Neuropsychologia 70 (2015) 421–428

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

Moving sounds within the peripersonal space modulate the motor system Alessandra Finisguerra a, Elisa Canzoneri b, Andrea Serino b,c, Thierry Pozzo a,d, Michela Bassolino a,n a

Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova 16163, Italy Laboratory of Cognitive Neuroscience, Center for Neuroprosthetics, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland c Department of Psychology, University of Bologna, 40127 Bologna, Italy d IUF, INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Université de Bourgogne, Dijon 21078, France b

art ic l e i nf o

a b s t r a c t

Available online 2 October 2014

Interactions between ourselves and the external world are mediated by a multisensory representation of the space surrounding the body, i.e. the peripersonal space (PPS). In particular, a special interplay is observed among tactile stimuli delivered on a body part, e.g. the hand, and visual or auditory external inputs presented close, but not far, from the same body part, e.g. within hand PPS. This coding of multisensory stimuli as a function of their distance from the hand has a role in upper limb actions. However, it remains unclear whether PPS representation affects the motor system only when stimuli occur specifically at the hand location or when they move within a continuous portion of space where the hand can potentially act. Here, in order to study these two alternatively hypotheses, we assessed the critical distance at which moving sounds have a direct effect on hand corticospinal excitability by using Transcranial Magnetic Stimulation (TMS). Specifically, TMS single pulses were delivered when a sound source was perceived at six different positions in space: from very close to subjects' hand (15 cm) to far away (90 cm). Moreover, sound direction was manipulated to test if stimuli approaching and receding from the hand might have the same relevance for the motor system. MEPs amplitude was enhanced when sounds were delivered within a limited distance from the hand (around 60 cm) as compared to when the sounds were beyond this space. This effect captures the spatial boundaries within which PPS representation modulates hand cortico-motor excitability. This spatially-dependent modulation of corticospinal activity was not further affected by the sound direction. Such findings support a strict link between the multisensory representation of the space around the body and the motor representation of potential approaching or defensive acts within that space. & 2014 Elsevier Ltd. All rights reserved.

Keywords: Peripersonal space Motor cortex Action Looming sound Transcranial Magnetic Stimulation

1. Introduction The existence of a representation of a delimited distance or area surrounding the body, the Peripersonal Space (PPS), has been previously demonstrated in monkeys and humans. Seminal studies reported a special interaction between tactile stimuli presented on a body part and multisensory (visual or auditory) external inputs presented close to, but not far from, the same body part (Rizzolatti et al., 1997; Rizzolatti et al., 1981; Graziano et al., 1999; Làdavas and Serino, 2008). Somatosensory and visual/ auditory receptive fields (RFs) are coded with respect to the body: if the body part where the tactile RF is anchored moves, the visual n Corresponding author. Present address: Center for Neuroprosthetics, École Polytechnique Fédérale de Lausanne (EPFL), Grand-Champsec 90, CH-1951 Sion, Switzerland. Tel.: þ 41 27 603 23 64. E-mail address: michela.bassolino@epfl.ch (M. Bassolino).

http://dx.doi.org/10.1016/j.neuropsychologia.2014.09.043 0028-3932/& 2014 Elsevier Ltd. All rights reserved.

RF shifts congruently (Avillac et al., 2005). It has been suggested that the encoding of spatial position of external objects in a body centered frame of reference supports the elaboration of appropriate motor re-actions toward stimuli potentially interacting with the body (Rizzolatti et al., 1997; Graziano and Cooke, 2006). This is in line with evidence in monkeys showing that neurons integrating multisensory information within the PPS around a certain body part are also involved in movements of the same body part (Duhamel et al., 1998; Fogassi et al., 1996; Graziano et al., 1994; Rizzolatti et al., 1997). In addition, electrical microstimulation of those brain areas containing PPS neurons (i.e., the Ventral Intraparietal area, VIP; Cooke et al., 2003, and the premotor polysensory zone, PZ, Graziano et al., 2002) evokes a constellation of motor acts mimicking normal monkeys behavior in response to potential threats. Similarly, authors have been widely referred to the functionality of PPS in supporting efficient motor behaviors also in humans (Bassolino et al., 2010; Cardellicchio et al., 2011;

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Costantini et al., 2010; Serino et al., 2007). Behavioral experiments have repeatedly shown that audio stimuli close to the body boost processing of tactile information on the same body part (Canzoneri et al., 2012; Serino et al., 2011) according to motor experiences (Bassolino et al., 2010; Canzoneri et al., 2013; Serino et al., 2007) and with the aim of supporting rapid motor responses. However, only recent studies directly support the existence of a motor coding of PPS in humans (Avenanti et al., 2012; Makin et al., 2009; Serino et al., 2009). For instance, static auditory stimuli presented close to the subjects' hand (5 cm), but not far (100 cm), enhances the activity of the corticospinal motor representation of the hand on very rapid time scale, i.e. within 50–75 ms, as measured through Transcranial Magnetic Stimulation (TMS) (Serino et al., 2009). Interestingly, if subjects are already planning a movement, the excitability of the motor cortex decreases when a visual stimulus appears close to the moving reaching hand (Makin et al., 2009). Thus, the excitability of the hand motor representation is modulated as a function of the location of external stimuli with respect to the hand and as a function of concurrent motor preparation. The above-mentioned studies compared the effect of static stimuli, presented either close or far from the hand, on the motor system excitability. Based on those results, it has been proposed that the hand-centered coding of space implemented by the PPS system exerts a role on the motor system in the rapid selection and control of manual defensive or acquisitive actions, for aversive and desired objects, placed close to the hand (Brozzoli et al., 2014; Makin et al., 2012). However, in everyday life external stimuli continuously move in space, as the different parts of the body do. For instance, in order to intercept a ball flying towards us, our brain needs to plan fast motor behaviors taking into account a portion of space that is not limited to the actual hand position, but it includes the whole portion of space where the hand can potentially act (see also Longo and Lourenco (2006) and Brozzoli et al. (2010), (2009)). To this aim, our motor system needs to process information along a continuum space, spanning near and far space, rather than simply representing objects as at fixed position in space, either near or far from the hand. In order to test this hypothesis, we assessed hand motor excitability by using single-pulse TMS during the presentation of sounds moving along a spatial continuum from a location very close to subjects' hand (15 cm) to far away (90 cm). The amplitude of motor evoked potentials (MEPs) induced by TMS as proxy of excitability of the motor system was compared when the acoustic stimuli were presented at different distances from the body. The farthest location at which perceptual stimulation may affect corticospinal excitability can be considered as the spatial boundary of the influence of PPS representation on the motor system, which might take into account just the immediate position close to the hand or a series of different positions where the hand can potentially act. We also compared the effects induced by the two different directions of the moving sounds, i.e. approaching/looming (IN sound) or receding (OUT sound) sounds. Evidence from previous behavioral studies (Canzoneri et al., 2012; Ghazanfar et al., 2002; Hall and Moore, 2003) and recordings in parietal and premotor areas both in monkeys and humans have highlighted that approaching stimuli might be more relevant for the PPS representation than receding ones (Bremmer et al., 2001, 2000; Canzoneri et al., 2012; Ghazanfar et al., 2002; Hall and Moore, 2003), probably in order to prepare for defensive responses. If this is also the case for the modulation of the motor system due to PPS representation, we expect to find different effects on MEPs during the presentation of IN and OUT sounds. For instance, MEPs amplitude might be generically lower or less spatially-tuned for OUT sounds as compared to IN sounds. Alternatively, it is possible that approaching and receding stimuli exert the same influence

onto the motor system. Indeed stimuli both moving toward or away from the hand, especially when located close to body, might be relevant to plan motor responses in the way they can suggest either defensive or object-directed approaching movements. If this is the case, then a similar spatially-dependent modulation of MEPs is expected both for approaching and receding sounds. In the present experiment, we directly tested those two alternative hypotheses by comparing the amplitude of motor responses evoked by single TMS pulse when the acoustic stimuli approached toward or receded from subject's hand.

2. Method 2.1. Subjects Eighteen healthy subjects (8 males, mean age 26.3 years7 3.9) participated in this study, but five out of them were not included in the analysis. One out of these five subjects had a distorted sound perception (i.e. he perceived the sounds moving from/to the backspace), three participants were not able to discriminate among the 6 sound positions (e.g. they perceived at the same distance two or more consecutive sound locations) and their sound perceived locations exceeded 2 standard deviations the group mean as highlighted by a control experiment (see Section 3.1). Moreover, one subject showed EMG pre-activation before the TMS pulse (see below). All participants were right-handed, as assessed by an adapted Italian version of the Edinburgh handedness inventory (Oldfield, 1971). They had normal or corrected-to-normal vision, touch and hearing. None of the subjects had contraindication to TMS. The study was performed with the approval of the local ethics committee ASL-3 (“Azienda sanitaria locale”, local health unit) Genoa and in accordance with the Declaration of Helsinki. All participants provided a written informed consent form, they were naive to the purpose of the study and they were remunerated for their time at the end of the experiment. 2.2. Transcranial magnetic stimulation TMS was delivered through a figure-eight coil (70 mm) connected to a single Magstim monophasic stimulator (Magstim 2002, Magstim Co., Whitland, UK). We determined the optimal position for activation of the right First Dorsal Interosseus (FDI) muscle (i.e. the scalp position from which maximal amplitude MEPs were elicited) by moving the coil in 0.5 cm steps around the presumed motor hand area by using a slightly supra-threshold stimulus. Resting motor threshold (rMT) of FDI muscle was defined as the minimum stimulus intensity able to produce a MEP of at least 0.05 mV in 5 of 10 consecutive trials and it was expressed as a percentage of maximum stimulator output. The coil was placed tangentially to the scalp with the handle pointing backward and laterally to form a 451 with the sagittal plane. This coil orientation induced a posterior–anterior current in the brain. The optimal position of the coil was then marked on a cap placed on the scalp with a pen to ensure the correct coil placement throughout the experiment. For the whole experiment the coil was fastened to an articulated mechanical arm. Electromyography (EMG) was recorded with silver disc surface electrodes positioned on the FDI in a tendon-belly configuration. EMG signals were amplified and filtered (20 Hz to 1 kHz) by use of a D360 amplifier (Digitimer). The signals were sampled at 5000 Hz, digitized using a laboratory interface (Power1401; Cambridge Electronics Design CED), and stored on a personal computer for display and later off-line data analysis by using the Signal software version 4. Each recording epoch lasted 400 ms, of which 100 ms preceded the TMS. The absence of voluntary contractions was continuously verified by visual monitoring of the EMG signal. However, trials with an EMG background activity ( 40.05 mV in the 100 ms preceding TMS pulse) were excluded from analysis. One subject was excluded from the further analysis since an EMG background activity ( 40.05 mV) was present in more than 10% of the trials. In the remaining participants, the presence of EMG background activity higher than 0.05 mV led to the exclusion of less than 2% of the trials. Mean value (SD) of rMT was 38.57 ( 7 4.14) mV. 2.3. Design 2.3.1. Main experiment Subjects were seated in a comfortable chair with their right arm resting in a prone position and were instructed to keep their hands still and as relaxed as possible. We first set up the device for the electromyography (EMG) and for the tactile stimulation. Then we proceeded to define the muscle hotspot location and the motor threshold at rest (rMT) (see Fig. 1). Three separate conditions were run: a baseline recording (PRE), followed by the experimental session (EXP) and then again a baseline block (POST). The TMS stimulation intensity was always 130% of rMT. Both baseline blocks consisted of 12 trials during which we measured cortical

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Fig. 1. Experimental set up. (a) The figure depicts the experimental set up. Blindfolded subject sat down on a chair with the arm placed 15 cm apart from the first sound source. The sound moved across the loudspeakers by approaching the subject's hand (IN sound, red arrow) or by receding from it (OUT sound, blue arrow). The TMS pulses, or an occasional tactile stimulus, were delivered when the sound was placed in one of the six possible depicted positions (15, 30, 45, 60, 75, 90). The loudspeakers were hidden for the whole duration of the experiment. (b) The position of the electromyography electrodes placed over the right First Dorsal Interosseus (FDI) muscle and the neurological electrodes for the tactile stimulation. (c) A picture of the loudspeakers array. (3D reconstruction and loudspeakers picture edited by Laura Taverna).

excitability at rest, with the subjects keeping their eyes closed and without any noise. To maintain attention throughout the baseline sessions, subjects were informed that, in some trials (N ¼2 in each baseline), they would be asked to detect infrequent tactile stimuli on the right hand. In these trials no TMS stimulation was delivered. Participants were blindfolded during the whole duration of the experiment; they oriented their head toward the front, with their right hand placed on an armrest close to a table. For the auditory stimulation, we used a custom-made device comprising an array of eight serial connected loudspeakers, placed 15 cm from each other. The device was placed beside the subject to cover a distance of 105 cm from the subjects' right hand. The loudspeakers were hidden from subjects' view, in order to prevent subjects from visually locating the origin of the sounds. In order to create the illusion of a sound source continuously moving in two different directions, i.e. approaching the body, IN sound, or receding from it, OUT sound, a dedicated device (a microcontroller) allowed for control of the flow of the volume among the different loudspeakers through an algorithm. Differently from the previous works where the sound intensity in space was manipulated in order to create an illusion of sound movement between two loudspeakers far apart (Canzoneri et al., 2012, 2013), in the present study the sounds originated from different 8 spatial sources so that the novelty of the present device consists in the possibility to precisely trigger

TMS stimulation with respect to the positions of the loudspeakers in space. Nevertheless, we note that the effect of sound moving was artificially created by manipulating the temporal sequence of activation of the different loudspeakers. In order to control that this manipulation had the same perceptual effects in all participants, we run a sound localization experiment (see Section 3.1). Custom-made Matlab software controlled sound administration and triggered the TMS pulse through the CED laboratory interface. The sound moves along a distance of 105 cm in 3 s (i.e. at a speed of 35 cm per second). Before each experimental block, the volume of the loudspeakers was calibrated by means of a phonometer so that the maximum intensity of the sounds emitted by the loudspeakers was the same (i.e. 70 dB) in the position closest to the hand for both IN and OUT sounds. We choose this relatively low sound intensity to avoid inducing any startle response in the EMG signal, in line with previous works by our own group (Serino et al., 2009, 2011; Canzoneri et al., 2012, 2013). During the experimental session, on each trial the auditory stimulus (either an IN or an OUT sound) was presented and TMS-induced MEPs were simultaneously recorded from the FDI muscle. Subjects were informed that for each trial the TMS pulse was administered concurrently with the task-irrelevant sound, that they had to ignore. They were asked to verbally respond as fast as possible to the rare tactile stimulation delivered on the dorsum of their right hand. The tactile stimulation was

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provided using a constant-current electrical stimulator (DS7A, Digitimer, Hertfordshire, United Kingdom), via a pair of neurological electrodes (Neuroline, Ambu, Ballerup, Denmark). Tactile stimuli were administered in the inter-trial interval at least 4–5 s apart from TMS pulses to avoid MEP contamination due to tactile stimuli or verbal responses (Classen et al., 2000; Terao et al., 1995). Error rates (including false alarm or omission to the tactile stimulus) were very low (2.7%) and were constant throughout the experiment. Crucially, in order to study the spatial distances at which sound can modulate the MEPs amplitude, in each trial a TMS pulse was delivered 50 ms after the instance in which the sound source was located in one of six possible positions (15, 30, 45, 60, 75, 90 cm) from the hand. The choice of this short time interval was based on Serino's study (Serino et al., 2009) demonstrating a specific MEP enhancement for near rather than far sound 50 ms after the sound onset. In summary, the overall experimental design included a random combination of 2 sound directions (IN and OUT) and 6 sound positions (Distances: 15, 30, 45, 60, 75, 90 cm). Each combination (direction and position) was randomly repeated 12 times, resulting in a total of 144 trials equally distributed across 4 experimental blocks. The TMS trials were randomly intermingled with 24 trials (2 repetitions for each of the 6 sound positions in the 2 sound directions) during which subject received the tactile stimulation, without TMS pulse. The inter-trial interval was controlled via software to ensure that it was always higher than 10 s (precisely, between 10 and 12 s) in order to avoid inducing a change in motor excitability (Chen et al., 1997). 2.3.2. Subjects' sound-localization judgments Moreover, at the end of the experiment we performed a control experiment in the same group of subjects to confirm that the sounds were actually perceived at different locations accordingly to the six actual sound source positions (Canzoneri et al., 2012). This order between the two tasks was chosen to avoid a possible influence on the TMS experiment due to an explicit judgment of sound position and direction. Participants were blindfolded and received tactile stimulation on their right hand when the moving IN or OUT sound was located at the 6 spatial positions. At the end of each trial, participants were asked to verbally indicate the perceived position of the sound in space when they had felt the tactile stimulation, on a scale from 1 (very close) to 90 (very far) from the hand position. Participants were explicitly invited to use the entire range between 1 and 90. A total of 72 trials were administered, i.e. 6 trials for each combination of sound direction and distance.

3. Results 3.1. Subjects' sound-localization judgments One subject was unable to perform the task since he perceived the sounds moving from/to behind the hand, outside the 1–90 proposed scale. In addition, three subjects were excluded since they were not able to discriminate among the 6 positions of sound in space perceiving at the same distance two or more consecutive sounds locations. In general, their sound perceived locations exceeded 2 standard deviations the group mean. For the remaining thirteen participants, to test if subjects actually perceived the sound source at different locations according to their spatial positions, a repeated measure ANOVA was run on the subjects'sound-localization judgments with Sound movement direction (IN and OUT) and Distance (15, 30, 45, 60, 75, 90) as within-subjects factors. Results indicated that participants perceived sounds at different positions in space and accordingly with their actual localizations [Distance: F (5, 60) ¼ 523.15, p o0.0001, mean 7SEM: actual position: 15 cm, perceived location: 17.88 71.37 cm; actual position: 30 cm, perceived location: 30.31 71.63 cm; actual position: 45, perceived location: 44.17 7 2.15 cm; actual position: 60, perceived location:¼ 63.367 2.33 cm; actual position: 75 cm, perceived location: ¼79.057 2.33 cm; actual position: 90 cm, perceived location:¼ 92.527 2.10], with no significant difference between IN and OUT sounds [Sound movement direction: F (1, 12) ¼0.061, p ¼0.80]. 3.2. Data pre-processing We calculated peak-to-peak amplitude (expressed in mV) of MEPs. MEPs exceeding 2 SD from the mean peak-to-peak amplitude, at the single subject level, as well as trials with EMG

pre-activation, were excluded from the data set. The remaining MEPs (92.07%, SD¼ 4.24%) were then averaged for each experimental condition separately for each subject and used for further analysis. First, we compared the amplitude of the MEPs recorded before (PRE) and after the experiment (POST) to exclude any general effect on cortical excitability due to TMS by means of a paired t-test. No difference was found between MEPs values recorded in these two baselines, PRE and POST (t ¼1.17; p ¼0.26), thus indicating that the overall excitability of the corticospinal system did not change over the course of the experiment. Then, we averaged the MEPs values of the two baselines in order to obtain the index of MEPs modulation (MEPi) induced by the sounds with respect to baselines. We calculated the ratio between the averaged MEPs recorded for each experimental condition (i.e. each sound position) and the averaged MEPs recorded at the baseline, multiplied by 100 (Serino et al., 2009). In this way, MEPi higher than 100% indicates an enhancement of corticospinal excitability with respect to the baseline, and vice versa for values lower than 100%. To assess the way in which the auditory moving stimuli affect the motor excitability depending on the sound distance from the hand and on the sound direction, we ran a repeated-measure ANOVA on MEPi values with Sound movement direction (IN and OUT) and Distances (15, 30, 45, 60, 75, 90) as within subject factors. 3.3. Modulation of cortical excitability The ANOVA on MEPi revealed a main effect of sound position on the cortical excitability [Distance: F (5, 60) ¼ 3.3 p ¼0.011]. As Fig. 2 shows, MEPi was higher when sounds were located at the three more proximal distances, i.e. 15, 30 and 45 cm, than when they were located at the other three more distal positions (60, 75, 90 cm). Post-hoc comparisons (Duncan, two-tailed) showed that MEPi for sounds located at 15, 30, and 45 cm were not different from each other (all p4 0.34). In contrast, MEPi at 15 cm was significantly enhanced with respect to the MEPi obtained at 60 (p ¼0.015), 75 (p ¼0.016) and 90 cm (p ¼0.016). Analogously, MEPi at 45 was significantly higher than those recorded at 60 (p ¼0.030), 75 (p ¼0.033) and 90 cm (p ¼0.033). Moreover, there was the same trend for MEPi obtained when the sound was at 30 cm (60: p ¼0.05, 75: p ¼0.05 and 90: p ¼0.05, one tailed). In addition, MEPi obtained at 60, 75 and 90 cm was not different from each other (all ps 40.97). This indicates that once a sound occurs within a distance o60 cm from the hand, it exerts an excitatory modulation over the hand motor representation with respect to sounds occurring further away. Second, no significant effect of the Sound movement direction was found (Sound movement direction: F (1,12) ¼1.24, p ¼0.28) (see Fig. 2), nor a significant interaction between the two main factors (Sound movement direction  Distances: F (5, 60) ¼ 1.14, p¼ 0.98). Thus, IN and OUT sounds exerted a similar effect on the hand corticospinal motor representation.

4. Discussion In the present study, we assess how an auditory stimulus moving toward or away from the body modulates the excitability of the hand corticospinal representation at rest. We found that the amplitude of MEPs recorded on FDI muscles when moving sounds were 15 away from the hand were similar to those recorded when the sounds were at 30 or 45 cm, but were greater respect to MEPs obtained when the sounds were located at 60, 75 or 90 cm from the recorded muscle. Differently stated, we found that the dynamic auditory stimuli moving within a limited space from

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Fig. 2. Spatial modulation of corticospinal excitability. The figure represents the mean indices of MEPs modulation (MEPi 7 se) for IN (red dots) and OUT sound (blue dots), on the ordinate, as a function of the sound positions (15, 30, 45, 60, 75, 90, on the abscissa). MEPi value (%) corresponds to the ratio between the averaged MEPs recorded in each condition and the averaged MEPs recorded in the baseline sessions (100%, dotted line). The sound position values represent the distances, in cm, from the subjects' hand. Mean MEPi value for the closest distance (15 cm) was significantly greater than the MEPi recorded in the furthest sound position (60, 75, 90 cm). No significant difference was found among MEPi recorded when the sounds were at the closest position (15 cm) and at the two adjacent locations (30 and 45 cm). Similarly MEPi at the three farthest positions (60, 75 and 90 cm) were comparable. These effects were independent of the direction of the moving sounds.

the body, that is o60 cm from the subjects' hand, modulate the hand motor excitability differently from stimuli delivered outside this boundary. This could correspond to the spatial limit within which the PPS representation anchored to the hand tunes the cortico-motor excitability related to the same body part. Importantly, this modulation did not depend from the sound movement direction; similar MEPs were recorded for approaching or receding stimuli. 4.1. A functional representation of the peripersonal space is encoded by the motor system In our study, we found that auditory stimuli moving in space enhance the excitability of the hand motor representation, in a very short time window, and only within a certain distance from the hand, specifically around 60 cm. This implies that stimuli presented along a spatial range encompassing different reachable positions determine motor activation as a function of where they are located with respect to the hand. In agreement with previous investigations in monkeys (Rizzolatti et al., 1997; Graziano and Cooke, 2006; Gallese and Sinigaglia, 2010), our results demonstrate that multisensory processing of stimuli near the hand is associated with the representation of potential motor acts within that space, extending beyond a position immediately close to the hand. This is in line with the view considering PPS as a motor space, therefore reflecting the potential actions directed toward the spatial locations where stimuli are presented (Rizzolatti et al., 1997; Coello et al., 2007; Gallese, 2007; Witt et al., 2005). Our findings extend and clarify the results by Serino et al. (2009) previously showing a motor facilitation induced by static auditory stimuli presented close to the body, i.e., within PPS, but not far from it. Crucially, in that work this spatial modulation acted with a definite time-course: near sounds enhanced the motor system in a very short time window, i.e. when the TMS pulse was

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delivered 50 ms after the sound onset. In contrast, later, (i.e. at 300 ms after the sound onset), the effect reversed, and far sounds were associated with higher MEPs. The authors suggested the differential effect (of near and far sounds on the motor system at the different temporal windows where TMS pulses were applied), could reflect the close temporal–spatial link between motor activation and stimulus position. In fact, the excitation of the hand representation found immediately after the stimulus onset can be associated to motor preparation toward near stimuli. The same effect related to far stimuli at 300 ms can be explained since at later temporal delays the far stimulus could potentially require a motor response. However, that was only a speculation, because in that paper static stimuli were administered and therefore it was not possible to study the effect due to the modulation of sound position in time. In contrast, in the present study, by using moving sounds we were able to capture the dynamics of the effects of stimuli at different distance from the hand in time. We found that even more distant stimuli, i.e. up to 60 cm, are effective in triggering immediate motor activation in a very short time delay (50 ms), as long they occur as within the space where the hand can potentially act. Another recent study investigating the sensory-to-motor coding of the space near the hand (Makin et al., 2009) suggested that the proximity of a visual stimulus with respect to the hand elicits a motor system modulation. In this case corticospinal excitability, within a short time interval (70–80 ms) decreased when a task irrelevant visual stimulus appeared close (but not far) to a hand engaged in a motor task (Makin et al., 2009). That cortical suppression seems due to an inhibition of the avoidance movement emerged when the stimulus approaches the responding hand because of a different response required by the on-going motor task (Boulinguez et al., 2008; Coxon et al., 2007). This hypothesis was corroborated by a control experiment, in which no fixed motor responses were asked from the participants. In the case of no explicit motor preparation, a near hand visual stimulus induced higher MEPs as compared to a far stimulus. Altogether these previous studies suggested that the position and the timing of the modulation exerted by external stimuli on the hand motor representation depends on the position of stimuli in space (i.e. at the hand location or far) and the current state of the motor system (i.e. rest versus motor response). In line with this, a recent study demonstrated that motor recruitment induced by the sight of an object implying a hand affordance (i.e. a cup with a handle) is modulated by the distance of the object with respect to the observer (Cardellicchio et al., 2011; Costantini et al., 2010). However, even if a static object can afford a grasping, a priori it does not imply an immediate contact as in the case of moving stimuli inducing a fast sensorimotor interaction. In fact, approaching or receding stimuli from the body immediately triggers the activation of our motor system, as when a bee is approaching during sunbathing, or when we need to reach an object flying away from our body. By using moving stimuli in space with respect to the hand position, the present study contributes shedding light into the nature of a spatially dependent modulation of the motor system by reproducing an ecologically plausible set up. Our findings provide a measure of the distance at which dynamic stimuli affects the cortical motor system. Interestingly, this spatial limit, i.e. about 60 cm, roughly corresponds to the same boundaries previously detected in a perceptual task as the distance at which dynamic sounds speed up the detection of a tactile stimulus on the hand, which was considered as the boundary of multisensory PPS (Canzoneri et al., 2012, 2013). Here we found that once stimuli are within PPS representation, i.e. have overcome those boundaries, then the relative position of sounds in front of the body did not further affect the motor excitability, suggesting

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that the PPS is perceived as a homogenous sector of space. The present neurophysiological data are coherent with the previous behavioral findings, given that no differences were found between the facilitation effect induced on reaction times to tactile stimuli by sounds administered at consecutive location within the PPS (Canzoneri et al., 2012). Thus, both cortico-motor facilitation and speeding effect on tactile detection due to the moving sounds seem to be constrained to the same spatial limit, and not to change linearly as a function of the distance. This indicates that the space around the hand is not represented in absolute metric, but rather as two different homogenous sectors, i.e. the space near the hand, the PPS, and the far space. One can hypothesize that the boundary found here between PPS and the far space would be related to participants' body metric in line with previous findings demonstrating that there is a systematic relation between the size of near space and the arm length (Longo and Lourenco, 2007). If so, it is possible that this border is also affected by manipulating the reachability, such as positioning the hand at different distances from the body or by assuming postures implying a different degree of motor preparation (e.g. opened versus closing hand) (Cardellicchio et al., 2011). However, these aspects have not been investigated in the present study and could be the aim of further investigations. In sum, the early facilitation of hand motor cortex we found here for moving auditory stimuli presented in several positions close but not far from the hand may have the function of preparing an immediate motor response for stimuli occurring within the whole working space around the hand. 4.2. The motor facilitation induced by auditory stimuli within PPS is independent of sound direction The use of dynamic stimuli allows disentangling if this mapping of the sensory representation of space onto the motor system primes defensive or approaching motor behaviors. Moving stimuli are indeed particularly important for the sensory-motor system as they might refer to potential threats, looming towards the body, or to receding objects we might want to catch. Interestingly, in the present study we obtained the same spatial modulation over corticospinal excitability for both approaching and receding sounds. This effect was partially surprising, if one considers that processing approaching information can be more relevant rather than that of receding stimuli, since the former may require rapid defensive responses. This hypothesis is supported by previous reports in monkey (Schiff et al., 1962) and in humans (Ball and Tronick, 1971; Neuhoff, 1998; Regan and Beverley, 1978; Seifritz et al., 2002; Vagnoni et al., 2012), showing that time-to-contact of looming stimuli and associated motor response is underestimated as compared to non-looming stimuli. In line with this hypothesis, also in the context of PPS representation, in the behavioral study performed by our group (Canzoneri et al., 2012), we found that, although both approaching and receding auditory stimuli modulated tactile detection accordingly to the sound position in space, approaching sounds had a stronger spatially dependent effect. Neurophysiological data in monkeys also confirm that the responses evoked in PPS neurons by approaching stimuli are usually stronger that those induced by receding stimuli (Colby et al., 1993; Duhamel et al., 1997; Fogassi et al., 1996; Maier et al., 2004). Further, fMRI studies in humans highlight a greater BOLD response in parietal and premotor areas in response to approaching as compare to receding visual and auditory stimuli (Bremmer et al., 2001). However, in the present study, we recorded the activity from the spinal tract, originating from the primary motor cortex, and we found no difference between approaching and receding sounds. Several factors can contribute to this null effect. First, it may be the case that an approaching-receding difference can be described at

behavioral level, or in associative areas, whereas in term of corticospinal excitability approaching or receding stimuli are equally mapped. The enhanced activity in the motor system that we found for both type of stimuli whenever close to the body reflects the functional role of PPS in everyday life. In monkeys, previous studies support this hypothesis showing that neurons encoding PPS are also involved in guiding both movements toward targets (Rizzolatti et al., 1997) or avoidance of obstacles or fast defensive responses (Cooke et al., 2003; Graziano and Cooke, 2006). While the stimuli direction can have a specific salience at higher associative level (e.g. Seifritz et al., 2002), the position of the stimulus per se rather, than its direction, can be crucial in modulating the activation of the motor system. Second, we cannot exclude the possibility that, by recording MEPs at further delays after TMS pulse, a difference between approaching and receding sounds could emerge. For instance, Serino et al., (2009) and Avenanti et al. (2012) found a differential modulation of MEPs induced by near and far sounds with TMS delays of 50 ms or 300 ms. However, that manipulation is possible only with static stimuli and cannot be implemented in the present design, because with the present setup higher temporal delays correspond to different positions of the moving sounds in space. Further, one can consider that MEPs and Reaction Times (RTs), as those recorded by Canzoneri et al., (2012), are different processes output, requiring dissimilar stages of information processing. It could be that the direction of the movement of an object is coded in a following stage thus influencing RTs measures, which are more cognitively mediated than the MEPs. Therefore, PPS representation can show specific features underlying a multisensory and motor elaboration of the nearby inputs, respectively. These speculations are in keeping with previous suggestions considering the possibility of “a specific remapping of multisensory perception within PPS representation as a function of the action requirements” (Brozzoli et al., 2010) (i.e. in perceiving or in responding with movements toward an object). Therefore, at a neural level, a different involvement of the fronto-parietal areas in multisensory and motor elaboration of the nearby inputs can be hypothesized. Altogether previous works suggested that the ventral premotor cortex (vPMC) is recruited in the spatial dependent modulation of both multisensory (audiotactile) interaction and motor activation (Avenanti et al., 2012; Serino et al., 2011), while the posterior parietal cortex (PPC, Brodmann's area 40) mediates the multisensory (Serino et al., 2011) but not the motor coding of near information (Avenanti et al., 2012; see Rossit et al. (2013), for a role of superior parietooccipital cortex in processing visual information for the control of arm movements). This possible dissociation at a neural level further puts forward a differentiation between a higher-level multisensory elaboration and a lower motor coding of objects' spatial features, which may explain the present different sensitiveness to movement direction. At last, approaching or receding stimuli may induce different effects depending on body limbs function to which PPS is anchored. For instance, while hands are constantly involved in approaching or defensive behaviors, other body part like the face enters in contact with external stimuli only when close to it. In line with this hypothesis, Teneggi et al. (2013) found that only approaching, and not receding, sounds modulate RTs to tactile stimuli administered on the face, differently from the case of hand stimulation. Thus, a multisensory representation of the space around the hand may have a particular selectivity for receding sound, differently from the representation around other body parts, because, usually approaching movements toward interesting objects are performed with the hand, rather than with other body parts (e.g. the head or the chest, see for instance Noel et al., 2014). Sensitivity to receding sound for the hand PPS system is partially

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evident at higher associative level, but it is particular evident in terms of motor system modulation.

5. Conclusion Our study is the first work assessing how spatial and directional features of a moving auditory stimulus can directly modulate corticospinal excitability within PPS representation. By using single pulse TMS and MEP recording as a probe of excitability of the hand corticospinal tract, we were able to directly evaluate how sensory information placed at different distances from the hand, along a continuum spanning near and far space, modulates the motor system. Findings highlight an excitatory modulation over the hand motor representation when sounds occur at different distances inferior to 60 cm from the hand with respect to sounds occurring further away. This boundary might correspond to the representation of PPS mapped into the primary motor cortex. Importantly, approaching or receding stimuli, whenever located within PPS, are equally relevant for the motor system. Such findings support the existence of a functional link between PPS space coding and the motor system activity in healthy humans.

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Moving sounds within the peripersonal space modulate the motor system.

Interactions between ourselves and the external world are mediated by a multisensory representation of the space surrounding the body, i.e. the peripe...
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