field of the metamodal brain theory [START_REF] Heimler | Origins of task-specific sensoryindependent organization in the visual and auditory brain: neuroscience evidence, open questions and clinical implications[END_REF][START_REF] Pascual-Leone | The metamodal organization of the brain[END_REF][START_REF] Proulx | Multisensory perceptual learning and sensory substitution[END_REF]. If the brain is organised as a task-dependent rather than as a sensory-dependent system, the 'visual' areas are not literally visual. They are involved in spatial processes but their inputs are not restricted to the retina. In early-blind participants, auditory and tactile perceptions are the main source of spatial information. Therefore, their visual cortices may already be strongly linked to auditory and somatosensory cortices, as they are the main provider of useful information. When learning to use the device, blind participants, accustomed to process auditory input with their visual (spatial) cortex, would recruit the cross-modal pathway. However, contrary to this hypothesis, a functional connectivity analysis made by [START_REF] Murphy | Topdown influence on the visual cortex of the blind during sensory substitution[END_REF] showed no difference in the auditory-visual cortex connectivity between blind and sighted people.

A second hypothesis is that sensory deprivation and the absence of visual input make visual areas more available to process new signals. As the retina does not send inputs to the cortex, blind participants may recruit those areas more easily. A privation study by [START_REF] Proulx | Seeing 'where' through the ears: effects of learning-by-doing and long-term sensory deprivation on localization based on image-to-sound substitution[END_REF] tested this hypothesis. Three sighted participants were blindfolded during three weeks. However, no major differences were found between deprived and control participants. Furthermore, a similar privation study with magnetoencephalography revealed that privation has an effect on the auditory cortex activity only when combined with learning [START_REF] Pollok | Image-to-sound conversion: experience-induced plasticity in auditory cortex of blindfolded adults[END_REF]. Privation alone did not produce changes. Thus, even if privation induces profound changes in the organisation of the brain [START_REF] Bavelier | Cross-modal plasticity: where and how?[END_REF], it appears that privation alone cannot explain the difference between blind and sighted people.

Finally, auditory capacities may have a role in the observed differences between sighted, early-blind, and late-blind people. Access to the cross-modal pathway may be conditioned by the quality of auditory inputs. As early-blind people have an enhanced auditory sensitivity [START_REF] Wan | Early but not late-blindness leads to enhanced auditory perception[END_REF], the signal may be sufficiently accurate to be directly processed by visual cortices. Two clues in the literature favour this hypothesis. First, the capacity to use a visualto-auditory device is theoretically linked to auditory capacities. As shown in Section 2.1, musicians have a better " 'visual' acuity when using the vOICe [START_REF] Haigh | How well do you see what you hear? The acuity of visual-to-auditory sensory substitution[END_REF]. Secondly, early-blind people have better low-level auditory capacities than the rest of the population [START_REF] Wan | Early but not late-blindness leads to enhanced auditory perception[END_REF] and they proved to be better at learning how to use the device (Stiles et al., 2015). This hypothesis makes sense with the two-stream theory [START_REF] Poirier | What neuroimaging tells us about sensory substitution[END_REF]. It is because blind people's auditory processes are accurate and because the signal is well discriminated that they have access to another type of treatment, a cross-modal one.

These three hypotheses are attempts to account for the observed differences between early-blind, late-blind, and sighted participants, as well as for the existence of two streams of processes. If prior cross-modal pathways and sensory deprivation have already been studied, the hypothesis of different auditory capacities has been evoked but not directly investigated yet. We believe that further research is needed to better understand the implication of audition in the use of visual-to-auditory devices, and more generally to understand the role of the input modality in sensory substitution.

Conclusion and Implications

The experiments conducted with sensory substitution devices have highlighted numerous individual differences in perceptual and spatial processes, at the behavioural, neural, and phenomenological levels. These individual differences have consequences both for the design of sensory substitution devices and for the understanding of the processes involved in a sensory substitution device use.

Implications for the Design of Sensory Substitution Devices

Although sensory substitution appears a promising technology to compensate visual impairments, they remain barely used by visually impaired people, however, either because their design is not optimal, or because their use involves too many constraints and cognitive effort [START_REF] Elli | Is there a future for sensory substitution outside academic laboratories?[END_REF]. Taking into account individual differences will allow an optimal appropriation of these devices. First, the choice of the conversion code will benefit from the identification of the cross-modal correspondences that may exist in the target population. For instance, the existence of an audio-tactile correspondence between pitch and tactile elevation in sighted but not in blind people [START_REF] Deroy | Differentiated audio-tactile correspondences in sighted and blind individuals[END_REF] questions the coding of spatial elevation by auditory frequency that is used in several visual-to-auditory devices. Second, the use of these devices can be eased by implementing flexible options as a function of the differences in the reference frames adopted by people (egocentric versus allocentric; trunk-centred versus head-centred). Note that the way each person uses the device (e.g., attributing tactile stimuli to either external objects as in vision or to proximal stimulations as in touch) may be characterized by the adoption of different reference frames, and the preference for one or another may in turn be an indicator of the perceptual experience that is associated with the use of the device.

In addition, identifying different perceptual strategies associated with different phenomenologies, with some people having more of a visual use of the device and other people having more of an auditory or tactile use, can have implications for the design of learning protocols. One possibility would be to respect each user's tendency and to customize the learning protocols as a function of the different types of use [START_REF] Elli | Is there a future for sensory substitution outside academic laboratories?[END_REF]. For instance, for people that have a visual use only, learning could be oriented toward integrating a real substitution device so that the experience becomes increasingly visual. This can be done by favouring tasks designed to better apprehend depth, to learn how to form global images of the objects. For people that have more tactile or auditory experiences, learning could be oriented toward favouring the processes specific to these modalities. For instance, learning to better discriminate auditory frequencies and auditory intensities will allow a better discrimination of the complex auditory stimuli coming from a visual-to-auditory device.

Finally, when designing learning protocols for using sensory substitution, more central sources of individual differences should be taken into account. For instance, aging has been shown to have an impact both on peripheral factors such as perceptual acuity and on central factors such as learning, attention, spatio-temporal integration, and memory [START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF]. As a consequence, the use of visual-to-tactile sensory substitution in older adults is challenging [START_REF] Levy-Tzedek | Aging and sensory substitution in a virtual navigation task[END_REF] and requires adapting learning protocols to this specific population.

Implications for the Conceptual Understanding of Sensory Substitution

The data collected on individual differences helps making advances in the understanding of the processes involved when using a sensory substitution device. At the sensory level, it was found that people with good musical abilities [START_REF] Brown | Seeing with sound? Exploring different characteristics of a visual-to-auditory sensory substitution device[END_REF] or good auditory abilities (Pesnot-Lerousseau et al., submitted) have better performance when using visual-to-auditory substitution devices. People with high visuo-spatial abilities have also better performance with visual-to-auditory devices [START_REF] Hanneton | Intermodal recoding of a video game: learning to process signals for motion perception in a pure auditory environment[END_REF]; but see [START_REF] Brown | Seeing with sound? Exploring different characteristics of a visual-to-auditory sensory substitution device[END_REF]. These results suggest that performance with the device relies on users' individual sensory abilities and that experience takes root both in the substituting and the substituted sensory modalities. The data collected on the subjective experiences, even if they remain too sparse to make strong claims, reveal that they are subject to inter-and intra-individual variability. The phenomenology associated with the use of the device appears to depend both on the task and on auditory abilities. The fact that there is dependence on both the task and individual abilities suggests that there is room for processes that are more cognitive, and thus more subject to individual variability. Finally, at the neural level, differences were observed between early-blind, late-blind, and sighted participants, which led to the hypothesis of two streams of processes, one linked to the substituting and substituted modalities and a cross-modal one. Overall, these results are in line with the view that sensory substitution devices are vertically integrated on pre-existing capacities (Deroy andAuvray, 2012, 2014) that involve cognitive and perceptual processes belonging both to the substituting and to the substituted sensory modalities.

Figure 1 .

 1 Figure 1. Three alternative views (deference, dominance, and vertical integration) on the processes involved in sensory substitution, with their specificities at the behavioural, neural, and phenomenological levels. Illustrative examples are given in parentheses.

Figure 2 .

 2 Figure 2. Illustration of the two neural streams described by Poirier et al. (2007). Early-blind participants use the cross-modal pathway (solid line). Sighted participants use the mentalimagery pathway (dashed line). We propose three hypotheses to explain this difference. (A) Blind participants already have enhanced cross-modal connections before training with the device. (B) Sensory deprivation allows the recruitment of visual areas. (C) Auditory or tactile abilities determine the recruitment of visual processes. As blind participants have better low-level auditory and tactile capacities, the recruitment of visual areas is facilitated.

Acknowledgements

This work was supported by the Mission pour l'Interdisciplinarité (CNRS, Auton, Sublima grant) and the labex SMART (ANR-11-LABX-65). GA is funded by a grant from the European Research Council (Wearhap, FP7, Nr. 601165). We thank Mirko Farina for his useful comments on a previous version of the manuscript.


AVERTISSEMENT

Ce document est le fruit d'un long travail approuvé par le jury de soutenance.

La propriété intellectuelle du document reste entièrement celle du ou des auteurs. Les utilisateurs doivent respecter le droit d'auteur selon la législation en vigueur, et sont soumis aux règles habituelles du bon usage, comme pour les publications sur papier : respect des travaux originaux, citation, interdiction du pillage intellectuel, etc.

Il est mis à disposition de toute personne intéressée par l'intermédiaire de l'archive ouverte DUMAS (Dépôt Universitaire de Mémoires Après Soutenance).

Si vous désirez contacter son ou ses auteurs, nous

UNIVERSITÉ GRENOBLE ALPES UFR DE MÉDECINE DE GRENOBLE

[Données à caractère personnel]

A mon jury et aux acteurs de cette thèse Au Dr Anna Castrioto, que j'ai connu comme tout jeune interne de neurologie lors de ma première garde et qui m'a transmis la fibre du mouvement depuis. Toujours directe et efficace, je n'aurais pas pu trouver meilleure cheffe de thèse ! Merci pour ta rigueur, ta disponibilité et ton soutien sans faille.

Au Pr Elena Moro, merci d'avoir accepté de présider cette thèse et pour votre pédagogie dans l'apprentissage les troubles du mouvement et en particulier dans la maladie de Parkinson.

Au Pr Stéphane Thobois, merci de me faire l'honneur de participer à ce jury de thèse et de nous partager votre expertise lyonnaise sur la maladie de Parkinson.

A Emmanuelle Schmitt, merci de m'avoir éclairé sur cette belle spécialité aussi fascinante que complexe qu'est la neuropsychologie. J'ai hâte d'approfondir ces connaissances lors de mon stage en cognitif au semestre prochain.

A Dimitri Sourd, jeune statisticien qui m'a bien aidé pour le maniement des données et tests statistiques.

A l'équipe de neurologie grenobloise

A Sarah Viguier, exilée dans le sud pour boire du Ricard au semestre dernier et bientôt ailleurs. Tu as été mon fidèle compagnon de galère comme de bons moments durant une longue année d'internat avec pas mal de remous. Merci d'avoir été là quand j'en avais besoin et revient-nous vite ! Au Dr Timour Vitte, le gars du Nord (Isère). Toujours là partout, au courant de toute rumeur plus ou moins fondée, le lanceur d'alerte, il en a pas l'air mais il a des talents d'influenceur.

Toujours disponible pour aider et pour aller courir, on en a encore de belles à faire ensemble ! A Camille Brochier, ma petite filleule de première année qui te disait toujours que tout allait Au Dr Isabelle Favre, efficace et directive mais toujours avec tact, merci pour ton soutien moral d'une grande aide quand j'en avais besoin. Au Pr Olivier Detante, grand orateur, investi dans la formation des internes, merci pour ta proximité avec nous qui met à l'aise tout le monde. Au Dr Pauline Cuisenier, qui me connait depuis la fin de l'externat, curieuse et qui n'a pas la langue dans sa poche, elle est toujours de bon conseil. Au Dr Katia Garambois, grâce à qui je n'oublie plus de regarder les artères vertébrales depuis leur ostium. A toutes les équipes paramédicales des services de neurologie, des bons médecins ça ne suffit pas à bien prendre en charge les patients (et parce qu'une bonne ambiance pour travailler c'est primordial).

A tous les externes pour leur aide précieuse dans chacun des stages où j'ai pu passer, en espérant leur avoir appris des choses et les avoir fait progresser à mon tour. Ma soeur Clara Culot, toujours là pour me rappeler que je ne suis pas parfait et faire un certain contraste avec mes parents, qui me ramène un peu sur terre. C'est de bonne guerre car je crois que c'est réciproque (mais on s'aime quand même hein, ne vous inquiétez pas).

Mes tantes, oncles et cousins, merci pour tous ces moments partagés avec notre grande famille, et qu'il y en ait encore beaucoup ! Comme vous me l'avez dit, c'est la première thèse de la famille, j'espère que cela en inspirera d'autres !

Mention spéciale

A tous ceux que je n'ai pas cité mais qui m'ont aidé à être tel que je devenu aujourd'hui, merci.

larger studies with longer follow-up and more suitable scales are needed to further explore these findings.

Key words: Parkinson's disease, cognition, depression, apathy, anxiety

Introduction

Parkinson's disease (PD) is the second most frequent neurodegenerative disease (after Alzheimer disease) (1). In the last decades, the burden related to PD has more than doubled, suggesting an increase in the future related to aging of population [START_REF] Dorsey | The Emerging Evidence of the Parkinson Pandemic[END_REF]. Whereas PD has been considered for a long time as merely a pure motor disease, recently more attention has been focused on non-motor symptoms. Among these latter, neuropsychiatric ones are very frequent, representing a major cause of impairment of quality of life [START_REF] Schrag | Quality of life and depression in Parkinson's disease[END_REF][START_REF] Benito-León | Impact of apathy on healthrelated quality of life in recently diagnosed Parkinson's disease: the ANIMO study[END_REF][START_REF] Martinez-Fernandez | Postoperative apathy can neutralise benefits in quality of life after subthalamic stimulation for Parkinson's disease[END_REF].

Neuropsychiatric symptoms include depression, apathy and anxiety, which are considered related to the disease itself. They have been defined as hypodopaminergic symptoms, as opposed to hyperdopaminergic symptoms (such as impulsive-compulsive behaviors, addictions or psychotic symptoms), which are related to the dopaminergic treatment. They can be present at the early stage of the disease, before or with the onset of motor symptoms, or later with the progression of the disease (6-9).

Apathy is defined as a lack of motivation accompanied by reduced goal-directed cognition, behavior and emotional involvement [START_REF] Robert | Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group[END_REF]. It affects almost 40% of patients with PD [START_REF] Den Brok | Apathy in Parkinson's disease: A systematic review and meta-analysis[END_REF]. It can present on its own or along with depression and/or anxiety, or cognitive impairment [START_REF] Béreau | Apathy in Parkinson's Disease: Clinical Patterns and Neurobiological Basis[END_REF]. Depression, defined as a persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities, concerns almost 40% of patients with PD [START_REF] Cong | Prevalence and clinical aspects of depression in Parkinson's disease: A systematic review and meta-analysis of 129 studies[END_REF].

Anxiety, defined as excessive worries in anticipation of a future threat and related behavioral disturbances (panic attack, social phobia, specific phobia, agoraphobia…), affects 30% of PD patients [START_REF] Broen | Prevalence of anxiety in Parkinson's disease: A systematic review and meta-analysis[END_REF].

These three symptoms seem to be interrelated, with the presence of one of them being a risk factor for developing another. Together, they have a significant impact on the quality of life of PD patients [START_REF] Schrag | Quality of life and depression in Parkinson's disease[END_REF][START_REF] Benito-León | Impact of apathy on healthrelated quality of life in recently diagnosed Parkinson's disease: the ANIMO study[END_REF][START_REF] Martinez-Fernandez | Postoperative apathy can neutralise benefits in quality of life after subthalamic stimulation for Parkinson's disease[END_REF].

Cognitive impairment is also very common in advanced PD, with dementia in more than 80% of PD patients with 20 years of evolution [START_REF] Emre | Dementia in Parkinson's disease: cause and treatment[END_REF][START_REF] Hely | The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years[END_REF][START_REF] Aarsland | Cognitive decline in Parkinson disease[END_REF][START_REF] Aarsland | Parkinson disease-associated cognitive impairment[END_REF].

In general population, depression and anxiety are associated with a higher risk of dementia [START_REF] Livingston | Dementia prevention, intervention, and care: 2020 report of the Lancet Commission[END_REF][START_REF] Kuring | Risk of Dementia in persons who have previously experienced clinically-significant Depression, Anxiety, or PTSD: A Systematic Review and Meta-Analysis[END_REF].

Several studies have tried to investigate the relationship between neuropsychiatric symptoms and cognitive decline in PD. Whereas psychotic symptoms seem to be a risk factor of cognitive impairment [START_REF] Marinus | Risk factors for non-motor symptoms in Parkinson's disease[END_REF], the association between cognitive symptoms and depression, apathy and anxiety is more ambiguous. Studies point towards a trend of worse cognition when presenting neuropsychiatric symptoms, but results are confounding with few longitudinal prospective studies with robust statistics.

In large meta-analysis, we can see that Mini-Mental State Examination (MMSE) score is statistically lower in patients with apathy or depression [START_REF] Den Brok | Apathy in Parkinson's disease: A systematic review and meta-analysis[END_REF][START_REF] Cong | Prevalence and clinical aspects of depression in Parkinson's disease: A systematic review and meta-analysis of 129 studies[END_REF].

In a review from Marinus et al., including 18 longitudinal studies, hallucinations and to a less extent depression were both independently associated with future development of cognitive impairment or dementia [START_REF] Marinus | Risk factors for non-motor symptoms in Parkinson's disease[END_REF].

A large Chinese study including 901 PD patients seemed to go in the same direction, finding a correlation between depression and hallucinations and parkinsonian dementia [START_REF] Wang | Assessment of cognitive impairment in patients with Parkinson's disease: prevalence and risk factors[END_REF].

Another meta-analysis, including 57 prospective cohort study, found that hallucination and this time anxiety are risk factors for developing cognitive impairment but not depression or apathy [START_REF] Guo | Predictors of cognitive impairment in Parkinson's disease: a systematic review and meta-analysis of prospective cohort studies[END_REF].

Two other studies, a small Swiss cohort (29 patients with no cognitive impairment) [START_REF] Toloraia | Anxiety, Depression, and Apathy as Predictors of Cognitive Decline in Patients With Parkinson's Disease-A Three-Year Follow-Up Study[END_REF] and an English cohort of early Parkinson's disease patients [START_REF] Dissanayaka | Anxiety is associated with cognitive impairment in newly-diagnosed Parkinson's disease[END_REF][START_REF] Dissanayaka | Anxiety disorders are associated with verbal memory impairment in patients with Parkinson's disease without dementia[END_REF], showed evidence supporting the hypothesis of anxiety predicting cognitive impairment.

Similarly, several studies have suggested that apathy is associated with an increased risk of developing cognitive impairment [START_REF] Dujardin | Apathy may herald cognitive decline and dementia in Parkinson's disease[END_REF][START_REF] Martin | Apathy as a behavioural marker of cognitive impairment in Parkinson's disease: a longitudinal analysis[END_REF][START_REF] Sampedro | Apathy Reflects Extra-Striatal Dopaminergic Degeneration in de novo Parkinson's Disease[END_REF]. Among these, in the de novo PD cohort of the Parkinson's Progression Markers Initiative (PPMI), apathy was associated with an increased risk of cognitive decline at 4 years of follow-up. According to this study, apathy would reflect the extra-striatal dopamine depletion [START_REF] Sampedro | Apathy Reflects Extra-Striatal Dopaminergic Degeneration in de novo Parkinson's Disease[END_REF].

The aim of this study was to assess whether neuropsychiatric symptoms in early PD can predict development of a future cognitive impairment.

Material and methods

Patients:

We analyzed data from a cohort of patients with de novo PD followed-up for 3-5 years (the Honeymoon and IMPACT studies). The IMPACT study assessed a subgroup of patients who had participated in the Honeymoon study, 3 to 5 years later, once dopaminergic medication was introduced, between 2017 and 2019. Patients were excluded in case of a diagnosis different from PD, or in case of dementia defined as MDRS lower than 130. 90 patients were enrolled in IMPACT. Among these, 4 patients were wrongly included because their MDRS was lower than 130.

Considering the aim of our study -to assess whether neuropsychiatric symptoms in early PD can predict development of a future cognitive impairment -we decided to include them in our study.

Assessment:

Patients were assessed under their chronic medication condition.

Behavioral symptoms (apathy, depression, anxiety and psychotic symptoms) were assessed with the Ardouin Scale of Behavior in Parkinson's Disease (ASBPD) [START_REF] Rieu | International validation of a behavioral scale in Parkinson's disease without dementia[END_REF]. This scale is a semi-structured interview, based on clinical impression, validated in PD. For each symptom, a score between 0 to 4 was assigned: 0 : no symptoms 1 : mild symptoms 2 : moderate symptoms 3 : marked symptoms 4 : severe symptoms.

Cognition was assessed with:

1) The Mattis Dementia Rating Scale 2 (MDRS-2), with a total score ranging from 0 to 144 points (with highest scores in cases of preserved cognition) [START_REF] Matteau | Mattis Dementia Rating Scale 2: screening for MCI and dementia[END_REF]. Pathological threshold depends on the age and is considered to be 130/144 for patient younger than 70 years old [START_REF] Pedraza | Robust and expanded norms for the Dementia Rating Scale[END_REF]. It contains 36 items, and it is divided in 5 parts.

-one assessing Attention on 37 points -one for Initiation/Perseveration on 37 points -one for Construction on 6 points -one for Conceptualization on 39 points -one for Memory on 25 points

2) The Frontal Assessment Battery (FAB), a specific scale to screen dysexecutive symptoms [START_REF] Dubois | The FAB: A frontal assessment battery at bedside[END_REF]. The score ranges from 0 to 18 points. Pathological threshold is under 16/18 (15/18 if patient didn't get the general certificate of secondary education). This scale is composed of 6 The Levodopa Equivalent Daily Dose (LEDD) was calculated according to Jost et al 2023 [START_REF] Jost | Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals[END_REF].

Outcomes:

As exploratory endpoints, we looked for a correlation between neuropsychiatric symptoms and cognitive impairment first at baseline in Honeymoon and second after 3 to 5 years of follow-up in IMPACT.

The primary end point was to study whether presenting at least one neuropsychiatric symptom among apathy, depression, anxiety and psychosis at baseline represents a risk factor for developing cognitive impairment in patients with early Parkinson's disease after 3 to 5 years of follow-up.

The secondary end points were to study whether:

-Apathy at baseline represents a risk factor of developing cognitive impairment after 3 to 5 years of follow-up.

-Depression at baseline represents a risk factor of developing cognitive impairment after 3 to 5 years of follow-up.

-Anxiety at baseline represents a risk factor of developing cognitive impairment after 3 to 5 years of follow-up.

-Psychotic symptoms at baseline represent a risk factor of developing cognitive impairment after 3 to 5 years of follow-up.

Statistical analyses:

Quantitative variables were presented as mean and standard deviation for those with normal distribution and as median and interquartile for those which were not. The normality of these variables was assessed by a Shapiro-Wilk Test.

Qualitative variables were presented as number and frequencies of patients.

Group comparisons were made using an appaired Student T-test for quantitative variables with a normal distribution, and a Wilcoxon test for quantitative variables with no normal distribution. For the qualitative variables, the McNemar test was used.

In order to perform the analysis, we used a qualitative composite criterion including apathy, anxiety, depression and psychotic symptoms. It was considered significant when the patient had at least one of the symptoms previously listed. We also studied each symptom alone and it was considered significant when ASBPD respective score was above 1.

This composite criterion and each neuropsychiatric symptom were evaluated function of the MDRS total score and each subscore, the FAB total score, and the verbal fluencies.

To assess the exploratory endpoints, we used linear regression model, adjusted on the following confounding factors: age, gender, MDS-UPDRS III and LEDD. We conducted the tests for the composite criterion and for each symptom as a quantitative variable and as a qualitative variable.

To assess the primary and secondary end points, we used a mixed model and adjusted the results on the same confounding factors as previously detailed. We also conducted statistical test for the composite criterion and for each symptom as a quantitative variable and as a qualitative variable as previously explained.

Excel from Office 2016, Jamovi 2.2.5 and Stata 15 were used for all analyses.

Significance was declared at p<0.05 level.

A Bonferroni correction was used for multiple comparisons (each symptom with each subscore, qualitative and quantitative tests), with a set p-value, of 0.0007 at baseline and 0.001 at 3-5 years.

Results

Clinical and demographical characteristics:

Table 1 shows different characteristics of the 198 patients enrolled in Honeymoon and 90 patients of IMPACT.

After 3 to 5 years of evolution, there was a trend towards a reduction in severity of neuropsychiatric symptoms compared to baseline (significant for apathy and depression but not for anxiety and the global composite criterion) (table 2).

There was no change of cognitive scores at 3 to 5 years of evolution compared to baseline (table 2). MDS-UPDRS subscales significantly worsened at 3 to 5 years of follow-up.

We had only one patient with hallucinations in IMPACT so we could not analyze this symptom for our study (table 2).

Exploratory endpoints:

At baseline, we found only one correlation between neuropsychiatric symptoms and cognition: depression seems to be positively related with categorical verbal fluencies (coefficient 0.77 p=0.038 for quantitative test and coefficient 1.41 p=0.115 for qualitative test).

The other regressions were non-significant.

After 3-5 years of evolution, apathy was inversely correlated to the MDRS initiation/perseveration score (coefficient -0.56 p=0.034 for the quantitative test and coefficient -1.25 p=0.57 for the qualitative test).

When applying a Bonferroni correction for multiple comparisons, none of the previous tests were statistically significant.

Primary endpoint:

There was no significant impact of the neuropsychiatric symptoms at baseline on MDRS total score and each subscore and on FAB total score at follow-up (table 3).

Neuropsychiatric symptoms CE (confidence interval)

p-value Evolution of MDRS total 0.17 (

Discussion

In this study, assessing a cohort of early Parkinson's disease, before the introduction of dopaminergic medication and 3 to 5 years later, we did not find a clear association between early neuropsychiatric symptoms and cognitive impairment.

Findings of linear regressions showed that at 3 to 5 years of follow-up, apathy has a negative impact on the MDRS initiation/perseveration section.

The mixed model did not show any correlation between the neuropsychiatric symptoms at baseline and the evolution of cognitive symptoms after a follow-up of 3 to 5 years. However, secondary analyses showed that depression and apathy have a negative impact on MDRS Construction section.

On the other hand, linear regressions found a trend towards a positive impact of depression on verbal fluencies at baseline, as well as a positive association of depression on MDRS Conceptualization at follow-up.

Whereas a negative impact of depression and apathy on Initiation and Construction are not unexpected, given the lack of initiative typical of the apathetic syndrome, the positive association of depression with verbal fluency and Conceptualization is more difficult to explain.

Our results should be interpreted cautiously, since none of them remained significant after Bonferroni correction.

Investigating the predictive role of neuropsychiatric symptoms and cognition is not easy, since apathy, depression and anxiety might also represent early symptoms in cognitive impairment.

Several studies have investigated the association of neuropsychiatric symptoms and cognition.

Dujardin et al. found that apathy was associated with a significantly worse cognitive evolution in a group of 40 patients. Differently from our study, patients included in their study had longer disease evolution (8 years in mean). Assessment tools might also have a role since apathy in their study was assessed by the Lille Apathy Rating Scale (LARS) [START_REF] Dujardin | Apathy may herald cognitive decline and dementia in Parkinson's disease[END_REF].

In the Spanish study of the PPMI cohort, a correlation was found between apathy and cognitive impairment. Similarly to our study, it was a cohort of early Parkinson's disease patients, but differently from our study, apathy was assessed with MDS-UPDRS I and patients with more severe cognitive impairment were not excluded at follow-up (29). Apart from these studies with a relatively small sample size, a larger one in China, with 901 patients, found an association between depression and cognitive symptoms. In this study, demented patients were not excluded and depression was assessed by Hamilton Depression Rating Scale (HAM-D) [START_REF] Wang | Assessment of cognitive impairment in patients with Parkinson's disease: prevalence and risk factors[END_REF].

Assessment tools, as well as other methodological issues, might explain the different results we found, compared to other studies.

The strengths of this study are first its design because it is a prospective, multicenter, longitudinal study. It included homogenous group of early PD patients with no treatment at baseline apart from rasagiline and in the literature, longitudinal studies in early state of PD are quite scarce.

One of the main limitations of this study is that patients with more severe cognitive impairment were excluded.

Another limitation that could explain the negative results, is the small sample size with a lack of power. Indeed, there were only 90 patients included in the mixed model and number of patients presenting neuropsychiatric symptoms significatively lowered after 3 to 5 years, probably due to introduction of dopaminergic medication, especially dopamine agonists, which can have an effect on neuropsychiatric symptoms [START_REF] Leentjens | The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies[END_REF][START_REF] Thobois | Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil[END_REF]. Statistics for psychotic symptoms were not possible, given the few patients presenting hallucinations at disease onset. Statistics for verbal fluencies were also not available after 3 to 5 years of follow-up so we could only analyze them with linear regression at baseline. It could be interesting in the future to use other scales of apathy such as the LARS [START_REF] Sockeel | The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease[END_REF], in order to evaluate the impact of different subtype of apathy on cognition [START_REF] Dickson | Are there distinct dimensions of apathy? The argument for reappraisal[END_REF].

To conclude, we found no impact of neuropsychiatric symptoms on the evolution of cognition in early Parkinson's disease.

However, in the exploratory analysis, there was a trend towards worse cognitive prognosis in patients with depression and apathy.

More focused and larger studies with longer follow-up and more suitable scales are needed to further explore these findings.

  D'ÉTAT DE DOCTEUR EN MÉDECINE SPÉCIALITÉ : NEUROLOGIE SOUTENUE PUBLIQUEMENT À LA FACULTÉ DE MÉDECINE DE GRENOBLE Le 24/10/2023 Par M. Alexis CULOT DEVANT LE JURY COMPOSÉ DE : Président du jury : Mme le Pr Elena MORO Membres : Mme le Dr Anna CASTRIOTO (directrice de thèse) M. le Pr Stéphane THOBOIS Mme Emmanuelle SCHMITT L'UFR de Médecine de Grenoble n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ; ces opinions sont considérées comme propres à leurs auteurs.

  bien et qu'elle gérait, ce qu'elle fait toujours ! Merci pour ta bonne humeur à toute épreuve et tes cours particuliers de rock, hâte de m'y remettre ! A Sami El Mimouni, si Timour est le lanceur d'alerte, Sami en est le réceptacle parfait. Toujours là pour te faire réfléchir sur des dilemmes existentiels… et te demander ce que tu vas manger ce soir (parce que oui, on commence à avoir faim). A Sylvain Colomb, mon cointerne de galère qui est le prochain à passer sur la liste des thèses. Le semestre prochain sera plus serein j'en suis sûr ! A Guillaume Chavy, le calme olympien qui met d'accord tout le monde, une patience à toute épreuve. A Lucie Dechambenoit, le juste équilibre entre douceur et fermeté. A Valentine Dupont, petite par la taille mais grande par l'esprit, tu seras j'en suis sûr une cointerne d'envergure. A Marie Giraud, que je n'ai pas encore trop eu l'occasion de connaitre mais ce ne saurait tarder. A Cristina Barsan qui était avec Nolwenn Pellerin ma complice de neurologie vasculaire, stage à la fois passionnant et éprouvant. Aux docteurs Inès Rachidi, le chipmunk, Pomme Morin, la star, Florent Lépilliet, l'éclopé, et Gauthier Willaume, le Pr Tournesol, anciens internes alors que j'étais encore un petit externe, vous êtes les premiers à m'avoir donné envie de me lancer dans la neurologie et je vous en suis grandement reconnaissant ! Au Dr Célia Chambon, merci de ton aide précieuse pour les statistiques, passe chez ton voisin un soir, je suis sûr qu'il t'offrira un verre ! Au Dr Anaëlle Bain, la force tranquille, qui je l'espère profite bien de sa dispo et va nous revenir en pleine forme. Au Dr Alexandre Berger, charismatique et polyvalent, un modèle à suivre. Au Dr Clémentine Bonaz, toujours droite et juste, sans jamais trop se prendre au sérieux. Au Dr Francesca Vodret qui m'a suivi en neurologie vasculaire et générale, pour ses conseils, sa bonne humeur et son « Dai Alexis ! » que j'entendrai toujours résonner dans ma tête. Au Dr Loïc Legris, futur grand professeur à n'en pas douter. Au Dr Guillaume Martin, et son avis éclairé, toujours présent quand on avait besoin d'aide lors de mon stage en liaison. Au Dr Sarah Alexandre, récemment partie vers Chambéry, merci pour ta gentillesse.

  A l'équipe de neurologie de Chambéry Aux docteurs Thomas Rieffel, Marie Barré et Vincent Tarel, merci d'avoir eu la patience de m'initier à l'art de l'EEG, même si cela n'a pas été toujours facile. Aux docteurs Lucie Berbineau, Nicolas Miret et Anaïs Daumas, merci pour tout ce que vous m'avez transmis dans le domaine de la neurologie périphérique et de l'ENMG. Aux docteurs Sébastien Marcel, Julien Gère, Clara Grosset-Janin et Clothilde Serve que j'ai moins côtoyé mais qui ont tous été très avenants avec moi. Parce qu'il n'y a pas que les neurologues Aux docteurs Sarah Ezra, Pierrick Thibert et Blaise Caveau, la team des internes en neurologie à Annecy qui m'ont bien coaché en tant que néo-interne. Au Dr Jagoda Dziewanowski (je crois que je l'ai bien écrit !), la petite fraise gériatre de neurovasculaire à Chambéry. Aux docteurs Romain Laurent, l'expert mondial du VEXAS, Yanis Azzedine, Orlane Chol et Duncan Faure, la team médecine interne qui trouve toujours une bonne place en neurologie générale, c'est un plaisir de travailler avec vous. A Justine Costes et Noémie Kaladzé, la team MPR qui met l'ambiance et font danser les patients en neurologie vasculaire.

  A mes amis A ceux qui sont là depuis la maternelle, je pense à Paul Wang et Delphine Rizzi, qui se sont exilés pour l'un en Suisse et pour l'autre à Nice, loin des yeux près du coeur comme on dit ! A ceux qui sont là depuis le collège ou le lycée, malgré les remous ils sont toujours présents, merci à eux qui m'ont pour certains un peu aidé pour les statistiques et pour d'autres surtout à décompresser : Francesco Cesana, Laura Coquet, Nicolas Pasqualini, Robin Heusch, Nathan Rajohnson. A Xavier Collado, compagnon de soirées jeux endiablées, Margaux Courtillé, mon binome d'externat, Nour El Housseini, l'ex-coloc de choc. A Maxime Hérouard, Dr Nathan Dawoud, Dr Perrine Petit, Solène Prunet, Albane Vanlemmens, Florence Berquet, Louise Deceunik, Magali Colombier, la team de l'internat covidé annecien. A Edwige Issartel et (tout récemment Dr) Elodie Guinet, pour les sorties ski et les soirées inter-coloc. A Marion Bordas, Raphaël Valldemosa, Emmanuel Vareilles, Laetitia Stricker, Agathe Secondy, Léa Octrovée, les joyeux colocataires de l'auberge espagnole chambérienne. A Jeanne Boubert, pour sa bonne humeur (quasi) au quotidien et son grain de folie dans la coloc de la Green Island et pour avoir supporté mon humeur fluctuante de pré-thèse. A ma famille Mes parents Nicole et Pascal Culot qui m'ont toujours soutenu dans mes projets, pour leur amour et la fierté qu'ils portent dans leurs yeux avec un regard bienveillant quoi que je fasse.

The

  Honeymoon study was a multicenter study. Patients were recruited and assessed in 6 French University Hospitals: Grenoble, Lyon, Strasbourg, Poitiers, Marseille and Clermont-Ferrand. It included 198 patients from 30 to 70 years, diagnosed with Parkinson's disease for less than 2 years, with no dopaminergic medication (with the exception of rasagiline), and no cognitive impairment (defined as Mattis Dementia Rating Score (MDRS) lower than 130 or Frontal Assessment Battery (FAB) score lower than 15). Patients underwent full neuropsychological examination.

-

  Sensivity to interference on 3 points -Inhibitory control on 3 points -Environmental autonomy on 3 points. Motor assessment was performed using the motor part of Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (34). The score ranges from 0 to 132, the higher the score, the greater the severity. This scale is composed of 4 parts: Part I : Non-motor Experiences of Daily Living Part II : Motor Experiences of Daily Living Part III : Motor Examination Part IV : Motor Complications

  Abbreviations : n = number of patients, % = frequencies of patients, M = mean, SD = standard deviation, m = median, Q1 = 25 percentiles, Q3 = 75 percentiles, LEDD = Levodopa Equivalent Daily Dose, *Amantadine n=3, Trihexylphenidine n=2, **Valproic acid n=1, Phenobarbital n=1, Lamotrigine n=1, Pregabaline n=1

7 <0

 7 Abbreviations : n = number of patients, % = frequencies of patients, M = mean, SD = standard deviation, m = median, Q1 = 25 percentiles, Q3 = 75 percentiles, ASBPD = Ardouin Scale of Behavior in Parkinson's Disease, MDRS = Mattis Dementia Rating Scale, FAB = Frontal Assessment Battery, MDS-UPDRS = Movement Disorder Society-Unified Parkinson's Disease Rating Scale

  Toloraia et al. found that anxiety was predicting of Mild Cognitive Impairment (MCI). As our study, it was a cohort of cognitive unimpaired patients, but anxiety was assessed by Beck Anxiety Inventory (BAI) (24). Similarly, Dissanayaka et al. demonstrated that anxiety disorders were associated with cognitive impairment (25), and more particularly with verbal memory impairment (26), in patients with Parkinson's disease without dementia. Anxiety in these studies was assessed by MDS-UPDRS I for the first one and by Hamilton Anxiety Rating Scale (HAM-A) for the second one.

Au Dr Catalina Co- clitu, pour sa disponibilité et son expertise dans les maladies inflammatoires. Au Dr Gérard Besson, grâce

  Au Dr Mathieu Vaillant, expert de la ponction lombaire sous hypnose, pour sa gentillesse et sa douceur légendaires. Au Dr Olivier Casez, pour ses avis d'éthique qui visent toujours juste et ses blagues plus ou moins douteuses mais faisant toujours mouche.

	à qui on pense à rechercher des maladies métaboliques dès qu'il y a un pro-
	blème d'oreille ou d'oeil.

Au Dr Valérie Fraix, la neurologue préférée des patients parkinsoniens, toujours disponible, qui prend toujours le temps d'expliquer clairement les choses et dont le savoir semble infini. Au Dr Sara Meoni, bientôt

  maman et qui commence à former les externes en troubles du mouvement, ils sont entre de bonnes mains.

Au Dr Sina Potel, rentré en terres bretonnes, pour son humour décalé et sa passion pour les mouvements anormaux. Au Dr Lorella Minotti et Pr Philippe Kahane, le

  binôme chic de choc de l'épilepsie.

	Au Dr Martial Mallaret, qui sait nous faire réfléchir et a toujours un nouveau petit signe cli-
	nique à nous apprendre.

Au Dr Laurent Vercueil, pour

  ses histoires toutes plus incroyables les unes que les autres, la neurologie est effectivement la plus belle des spécialités.

Aux docteurs Olivier Moreaud et Mathilde Sauvée, j

  'ai hâte de passer au centre mémoire pour perfectionner mes connaissances dans le domaine de la cognition, très intriqué avec celui des mouvements anormaux.

	A l'équipe de neurologie d'Annecy

Aux docteurs Jean-Henri Ruel, Julie Guellerin, Mathieu Bonnerot, Jennifer Roudil, Gilles Ro- dier, Deborah Grosset-Janin, Sophie Jeannin, Nathalie Morel, Wilfried Vadot, Isabelle Ber- ger, Sandra Felix, merci

  à tous de votre accueil et de m'avoir accompagné dans mes premiers pas en tant qu'interne de neurologie.

	Mention spéciale au Dr Bérangère Ruel pour sa présence et pour m'avoir appris les rudi-
	ments des maladies neurologiques périphériques.

Table 1 :

 1 Participant's characteristics at T0 (Honeymoon) and T5 (IMPACT)

	T0 (on 90	T5 (on 90 patients)	p-value
	patients)

Table 2 :

 2 Comparison of patient's neuropsychiatric, cognitive and motor tests between Honey Moon (T0) and IMPACT (T5)

Table 3 :

 3 Mixed model of neuropsychiatric symptoms at baseline function of the evolution of neuropsychiatric tests

Remerciements

Objective: To assess whether neuropsychiatric symptoms (apathy, depression, anxiety) at disease onset are correlated with a cognitive decline in early course of PD.

Methods:

We included patients, enrolled in a multicenter French study, the Honeymoon study, assessing de novo PD patients. Part of this cohort was assessed at 3 to 5 years of follow-up, in the IMPACT study. We evaluated the relationship between anxiety, depression and apathy (assessed with the Ardouin Scale of Behavior in PD (ASBPD)) and cognition (using the MATTIS Dementia Rating Scale (MDRS) and the Frontal Assessment Battery (FAB)), with a mixed model.

Results: 198 patients were assessed at baseline and 90 patients at 3 to 5 years at follow-up.

There was no significant change of cognitive performances at 3 to 5 years of evolution compared to baseline, whereas neuropsychiatric symptoms improved at last follow-up. We found no impact of neuropsychiatric symptoms on the evolution of cognition after 3 to 5 years of disease (primary outcome). However, the exploratory analysis showed an association between respectively depression (coefficient -0.97; p= 0.012), apathy (coefficient -0.65; p=0.048) and worse cognitive evolution in the subscale MDRS construction. They also showed a positive association between depression and MDRS conceptualization (coefficient 1.00; p=0.031). These tests did not reach statistical significance after correction for multiple comparisons (secondary outcomes).

Conclusion:

Our study did not confirm previous data on neuropsychiatric symptoms being predictive of cognitive decline in patients with PD. These results should be interpreted cautiously because patients with dementia were not included in the study. More focused and

Secondary endpoints:

We found a negative association between respectively depression (coefficient -0.97; p=0.012), apathy (coefficient -0.65; p=0.048) and cognitive evolution at follow-up in the subscale MDRS Construction (table 4 and5).

Depression was significant with both quantitative and qualitative analysis when apathy was only significant with the quantitative analysis (table 4 and5).

We also found a positive association between depression and cognitive evolution at followup in the subscale MDRS Conceptualization (coefficient 1.00; p=0.031 for the quantitative analysis) (table 5).

Again, when applying Bonferroni correction for multiple analyses, none of these tests were statistically significant.