Vestibular Cognition [1 ed.] 9789004342248, 9789004342231

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Vestibular Cognition

Vestibular Cognition Edited by

Elisa R. Ferrè and Laurence R. Harris

LEIDEN • BOSTON 2017

Originally published as Volume 28, No. 5–6 (2015) of Brill’s journal Multisensory Research. Cover image: M.C. Escher’s “Relativity” © 2016 The M.C. Escher Company B.V. - Baarn The Netherlands. All rights reserved. www.mcescher.com Cover design by Celine van Hoek. The Library of Congress Cataloging-in-Publication Data is available online at http://catalog.loc.gov LC record available at http://lccn.loc.gov/

ISBN 978-90-04-34223-1 (hardback) ISBN 978-90-04-34224-8 (e-book) Copyright 2017 by Koninklijke Brill NV, Leiden, The Netherlands. Koninklijke Brill NV incorporates the imprints Brill, Brill Hes & De Graaf, Brill Nijhoff, Brill Rodopi and Hotei Publishing. All rights reserved. No part of this publication may be reproduced, translated, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission from the publisher. Authorization to photocopy items for internal or personal use is granted by Koninklijke Brill NV provided that the appropriate fees are paid directly to The Copyright Clearance Center, 222 Rosewood Drive, Suite 910, Danvers, MA 01923, USA. Fees are subject to change. This book is printed on acid-free paper and produced in a sustainable manner.

Contents Preface E. R. Ferrè and L. R. Harris

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Prediction in the Vestibular Control of Arm Movements J. Blouin, J.-P. Bresciani, E. Guillaud and M. Simoneau

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The Components of Vestibular Cognition — Motion Versus Spatial Perception B. M. Seemungal

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Gravity in the Brain as a Reference for Space and Time Perception F. Lacquaniti, G. Bosco, S. Gravano, I. Indovina, B. La Scaleia, V. Maffei and M. Zago

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Contribution of Bodily and Gravitational Orientation Cues to Face and Letter Recognition M. Barnett-Cowan, J. C. Snow and J. C. Culham

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Internal Models, Vestibular Cognition, and Mental Imagery: Conceptual Considerations F. W. Mast and A. W. Ellis

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The Effects of Complete Vestibular Deafferentation on Spatial Memory and the Hippocampus in the Rat: The Dunedin Experience P. F. Smith, C. L. Darlington and Y. Zheng

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Making Sense of the Body: the Role of Vestibular Signals C. Lopez

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Vestibular–Somatosensory Interactions: A Mechanism in Search of a Function? E. R. Ferrè and P. Haggard

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Disrupting Vestibular Activity Disrupts Body Ownership A. E. N. Hoover and L. R. Harris

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Beyond the Non-Specific Attentional Effect of Caloric Vestibular Stimulation: Evidence from Healthy Subjects and Patients G. Bottini and M. Gandola

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Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration M. Kaliuzhna, D. Vibert, P. Grivaz and O. Blanke

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Vestibular Function and Depersonalization/Derealization Symptoms K. Jáuregui Renaud

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The Moving History of Vestibular Stimulation as a Therapeutic Intervention L. Grabherr, G. Macauda and B. Lenggenhager

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Index

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Preface Elisa R. Ferrè 1,2,∗ and Laurence R. Harris 3,∗ 1

Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London, WC1N 3AR, UK 2 Department of Psychology, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK 3 Centre for Vision Research, York University, 4700 Keele St, Toronto (ON), M3J 1P3, Canada

“How many senses do you have?” Most of us would probably respond with the traditional five senses we were taught in school: sight, hearing, smell, taste and touch. However, there is an additional sensory modality that is significantly involved in almost all our behaviours. The vestibular system is a sophisticated set of organs located in the inner ear. It comprises the semicircular canals, which detect rotational accelerations of the head in three-dimensional space (i.e., pitch, yaw and roll), and the otolith organs (utricle and saccule), which code translational acceleration, including the orientation of the head relative to gravity. Together these signals provide continuous information to the brain that can be used to update body position and to maintain orientation in the surrounding space. Most scientists consider the vestibular system as an organ specialized for balance, orientation and the control of eye movements. However, the vestibular system is always on and turns out to be involved in almost all our interactions with the external world in ways that go far beyond these fundamental reflexes. Vestibular signals have extensive projections throughout the cerebral cortex and cerebellum, including areas traditionally considered as visual, somatosensory, motor, memory-related and affective. Knowledge of this extended vestibular network comes from neuroimaging studies of the effects of artificial vestibular stimulation, achieved by applying transmastoidal electric current or caloric ear irrigation. Both methods of artificially stimulating the vestibular system can reduce symptoms of various neuropsychological, *

To whom correspondence should be addressed. E-mail: [email protected]; [email protected]

© Koninklijke Brill NV, Leiden, 2017

DOI:10.1163/9789004342248_002

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neurodevelopmental and neurodegenerative disorders, consistent with the idea that vestibular signals can potentially influence any process that involves reference to external space. However, the vestibular system has long been neglected in basic science. The absence of any obvious conscious sensation associated with vestibular signals has led to the unwarranted assumption that vestibular processing is automatic, and makes no contribution to conscious mental life. Over the last decade, emerging studies have demonstrated that sensory information provided by the vestibular system is deeply involved in several cognitive processes. This book, contains reviews and original articles focusing on the vestibular system’s effects on higher cortical function and seeks to provide a comprehensive overview of the key findings on vestibular cognition. Here we treat the vestibular system not only as an autonomic system for governing selfmotion, but also as a system that potentially contributes to higher cognition, behavioural control and well-being. In this book, we distinguish specific cognitive sub-functions and highlight how basic vestibular input contributes to each. The broad range of these functions is consistent with the broad spread of vestibular projections throughout the cortex. In particular, the vestibular contribution to cognition can be divided in three main functional components. First, a sensorimotor component which includes pathways for the sensory integration and perceptual responses of vestibular, visual, proprioceptive and somatosensory information. Second, a spatial component which includes pathways for spatial navigation, decision making, spatial orientation, attention and higher cognitive behaviours. Third, a bodily-self component which includes pathways for the integration of information regarding ongoing sensory processes relative to the current state of the body. This book considers each of these components. Vestibular signals are fundamental to higher sensorimotor control. As reviewed by Blouin, Bresciani, Guillaud and Simoneau, moving an arm during body motion requires compensatory movements that rely on efficient vestibulomotor transformations. Critically, such transformations cannot be considered as reflexes, rather they appear to be influenced by vestibular-based predictive mechanisms to counteract the disruptive effect that body motion would otherwise introduce. Seemungal further shows how self-motion perception is decoupled from the more reflex aspects of vestibular functioning. Under normal circumstances, the vestibular system supplies a signal that has been shown to play a fundamental role in spatial cognition. Combining vestibular signals about the head’s orientation relative to gravity with other proprioceptive information about head position relative to the body provides sufficient information to map body position onto the ground surface. This could explain how gravity influences our spatial orientation as summarized by Lacquaniti, Bosco, Gravano, Indovina, La Scaleia, Maffei and Zago.

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Accordingly, Barnett-Cowan, Snow and Culham demonstrate that the recognition of faces and letters is influenced by both gravity and body orientation. Mast and Ellis suggest a systematic computational approach to providing a coherent framework for investigating such vestibular contribution to spatial transformations. Evidence of the effect of bilateral vestibular deafferentation on spatial memory is reviewed by Smith, Darlington and Zheng highlighting the vestibular contribution to neural-cognitive maps of environmental, navigational space, possibly located in the hippocampus and parietal regions, confirming the vestibular contribution to the brain’s Global Positioning System. The vestibular system also contributes to high-level bodily perception, such as the sense body ownership, the sense of being located within the body, and the anchoring of perspective to the body, as reviewed by Lopez. Ferrè and Haggard focus on the interaction between vestibular and bodily somatosensory signals. They proposed that the target of such interactions is a form of self-representation, which is important to link the spatial description of one’s own body to the spatial description of the outside world. Original results by Hoover and Harris show that disruptive artificial vestibular stimulation affects the sense of body ownership, altering the boundaries between self and others. Clinical observations in brain-damaged patients confirm the essential role of vestibular signals in maintaining a coherent self-representation. Bottini and Gandola summarize the effects of artificial vestibular stimulation on impaired bodily awareness. Even more dramatically, vestibular dysfunction contributes to autoscopic phenomena, such as the impression of seeing one’s own body in extrapersonal space. Out-of-body experiences, in which patients localise the self outside their own body and experience seeing their body from this disembodied location, were attributed to failures in integrating multisensory bodily information due to conflicting visual and vestibular information. Kaliuzhna, Vibert and Blanke analyse the behaviour of a patient with vestibular damage when presented with out-of-body experiences. They describe abnormalities in visuo-vestibular and visuo-tactile integration that have previously been shown to experimentally induce out-of-body illusions. Additionally, vestibular damage can produce psychiatric-like symptoms of depersonalisation, defined as ‘subjective experience of unreality and detachment from the self ’, and derealisation, ‘the experience of the external world appearing strange or unreal’. Jauregui-Renaud proposed that depersonalization/derealisation are a consequence of a sensory mismatch between disordered vestibular input and other sensory signals of orientation. It has been recently suggested that artificial vestibular stimulation may be adopted as rehabilitation technique. Critically, Grabherr, Macauda and Lenggenhager reviewed the existing literature on vestibular stimulation as a form of therapy for a range of psychiatric, neurological and neurodevelopmental conditions and presented its successes and drawbacks.

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These studies and reviews confirm the vestibular system as playing a fundamental and hitherto largely unsuspected role in almost all aspects of cognition. We hope that this collection will provoke the same enthusiasm in you it did in us.

Prediction in the Vestibular Control of Arm Movements Jean Blouin 1,∗ , Jean-Pierre Bresciani 2,3 , Etienne Guillaud 4 and Martin Simoneau 5 1

Laboratory of Cognitive Neuroscience, CNRS, Aix-Marseille University, FR 3C 3512, Marseille, France 2 University of Fribourg, Department of Medicine, Fribourg, Switzerland 3 LPNC, University Grenoble Alpes and CNRS, F-38000 Grenoble, France 4 CNRS and University of Bordeaux, UMR 5287 INCIA, Bordeaux, France 5 Faculté de Médecine — Département de Kinésiologie, Université Laval and Centre de recherche du CHU de Québec, Québec, QC, Canada

Abstract The contribution of vestibular signals to motor control has been evidenced in postural, locomotor, and oculomotor studies. Here, we review studies showing that vestibular information also contributes to the control of arm movements during whole-body motion. The data reviewed suggest that vestibular information is used by the arm motor system to maintain the initial hand position or the planned hand trajectory unaltered during body motion. This requires integration of vestibular and cervical inputs to determine the trunk motion dynamics. These studies further suggest that the vestibular control of arm movement relies on rapid and efficient vestibulomotor transformations that cannot be considered automatic. We also reviewed evidence suggesting that the vestibular afferents can be used by the brain to predict and counteract body-rotation-induced torques (e.g., Coriolis) acting on the arm when reaching for a target while turning the trunk. Keywords Vestibular information, body motion, reaching movement, deafferented patient, Coriolis, biomechanical model

1. Introduction Our sensory systems underlie our perception of our own body and of its interaction with the external word. Yet, the role played by afferent signals, arising *

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_003

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for instance from visual, somatosensory and vestibular receptors, goes far beyond perceptual-related processes. In particular, sensory signals provide rich and reliable information for the motor system to plan and control goal-directed movements, such as those that we frequently perform with the hand. In their simplest description, these movements consist in transforming information related to the spatiotemporal goal of the movement into appropriate motor commands. Because many of our daily arm movements are directed towards visual objects or specific regions of our body, a substantial amount of research has focused on the neural processes responsible for converting visual (Beurze et al., 2007; Blouin et al., 2014; Burnod et al., 1999; Reichenbach et al., 2009, 2011) or proprioceptive (Bernier et al., 2007, 2009; Reichenbach et al., 2014; Van Beers et al., 2002) signals into motor commands. However, there are several situations in which sensory inputs related to body motion in space are important to control arm movements. This is the case for instance when filling a glass at the tap while rotating the trunk or when trying to balance a serving tray of filled glasses while turning the trunk. In these examples, in order to achieve the intended motor task (i.e., fill the glass or keep the glass upright), the brain must generate compensatory hand movements with the same velocity but in the direction opposite to body, and these compensatory movements must occur quickly. Here we review work performed by our group as well as by others showing that the control of arm movements during body motion involves, especially during passive displacements, the processing of vestibular signals. Several of the reviewed studies were specifically designed to provide insight into the nature of this vestibular control of arm movement. Other aspects of the control of arm movements have already been reviewed in the literature and will not be considered here (see for instance, Avella and Lacquaniti, 2013; Desmurget and Grafton, 2000; Desmurget et al. 1998; Khan et al., 2006; Shadmehr et al., 2010). Together, the studies reviewed here suggest that the compensatory arm movements produced during body motion rely on rapid and efficient vestibulomotor transformations but cannot be considered as being automatic in nature. These sensorimotor transformations appear to be under the influence of vestibular-based predictive mechanisms which would allow the central nervous system to counteract the detrimental effect of motion-induced torques (e.g., Coriolis) on the hand position and trajectory during body motion.

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2. Integration of Vestibular and Cervical Information to Code Trunk Motion The vestibular system is a good candidate for providing body motion information to the arm motor system during self-motion. This is because signals from the semicircular canals and otoliths convey information about angular and linear head velocity with respect to the external environment (after integration of the acceleration stimulus due to the mechanics of the vestibular system — Goldberg and Fernandez, 1975). However, in order to generate appropriate compensatory arm movements during whole body motion, the brain needs to be informed about trunk motion rather than head motion. Indeed, rotating the head while the trunk remains stationary would have no effect on the position or motion of the arm. Thus, vestibular information alone would be insufficient to control arm movements. One mechanism by which the brain could be informed about trunk motion in space is through the combination of vestibular and neck proprioceptive signals (Ali et al., 2003; Blouin et al., 2007; Cohen, 1961; Ivanenko et al., 1999; Mergner et al., 1983). The importance of cervical afferents for coding trunk displacements has been notably evidenced in studies with deafferented patients. In previous experiments, we tested a rare patient (GL) with a largefiber sensory neuropathy that resulted in a severe loss of position sense from the nose down to the feet, thus including the cervical region (see Forget and Lamarre, 1995 for a detailed clinical description of this patient). Despite a normal vestibular system (as attested by vestibulo-ocular reflex assessment), the accuracy with which this patient determined the magnitude of passive body rotations in the dark was largely deteriorated when compared to healthy control participants (Blouin et al., 1995). More specifically, the patient showed large overestimation of body rotations that might suggest improper calibration at the perceptual level of the vestibular inputs. In healthy subjects, this calibration could involve neck proprioception because it provides reliable information about changes in head-to-trunk positon during and after head rotations (Blouin et al., 1998a, b; Mergner et al., 1991; Nakamura and Bronstein, 1995). But, the most compelling demonstration of the critical role of neck proprioceptive input to code trunk motion stemmed from the patient’s large increase of body oscillations when her head was rotated ∼50° about the yaw axis while she was seated (without seat back) with her eyes closed (Blouin et al., 2007, see Fig. 1). In this experiment, in order to weaken head motion perception through vestibular inputs, the patient’s head was slowly rotated (50° in ∼15 s, rotation mostly sub perceptual threshold). With the head subliminally turned towards her shoulder, and with the lack of neck proprioception, the vestibular signals elicited during body oscillations did not provide veridical information about her trunk displacements in space (note that with the eyes closed, body oscil-

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Figure 1. Mean center of pressure (CoP) displacement over time exerted on the platform on which the deafferented subject was seated in the different experimental conditions. The patient’s stability was considerably deteriorated when she had the head unconsciously turned towards her shoulder. Figure adapted from Blouin et al. (2007).

lations were much larger in the patient than in the control healthy subjects). The fact that the postural responses were based on head motion rather than on trunk motion likely led to a series of inappropriate postural adjustments with respect to the actual patient’s body oscillations resulting in the observed increase of body sway. 3. Vestibular Information: an Important Input Signal to Control Arm Movement Direct evidence that goal-directed arm movements are under the online guidance of vestibular information was obtained in studies that stimulated the participants’ labyrinths at the onset of reaching movements towards earthfixed memorized visual targets (Bresciani et al., 2002a; Mars et al., 2003). In these studies, the stimulations were produced using bipolar galvanic vestibular stimulations (GVS, see Fitzpatrick and Day, 2004) and, depending on the paradigm used, participants’ trunk remained either stationary (Bresciani et al., 2002a) or moved forward to accompany the manual reaching (Mars et al., 2003). When GVS simulated leftward body motion (i.e., cathode left), the hand trajectory deviated to the right (Fig. 2). In contrast, left hand deviation was observed when the cathode was located on the right side. The direction of hand deviations provided strong indications that the change in hand trajectory, which occurred ∼250 ms after GVS onset in Bresciani et al. (2002a), constituted a response delivered by the arm motor system to compensate for a vestibular-evoked illusory displacement of the body. More specifically, the hand deviation observed during the illusory displacement likely aimed at preserving the planned hand-in-space trajectory unaltered. Remarkably, in the study of Bresciani and colleagues (Bresciani et al., 2002a), all sensory af-

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Figure 2. Mean hand directions measured every 50 ms when subjects reached for a memorized visual target located straight-ahead in darkness (0° in the graph). At the onset of the movement, a 3 mA rectangular, unipolar binaural direct electric current stimulated the vestibular system (using electrodes on the mastoid processes). The anode could be either located on the left or the right side (stimulating the right and left labyrinth, respectively). Dashed lines indicate the time at which hand directions recorded in both conditions became significantly different. The data were normalized with respect to those recorded in a control condition without GVS. Negative and positive normalized directions, respectively represent left and right deviations from mean control trajectories. Figure from Bresciani et al. (2002a) with kind permission of Elsevier.

ferents but the GVS-induced vestibular input informed the brain about body stability (a bite-board prevented head and body motion). This irrefutably confirmed the powerful influence of vestibular information to the control of spatially-oriented arm movements. More recently, Moreau-Debord and colleagues (2014) showed that this GVS effect on hand trajectory was modulated by head orientation, consistent with a transformation of the vestibular cues from head-centered to body centered reference frame. The fact remains, however, that the deviations of hand path observed in previous studies after GVS do not provide definitive information about subjects’ ability to process vestibular information to preserve reaching accuracy. A method that can be used to challenge the capacity of the brain to process vestibular information to accurately control arm movement consists in asking individuals submitted to passive whole-body displacements in darkness to continuously point at a remote memorized target or to stabilize the hand in space during these displacements. The advantage of this procedure is twofold. Because passive body displacement can be easily measured and quantified in terms of direction, speed, and amplitude, it allows for establishing whether the arm motor response accurately compensates for body displacements. The other important advantage is that, in the absence of visual feedback, the vestibular information obtained during passive body motions appears as the only sensory cue that can be used to generate appropriate compensatory arm movements. Indeed, although passive body motion stimulates a panoply of

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sensory receptors (e.g., cutaneous mecanoreceptors and graviceptors embedded in the abdominal viscera (Mittelstaedt, 1992, 1995), somatosensory input resulting from motion of the arm due to inertial forces), it is unlikely that inputs from non-vestibular receptors can provide precise information about spatiotemporal characteristics of body motion. All previous studies that used passive body motion highlighted the capacity of individuals to stabilize their hand (or pointer) in space during body motion in darkness (Blouin et al., 2010; Bresciani et al., 2005; Frissen et al., 2011; Guillaud et al., 2006a; Ivanenko and Grasso, 1997; Ivanenko et al., 1997a, b; Philbeck et al., 2001; Schomaker et al., 2011). Even more remarkably perhaps, individuals who undergo whole-body rotations while reaching for an earth-fixed memorized target can modulate online the hand trajectory to preserve reaching accuracy. This is illustrated in Fig. 3, taken from Bresciani et al. (2002b), showing the mean hand trajectories produced by one participant submitted to 40° counterclockwise (CCW) or 40° clockwise (CW) rotations at the onset of reaching movement towards a memorized target located at 20°. The reaching trajectories are compared to the trajectory observed in a control condition where the participant was not rotated during reaching. The body rotations, which were produced by a motorized chair, had Gaussian velocity profile to simulate natural self-generated head rotations (Blouin et al., 1998a; Guitton and Volle, 1987). The figure shows the 2D hand trajectories in space (Fig. 3A) and with respect to body midline (egocentric view, Fig. 3B). It can be seen that hand trajectories in space remained similar in conditions with or without body rotations (trajectories from all conditions are superimposed in space). The preserved spatial constancy resulted from egocentric hand paths (i.e., with respect to body midline) that were markedly different depending on rotation direction (Fig. 3B). 4. Vestibulo-Manual Control: a Sensorimotor Process Largely Independent of Cognitive Factors Vestibular information is known to be involved in spatial updating (cognitive process) and in the control of movement (sensorimotor process). Two distinct mechanisms could then underlie the vestibular control of arm-reaching movements during body rotation. First, the compensatory arm movements could result from a continuous updating of the internal representation of the bodytarget relative position during self-motion. Alternatively the arm movement could stem from a more direct sensorimotor transformation between vestibular input and arm motor commands. We conducted a series of experiments to determine which of these two alternatives was more likely to explain the reaching adjustments observed during body rotations.

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Figure 3. Mean hand trajectories produced by a subject when reaching for a 20° memorized visual target in a condition without body rotation, and in conditions with body rotations during the reaching movements (40° CW and CCW rotations). The same trajectories are represented in an earth-fixed reference frame (A) and in the subject’s reference frame (B). Figure taken from Bresciani et al. (2002b) with kind permission of Wolters Kluwer Health.

In one of these studies, we used an original procedure in which we separately and specifically adapted (i) the vestibular-based spatial updating and (ii) sensorimotor processes (Bresciani et al., 2005). We then tested whether these modifications transferred to (i.e., impacted) the compensatory arm movements observed during body motion. Our rationale was that if a given process underlies a given behavior, any adaptive modification of this process (here either the cognitive or sensorimotor process) should give rise to observable modification of the behavior (here, the compensatory arm movements during body rotation). The specific methods used to produce these adaptive modifications are too lengthy to be detailed here. Full details of each adaptive procedure can be found in the original paper (Bresciani et al., 2005). Briefly, adaptation of the vestibular-based updating process aimed at modifying the matching between vestibular input and the perceived amplitude of body rotation in space. More specifically, the purpose of the procedure was to make the subjects underestimate the amplitude of body rotation. Adaptation of the vestibular-based sensorimotor process (referred here as the vestibulomotor process) aimed at modifying the matching between vestibular input and the arm motor commands that allow keeping the hand stable in space during body rotation. More specifically, the goal of the vestibulomotor adaptation was to reduce the gain of the transfer function between vestibular input and arm motor output. Importantly, both adaptive procedures proved to be efficient in bringing adaptive modifications to their targeted process. In other words, after the adaptation of the vestibular-based spatial updating, participants underestimated body rotation amplitude. After the adaptation of the vestibulomotor process, the amplitude of the arm movements produced during body rotation was insufficient to stabilize the hand-in-space during body rotations. After each adaptive proce-

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Figure 4. Mean hand trajectories produced by a subject during 20°, 30° and 40° body rotations in the pre and post blocks of the sensorimotor adaptation condition. The adaptation of the vestibulomotor transformation markedly impacted the trajectories of reaching movements performed during passive body rotations. Figure taken from Bresciani et al. (2005) with kind permission of Springer Science+Business Media.

dure, the subjects had to reach for a memorized earth-fixed target during passive CCW body rotations in darkness. The adaptation of the vestibular-based spatial updating process had no effect on the compensatory arm movements (i.e., hand trajectories and reaching endpoints were both similar before and after the adaptation). However, adaptation of the vestibulomotor process brought significant changes in the compensatory arm movements during the rotations. This can be seen in Fig. 4 that shows the mean hand paths recorded in a subject when reaching for a 10° target during 20°, 30° and 40° counterclockwise rotations, both before and after adaptation of the vestibulomotor processes. The hand paths produced during body rotations were markedly deviated to the left after adaptation (solid lines, indicating undercompensation for the CCW body rotation) compared to those produced before adaptation (broken lines). Together, these results are in line with the suggestion that during passive selfmotion, the vestibular control of arm-reaching movements essentially derives from a sensorimotor process by which arm motor output is modified on-line to preserve hand trajectory in space despite body displacement. These results also suggest that, in contrast, the updating process which maintains up-to-date the egocentric representation of the visual space during body motion contributes little to the arm motor compensation during body rotations.

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Figure 5. EMG response times (pectoralis major and posterior deltoid muscles) with and without prior information about arm movement direction when the goal of the movement was to stabilize the hand during body rotation (‘Vestibular’ and ‘Combined’ conditions) or to track the moving target with the finger (‘Visual’ condition). Providing advance information had no effect on the latency of the muscular activities responsible to keep the hand stationary during body rotations but largely reduced electromyographic (EMG) response times during visually-tracking arm movements. Figure taken from Blouin et al. (2010) with kind permission of Wolters Kluwer Health.

The limited contribution of cognitive processes in the vestibular control of arm movements was further evidenced in a study in which we provided advance information to the subjects about the direction of the required arm movement to keep the (unseen) hand stationary in space during passive wholebody rotation (Blouin et al., 2010). Providing either true or false information about the required movement direction had no effect on the latency of the arm motor response [the first burst of electromyographic (EMG) activity was observed ∼160 ms after body rotation onset]. This was the case regardless of whether an earth-fixed visual anchor for the finger was displayed or not during body rotation (conditions ‘Combined’ and ‘Vestibular’, respectively in Fig. 5). This contrasted with the marked effect of providing advance information about the future direction of a moving visual target that the subjects had to track with the unseen finger (a task that is considered to depend largely on cognitive processes (Masson et al., 1995; Mrotek et al., 2006; Poulton, 1981)). In this visuo-manual tracking task, the pre-cue on movement direction reduced EMG response time by ∼120 ms (condition ‘Visual’ in Fig. 5). It is worth noting that the required horizontal arm movement with respect to the trunk was the same (i.e., amplitude and speed) in this manual tracking task and in the body rotation condition during which participants had to maintain the hand stationary in space.

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Even more surprisingly, in 86% of the trials of the visuo-manual tracking task in which the subjects received false pre-cues about the future movement direction, a burst of EMG activity appeared first in the antagonist muscle, i.e., the muscle moving the arm in the direction congruent with the false pre-cues, but opposite of the direction of the target that the subjects had to track. This effect of the false pre-cues was seldom observed when the subjects had to keep the hand stationary in space during body rotation. It is worth noting that the EMG response time recorded in the visuo-manual tracking task with no precueing (i.e., ∼350 ms) was more than twice as long as those observed when subjects had to stabilize the hand in space during body rotation (i.e., ∼165 ms). Importantly, tested in the same paradigm, the deafferented patient GL showed EMG response times that closely matched those recorded in healthy subjects (see Fig. 6). This result strongly hints at a vestibular origin (rather than at a proprioceptive) to the compensatory arm movements observed during body rotations. Taken together, these results suggest that the vestibular control of arm movements is more immune to cognitive processes than visually driven tracking arm movements. This distinction between vestibular and visual control of movements was also evidenced by Barnes and Paige (2004) for the control of eye movements and by Guerraz and Day (2005) for the control of balance. Performing a motor task that is largely controlled by automatic processes is known to have little or no effect on the performance of a simultaneously performed task which involves other effectors (Ehrenfried et al., 2003; Fleury et al., 1994; Lajoie et al., 1993; Teasdale and Simoneau; 2001; Yardley et al., 1999, 2002). We exploited this well-known phenomenon to assess the automatic nature of the vestibular control of arm movement by comparing the amount of interference of reaching movements performed with or without whole-body rotations on a concurrent cognitive task (Guillaud et al., 2006b). This cognitive task consisted of responding verbally as fast as possible to an auditory stimulus (50 ms beep). We found that the reaction times to the auditory stimulus was ∼120 ms longer when participants were rotated during reaching movements than when they remained stationary. Note that we also observed that the reaction times to the stimulus were ∼40 ms longer when subjects were submitted to passive body rotations without concurrent reaching movement compared to the condition without the rotation and reaching movement. This reaction time increase may be due to the massive flow of whole-body motion-related information reaching the brain (e.g., from labyrinths, skin, body graviceptors) while subjects were processing and responding to the auditory stimulus. More importantly, the larger reaction time increase observed when subjects were reaching for a target during whole-body rotation suggests that the control of arm movement during body motion cannot be considered as being an automatic motor task.

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Figure 6. EMG recordings of the arm muscles from representative trials by a healthy subject (upper panel) and by a deafferented subject (lower panel) when the goal of the arm movement was to stabilize the hand during body rotation (‘Vestibular’ and ‘Vestibular+Visual’ conditions) or to track a moving target with the finger when the body remained stationary (‘Visual’ condition). Irrespective of the goal of the movements, clear EMG bursts occurred in the posterior deltoid muscle during CW arm movements and in the pectoralis major muscle during CCW arm movements. The latency of the EMG response was considerably shorter for movements that compensate for body rotation (thereby keeping the hand stationary in space) than for visually-guided manual tracking (in the graphs, the onset of chair rotation or visual target motion occurred at 0 s). Figure taken from Blouin et al. (2010) with kind permission of Elsevier.

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5. Body Rotation Induces Perturbing Torques on the Arm during Reaching Movements Rotating the trunk when reaching for a target induces centrifugal and Coriolis torques that deviate the hand away from the planned trajectory in the opposite direction to the rotation (Bortolami et al., 2008a, b; Guillaud et al., 2006b; Pigeon et al., 2003). The impact of these forces on the arm is particularly noticeable when subjects reach for a target during sustained passive body rotation at constant velocity. Because the vestibular receptors are sensitive to acceleration, sensation of body motion rapidly vanishes when angular velocity reaches a constant value (Dodge, 1923; Goldberg and Fernandez, 1971; Laurens and Angelaki; 2011). When reaching for a body-fixed target in such conditions, the hand trajectory and the endpoint of the reaching movement largely deviate in the direction of the Coriolis force applied on the arm (Bortolami et al., 2008b; Bourdin et al., 2001; Coello et al., 1996; Lackner and DiZio, 1992, 1994; Sarlegna et al., 2010). As the magnitudes of centrifugal and Coriolis torques depend on trunk angular kinematics, errors in coding trunk kinematics may therefore have detrimental effects on reaching accuracy. We have adapted the biomechanical model of Pigeon et al. (2003) to assess the consequences of such errors on reaching accuracy (Simoneau et al., 2013). Our feedforward model simulated underestimation of torso acceleration occurring during the planning stage of reaching, and excluded any online correction of hand deviation based on sensory feedback (e.g., proprioceptive, vestibular or visual information). Results of the model demonstrate that even small errors in perceiving or predicting the kinematics of torso rotation may impair the accuracy of reaching movements. For instance, underestimating by only 10% CCW torso rotation having a sinusoidal velocity profile peaking at 3 rad/s induced a final hand deviation as large as 11 cm when reaching for a straight-ahead target. Therefore, the high accuracy with which subjects reach for targets during self-initiated or imposed discrete torso rotation (Bortolami et al., 2008b; Bresciani et al., 2002b, 2005; Pigeon et al., 2003) or continuously point at a remote target during body displacement without visual feedback (Blouin et al., 2010; Bresciani et al., 2005; Frissen et al., 2011; Guillaud et al., 2006a; Ivanenko and Grasso, 1997; Ivanenko et al., 1997a; Loomis et al., 1992; Philbeck et al., 2001) suggests that the brain precisely estimates trunk kinematics and takes into account the additional torques generated by the torso rotation. 6. Vestibular-Based Prediction of Body Rotation Induced Torques on the Arm During Reaching Movements Torso rotation usually accompanies the arm movement when reaching for an eccentric object. During such voluntary torso rotation, the self-induced

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Coriolis force applied on the arm could be compensated for by anticipatory pre-programmed processes (Bortolami et al., 2008b; Pigeon et al., 2003). However, anticipatory pre-programmed processes cannot intervene when subjects are submitted to passive rotations during reaching movements. The high accuracy with which subjects reach for a target in such conditions (as discussed above), even when visual feedback is not available, suggests that other mechanisms might be involved for compensating for the perturbing forces acting on the arm. The amplitude and direction of the rotation-induced torques depend on the velocity and direction of trunk rotation. Given the high computational capabilities of the brain (Angelaki et al., 2004; Merfeld et al., 1999; Sarway et al., 2013), the vestibular signal generated during body rotation could provide valuable information for estimating the rotation-induced torques on the arm. The results of an elegant study by Bockisch and Haslwanter (2007) have provided convincing support for this hypothesis. In their study, the authors exploited the velocity-storage mechanisms which allow prolonging vestibular signals (Raphan et al., 1979; Shaikh et al., 2013; Sinha et al., 2008) and therefore sensation of rotation when body rotation rapidly decelerates to a stop. As classically observed in such conditions (e.g., St George et al., 2011), when the strong deceleration occurred after sustained rotation at constant velocity, participants perceived that they were rotated in the opposite direction. This is because the response of the vestibular receptors during motion deceleration in a given direction is similar to the response evoked when accelerating in the opposite direction. The authors found that the hand trajectories produced immediately after the rotation were deviated in the same direction as the illusory body rotations. The direction of the hand deviation suggested that the immobile subjects anticipated the (nonexistent) perturbing torques based on the vestibular signals and attempted to compensate for them. Note that similar hand deviation was observed by Cohn et al. (2000) when illusory body rotation was induced using a rotating visual field. Bockisch and Haslwanter’s (2007) findings provided a nice demonstration that vestibular information can be processed by the brain to predict rotationinduced torques applied on the arm. However, they do not provide clear indication as to the accuracy of the prediction. This is due, first, to the difficulty to precisely quantify either the actual vestibular stimulation during the reaching movements or the perturbing torques that are normally associated with it during real body rotations. For instance, in Bockisch and Haslwanter’s (2007) study, the vestibular stimulation during the reaching could only be estimated with the assumption that the cupula returned to the resting position with a time constant of 6 s. Moreover, and perhaps most importantly, because the processing of arm somatosensory inputs may have resulted in trajectory corrections (their subjects had to reach for a target positioned straight-ahead), neither the

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hand path curvature nor the reached endpoint could provide clear images of the vestibular based prediction of the perturbing torques. To gain insight into the accuracy of the vestibular-based prediction of the torques induced by body rotations, we asked the deafferented patient GL to reach for a memorized visual target located straight-ahead while her torso was rotated in complete darkness thus without visual feedback of the hand (Guillaud et al., 2011). In one condition, a headrest attached to the motorized chair prevented head-on-trunk displacement. Therefore the trunk motion induced by the chair rotation stimulated the patient’s vestibular system. In another condition, an experimenter held the patient’s head stationary in space during chair rotations. With this manipulation, the patient’s perception of the torso rotations under the stationary head was greatly degraded by the absence of rotation induced vestibular signals and by her loss of somatosensory information of the cervical region. Importantly, as the torso rotations (triggered at reaching onset) were identical in both conditions (i.e., amplitudes of ±25° and ±40°), the rotation-induced torques applied on the arm were also similar. In both conditions (i.e., head fixed and head rotation), the deafferented patient’s hand similarly and considerably deviated from body midline in the direction opposite to the body rotation (see Fig. 7). When the patient’s head was prevented from rotating (i.e., in absence of vestibular stimulation), the hand deviation remained uncorrected at the end of the reaching movement. Strikingly, the hand path deviations evoked by the torso rotation were corrected when the patient’s head rotated with the trunk, that is, when vestibular inputs provided infor-

Figure 7. Mean maximal lateral hand deviations (gray bars) and mean final hand deviations (black bars) measured when a deafferented patient was rotated at the onset of her reaching movement towards a memorized visual target located straight-ahead. In the Head Fixed condition (left panel), the patient’s head was maintained stationary in space during the body rotation. In the Head Rotation condition (right panel), the patient’s head rotated with her trunk allowing the vestibular system to be stimulated by the rotation. The data were normalized with respect to the data recorded in a condition without trunk rotation. Error bars indicate between trials standard deviations. Figure taken from Guillaud et al. (2011) with kind permission of Elsevier.

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mation about the rotations. These path corrections occurred despite the fact that the patient had no sensation of hand trajectory deviation (and correction). These findings therefore provide compelling evidence that vestibular information can be processed for predicting the consequence of the rotation dynamics on the reaching arm movements. Acknowledgements We thank Gerome Manson for helpful comments made on an earlier version of the paper. References Ali, A. S., Rowen, K. A. and Iles, J. F. (2003). Vestibular actions on back and lower limb muscles during postural tasks in man, J. Physiol. 546, 615–624. Angelaki, D. E., Shaikh, A. G., Green, A. M. and Dickman, J. D. (2004). Neurons compute internal models of the physical laws of motion, Nature 430, 560–564. Avella, A. and Lacquaniti, F. (2013). Control of reaching movements by muscle synergy combinations, Front. Comput. Neurosci. 7, 1–7. Barnes, G. R. and Paige, G. D. (2004). Anticipatory VOR suppression induced by visual and nonvisual stimuli in humans, J. Neurophysiol. 92, 1501–1511. Bernier, P. M., Gauthier, G. M. and Blouin, J. (2007). Evidence for distinct, differentially adaptable sensorimotor transformations for reaches to visual and proprioceptive targets, J. Neurophysiol. 98, 1815–1819. Bernier, P. M., Burle, B., Hasbroucq, T. and Blouin, J. (2009). Spatio-temporal dynamics of reach-related neural activity for visual and somatosensory targets, Neuroimage 47, 1767– 1777. Beurze, S. M., De Lange, F. P., Toni, I. and Medendorp, W. P. (2007). Integration of target and effector information in the human brain during reach planning, J. Neurophysiol. 97, 188– 199. Blouin, J., Vercher, J. L., Gauthier, G. M., Paillard, J., Bard, C. and Lamarre, Y. (1995). Perception of passive whole-body rotations in the absence of neck and body proprioception, J. Neurophysiol. 74, 2216–2219. Blouin, J., Labrousse, L., Simoneau, M., Vercher, J. L. and Gauthier, G. M. (1998a). Updating visual space during passive and voluntary head-in-space movements, Exp. Brain Res. 122, 93–100. Blouin, J., Okada, T., Wolsley, C. and Bronstein, A. (1998b). Encoding target-trunk relative position: cervical versus vestibular contribution, Exp. Brain Res. 122, 101–107. Blouin, J., Teasdale, N. and Mouchnino, L. (2007). Vestibular signal processing in a subject with somatosensory deafferentation: the case of sitting posture, BMC Neurol. 7, 25. DOI:10.1186/1471-2377-7-25. Blouin, J., Guillaud, E., Bresciani, J. P., Guerraz, M. and Simoneau, M. (2010). Insights into the control of arm movement during body motion as revealed by EMG analyses, Brain Res. 1309, 40–52.

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The Components of Vestibular Cognition — Motion Versus Spatial Perception Barry M. Seemungal ∗ Division of Brain Sciences, Imperial College London, Charing Cross Hospital, London W6 8RF, UK

Abstract Vestibular cognition can be divided into two main functions — a primary vestibular sensation of self-motion and a derived sensation of spatial orientation. Although the vestibular system requires calibration from other senses for optimal functioning, both vestibular spatial and vestibular motion perception are typically employed when navigating without vision. A recent important finding is the cerebellar mediation of the uncoupling of reflex (i.e., the vestibular-ocular reflex) from vestibular motion perception (Perceptuo-Reflex Uncoupling). The brain regions that mediate vestibular motion and vestibular spatial perception is an area of on-going research activity. However, there is data to support the notion that vestibular motion perception is mediated by multiple brain regions. In contrast, vestibular spatial perception appears to be mediated by posterior brain areas although currently the exact locus is unclear. I will discuss the experimental evidence that support this functional dichotomy in vestibular cognition (i.e., motion processing vs. spatial orientation). Along the way I will highlight relevant practical technical tips in testing vestibular cognition. Keywords Vestibular cognition, vestibular motion perception, vestibular spatial perception, perceptuo-reflex uncoupling, TMS (transcranial magnetic stimulation), VBM (voxel-based morphometry), DTI (diffusor tensor imaging)

1. Introduction The vestibular system’s key ecological role is to provide a rapid signal of our self-motion to the central nervous system. Indeed given that vestibular cues indicate our self-motion to the brain more rapidly than any other sensory system (e.g., latency to the cerebral cortex is 0.05; corrected) for the relevant analysis. Adapted from Nigmatullina et al., 2015.

such sites cover a large area of cerebral cortex, and that such stimulation may propagate across networks, we speculate that self-motion perception may require a brain network for its elaboration. This notion is compatible with the findings that there are no cortical neurones that respond solely to vestibular input (Guldin and Grusser, 1998). Ecologically it makes sense that signals of self-motion ramify throughout the brain since all functions must be modified when we are on the move. 8. Vestibular Activation Causing Illusory Self-Motion Modulates Visual Cortical Excitability Ecologically, visual input critically interacts with vestibular perceptual functioning, a commonplace example being the ‘train illusion’, the feeling that one’s stationary train has left the platform when looking at a passing train. This illusion is a manifestation of this visual–vestibular interaction whereby visual motion signals of optic flow provoke illusory self-motion in the absence of vestibular stimulation. We were able to investigate visual–vestibular interaction in the dark by eliciting illusory self-motion via cold water caloric irrigation and simultaneously probing changes in visual cortical excitability with single pulse TMS (Seemungal et al., 2013). Previous studies have assessed visual–vestibular interaction and shown an inhibition of visual cortical responses during vestibular activation as assessed by functional neuro-imaging (Bense et al., 2001; Bottini et al., 2001; Dieterich and Brandt, 2008; Stephan et al., 2005; Wenzel et al., 1996) or neurophysiologically via evoked potentials (Probst and Wist, 1990). Some studies, however, indicated no effect of vestibular activation on visual cortical

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Figure 6. The effect of vestibular activation upon visual cortical excitability. (A) Subjects’ phosphene threshold (TMS intensity required to produce 50% phosphene reports) was obtained. The same TMS intensity was used to probe the change in probability of phosphene reports during vertigo and then in recovery phases. TMS was applied to early visual cortex or ‘EVC’

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function (Iida et al., 1997; Lobel et al., 1998; Suzuki et al., 2001). We thus asked whether we could directly probe visual cortical activity during vestibular stimulation and in addition separately probe excitability in visual motion cortex, including human V5/MT, versus early visual cortex, including area V1 and V2 (Seemungal et al., 2013). In this study (Seemungal et al., 2013), we utilised the ability of a TMS pulse applied to visual cortex to elicit a perceived flash of light called a phosphene (Brindley and Lewin, 1968). The probability of eliciting a phosphene is related to the instantaneous visual cortical excitability (Aurora et al., 1998). The experimental setup and protocol is described in Fig. 6A. We found (Fig. 6B) that vestibular activation inhibits V5/MT excitability. In contrast, excitability of the early visual cortex (V1/2) was increased. Such an arrangement may be ecologically advantageous during self-motion as potentially disorientating optic flow cues may be suppressed without affecting other visual function such as visual form discrimination. Supporting this idea is the enhancement of visual discrimination in humans during vestibular activation (Guedry, 1974; Guedry and Ambler, 1972; Tong et al., 2006). Interestingly, the effect of vestibular activation on suppressing visual motion cortex appeared to be specific to vestibular signals since illusory self-motion provoked by auditory vection caused an increase in visual motion excitability (see Supplementary Information, Seemungal et al., 2013). 9. Conclusions In our rTMS navigation experiment (Seemungal et al., 2008), we disrupted vestibular spatial orientation but not self-motion perception, implying that the neural substrates of vestibular spatial and vestibular motion perception are non-overlapping. This could indicate that the vestibular perceptual system can be divided into two streams: a vestibular spatial stream and a vestibular motion stream with vestibular spatial perception being mediated by posterior parietal brain areas. Regarding the neural substrate underlying vestibular motion perception, functional neuro-imaging studies have shown correlations between brain activation and vestibular stimulation without being able to directly probe aspects of vestibular perception. Direct electrical stimulation of the cerebral cortex in awake patients has elicited sensations of self-motion in a wide range of brain areas across the parietal and posterior temporal cortex (Blanke et al., 2000; Kahane et al., 2003). Conspicuously absent from the literFigure 6 (Continued). (V1/V2) in one experiment and then to visual motion cortex (V5/MT) in another experiment. (B) During vestibular activation, excitability (which is proportional to the probability of reporting a phosphene) was increased for EVC but reduced for V5/MT. Adapted from Seemungal et al., 2013.

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ature, however, is any systematic study quantifying a loss of vestibular motion perception from focal brain lesions. In contrast, our DTI data in a large group of healthy subjects suggest that vestibular motion perception may be mediated by a widespread cortical network (although these data were also correlational, albeit with a quantified measure of vestibular perception). It may be, however, that rather than vestibular motion perception relying upon a network for its elaboration, there is significant redundancy built into this system. Further work will be required to assess this notion of a distributed neural substrate for vestibular motion perception. References Aurora, S. K., Ahmad, B. K., Welch, K. M., Bhardhwaj, P. and Ramadan, N. M. (1998). Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine, Neurology 50, 1111–1114. Barbey, A. K., Koenigs, M. and Grafman, J. (2011). Orbitofrontal contributions to human working memory, Cereb. Cortex 21, 789–795. Bense, S., Stephan, T., Yousry, T. A., Brandt, T. and Dieterich, M. (2001). Multisensory cortical signal increases and decreases during vestibular galvanic stimulation (fMRI), J. Neurophysiol. 85, 886–899. Blanke, O., Perrig, S., Thut, G., Landis, T. and Seeck, M. (2000). Simple and complex vestibular responses induced by electrical cortical stimulation of the parietal cortex in humans, J. Neurol. Neurosurg. Psychiatr. 69, 553–556. Bottini, G., Karnath, H. O., Vallar, G., Sterzi, R., Frith, C. D., Frackowiak, R. S. and Paulesu, E. (2001). Cerebral representations for egocentric space: functional-anatomical evidence from caloric vestibular stimulation and neck vibration, Brain 124, 1182–1196. Brindley, G. S. and Lewin, W. S. (1968). The sensations produced by electrical stimulation of the visual cortex, J. Physiol. 196, 479–493. Brookes, G. B., Gresty, M. A., Nakamura, T. and Metcalfe, T. (1993). Sensing and controlling rotational orientation in normal subjects and patients with loss of labyrinthine function, Otol. Neurotol. 14, 349–351. de Waele, C., Baudonniere, P. M., Lepecq, J. C., Tran Ba Huy, P. and Vidal, P. P. (2001). Vestibular projections in the human cortex, Exp. Brain Res. 141, 541–551. Dieterich, M. and Brandt, T. (2008). Functional brain imaging of peripheral and central vestibular disorders, Brain 131, 2538–2552. Guedry Jr, F. E. (1974). Psychophysics of vestibular sensation, in: Vestibular System Part 2: Psychophysics, Applied Aspects and General Interpretations, H. H. Kornhuber (Ed.), Handbook of Sensory Physiology, Vol. 6/2, pp. 3–154. Springer, Berlin, Germany. Guedry, F. E. and Ambler, R. K. (1972). Assessment of reactions to vestibular disorientation stress for purposes of aircrew selection, in: AGARD Conference on Predictability of Motion Sickness in the Selection of Pilots, Neuilly-sur-Seine, France, Conference Proceedings 109. Guldin, W. O. and Grusser, O. J. (1998). Is there a vestibular cortex?, Trends Neurosci 21, 254–259. Iida, M., Sakai, M. and Igarashi, M. (1997). Visual-vestibular interaction — an evoked potential study in normal human subjects, Tokai J. Exp. Clin. Med. 22, 137–139.

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Kahane, P., Hoffmann, D., Minotti, L. and Berthoz, A. (2003). Reappraisal of the human vestibular cortex by cortical electrical stimulation study, Ann. Neurol. 54, 615–624. Kheradmand, A. and Zee, D. S. (2011). Cerebellum and ocular motor control, Front. Neurol. 2, 53. Lobel, E., Kleine, J. F., Bihan, D. L., Leroy-Willig, A. and Berthoz, A. (1998). Functional MRI of galvanic vestibular stimulation, J. Neurophysiol. 80, 2699–2709. Maguire, E. A., Gadian, D. G., Johnsrude, I. S., Good, C. D., Ashburner, J., Frackowiak, R. S. and Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers, Proc. Natl Acad. Sci. USA 97, 4398–4403. Mayne, R. (1974). A systems concept of the vestibular organs, in: Vestibular System Part 2: Psychophysics, Applied Aspects and General Interpretations, H. H. Kornhuber (Ed.), Handbook of Sensory Physiology, Vol. 6/2, pp. 493–580. Springer, Berlin, Germany. Meng, H., May, P. J., Dickman, J. D. and Angelaki, D. E. (2007). Vestibular signals in primate thalamus: properties and origins, J. Neurosci. 27, 13590–13602. Nigmatullina, Y., Hellyer, P. J., Nachev, P., Sharp, D. J. and Seemungal, B. M. (2015). The neuroanatomical correlates of training-related perceptuo-reflex uncoupling in dancers, Cereb. Cortex 25, 554–562. Okada, T., Grunfeld, E., Shallo-Hoffmann, J. and Bronstein, A. M. (1999). Vestibular perception of angular velocity in normal subjects and in patients with congenital nystagmus, Brain 122, 1293–1303. Probst, T. and Wist, E. R. (1990). Electrophysiological evidence for visual–vestibular interaction in man, Neurosci. Lett. 108, 255–260. Seemungal, B., Gunaratne, I., Fleming, I., Gresty, M. and Bronstein, A. (2004). Perceptual and nystagmic thresholds of vestibular function in yaw, J. Vestib. Res. 14, 461–466. Seemungal, B. M., Glasauer, S., Gresty, M. A. and Bronstein, A. M. (2007). Vestibular perception and navigation in the congenitally blind, J. Neurophysiol. 97, 4341–4356. Seemungal, B. M., Rizzo, V., Gresty, M. A., Rothwell, J. C. and Bronstein, A. M. (2008). Posterior parietal rTMS disrupts human Path Integration during a vestibular navigation task, Neurosci. Lett. 437, 88–92. Seemungal, B. M., Masaoutis, P., Green, D. A., Plant, G. T. and Bronstein, A. M. (2011). Symptomatic recovery in Miller Fisher Syndrome parallels vestibular-perceptual and not vestibular-ocular reflex function, Front. Neurol. 2, 2. Seemungal, B. M., Guzman-Lopez, J., Arshad, Q., Schultz, S. R., Walsh, V. and Yousif, N. (2013). Vestibular activation differentially modulates human early visual cortex and V5/MT excitability and response entropy, Cereb. Cortex 23, 12–19. Shaikh, A. G., Palla, A., Marti, S., Olasagasti, I., Optican, L. M., Zee, D. S. and Straumann, D. (2013). Role of cerebellum in motion perception and vestibulo-ocular reflex-similarities and disparities, Cerebellum 12, 97–107. Stephan, T., Deutschlander, A., Nolte, A., Schneider, E., Wiesmann, M., Brandt, T. and Dieterich, M. (2005). Functional MRI of galvanic vestibular stimulation with alternating currents at different frequencies, Neuroimage 26, 721–732. Suzuki, M., Kitano, H., Ito, R., Kitanishi, T., Yazawa, Y., Ogawa, T., Shiino, A. and Kitajima, K. (2001). Cortical and subcortical vestibular response to caloric stimulation detected by functional magnetic resonance imaging, Brain Res. Cogn. Brain Res. 12, 441–449.

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Taubert, M., Draganski, B., Anwander, A., Muller, K., Horstmann, A., Villringer, A. and Ragert, P. (2010). Dynamic properties of human brain structure: learning-related changes in cortical areas and associated fiber connections, J. Neurosci. 30, 11670–11677. Tong, J., Patel, S. S. and Bedell, H. E. (2006). The attenuation of perceived motion smear during combined eye and head movements, Vis. Res. 46, 4387–4397. Tyrrell, R. A. and Owens, D. A. (1988). A rapid technique to assess the resting states of the eyes and other threshold phenomena: the modified binary search (MOBS), Behav. Res. Methods Instrum. Comput. 20, 137–141. Valero-Cabre, A., Payne, B. R., Rushmore, J., Lomber, S. G. and Pascual-Leone, A. (2005). Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: a 14C-2DG tracing study in the cat, Exp. Brain Res. 163, 1–12. Waespe, W., Cohen, B. and Raphan, T. (1985). Dynamic modification of the vestibulo-ocular reflex by the nodulus and uvula, Science 228, 199–202. Wenzel, R., Bartenstein, P., Dieterich, M., Danek, A., Weindl, A., Minoshima, S., Ziegler, S., Schwaiger, M. and Brandt, T. (1996). Deactivation of human visual cortex during involuntary ocular oscillations. A PET activation study, Brain 119, 101–110.

Gravity in the Brain as a Reference for Space and Time Perception Francesco Lacquaniti 1,2,3,∗ , Gianfranco Bosco 1,2,3 , Silvio Gravano 2,3 , Iole Indovina 2,3 , Barbara La Scaleia 3 , Vincenzo Maffei 3 and Myrka Zago 3 1

3

Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy 2 Centre of Space Bio-medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy Laboratory of Neuromotor Physiology, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy

Abstract Moving and interacting with the environment require a reference for orientation and a scale for calibration in space and time. There is a wide variety of environmental clues and calibrated frames at different locales, but the reference of gravity is ubiquitous on Earth. The pull of gravity on static objects provides a plummet which, together with the horizontal plane, defines a three-dimensional Cartesian frame for visual images. On the other hand, the gravitational acceleration of falling objects can provide a time-stamp on events, because the motion duration of an object accelerated by gravity over a given path is fixed. Indeed, since ancient times, man has been using plumb bobs for spatial surveying, and water clocks or pendulum clocks for time keeping. Here we review behavioral evidence in favor of the hypothesis that the brain is endowed with mechanisms that exploit the presence of gravity to estimate the spatial orientation and the passage of time. Several visual and non-visual (vestibular, haptic, visceral) cues are merged to estimate the orientation of the visual vertical. However, the relative weight of each cue is not fixed, but depends on the specific task. Next, we show that an internal model of the effects of gravity is combined with multisensory signals to time the interception of falling objects, to time the passage through spatial landmarks during virtual navigation, to assess the duration of a gravitational motion, and to judge the naturalness of periodic motion under gravity. Keywords Internal model, interception, self-motion, microgravity, vestibular, perceived vertical

*

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_005

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1. Introduction Reference to gravity is crucial to assess the orientation of our body and limbs in space, to maintain postural equilibrium and move around, to interpret the outside world and to navigate through it. The mechanisms involved in building a spatial reference to gravity have been studied extensively, and several excellent reviews exist on this topic (e.g., Angelaki and Cullen, 2008; Berthoz, 2000; Harris et al., 2011; Howard, 1982; Klatzky, 1998; Lackner and DiZio, 2005; Paillard, 1991). Here we consider one specific but important aspect of spatial orientation, namely the subjective estimate of the orientation of the visual vertical. In this perceptual behavior we see epitomized the key features of spatial orientation, with the fusion of multisensory information and the role of a prior expectation of the direction of gravity. We also briefly review the issue of the spatial orientation cues for the recognition of objects and people. Next, we concentrate on the much less explored issue concerning the role of a gravitational reference to mark the timing of actions and perceptions. Considerable work has been carried out in the field of time perception and motor timing, with a special emphasis on the demonstration of time distortions and what they can reveal about neural timing mechanisms (see for instance, Buhusi and Meck, 2005; Lewis and Miall, 2003; Mauk and Buonomano, 2004; Merchant et al., 2013). By contrast, the idea that the brain constantly strives to maintain accurate time estimates by calibrating them against physical laws from the outside world has received much less attention (Eagleman, 2004; Eagleman et al., 2005; Zago et al., 2011a). This hypothesis is especially relevant for the estimates of the duration of a target motion. Thus, the position of a moving object at a given time in the near future can be predicted by a forward internal model (Davidson and Wolpert, 2005; Zago et al., 2009) and can be compared with sensory feedback to calibrate the time estimates (Eagleman, 2004). In the second part of this review, we consider some evidence that the brain takes advantage of an internal model of the effects of gravity to maintain accurate time estimates. As in the case of spatial orientation, the time estimates of gravitational motion also rely on multisensory signals combined with a prior model of physics. In the final part of the review, we discuss the nature of this internal model and how it can predict the outcomes of realistic scenarios. We will only briefly mention some neural substrates of the internal model of gravity, as this issue has been thoroughly covered in a recent review (Lacquaniti et al., 2013). 2. Subjective Vertical It has long been known that humans can accurately estimate the direction of the Earth’s vertical, but the contributing mechanisms have been the topic of

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continuing debate (see Bischof, 1974). Koffka (1935) proposed that the sense of the vertical and horizontal is mainly determined by the contours of the visual field (the horizon, walls, floors). Objects and our own body posture would be perceived as upright or tilted only in relation to this visual reference frame. By contrast, Gibson and Mowrer (1938) argued that the visual vertical and horizontal are not determined by visual cues but by postural stimuli, and ultimately by the force of gravity acting on the body. A few years later, Gibson (1952) reconsidered his position in the wake of the apparently contradictory results obtained by Asch and Witkin (1948) and by Mann et al. (1949). In the study by Asch and Witkin (1948), perceptual judgments of the vertical appeared to be mainly based on the visual field cues, being little influenced by the direction of the pull of gravity on the body. The opposite was found by Mann et al. (1949) who reported a prevalence of the postural cues. Gibson (1952) then suggested that the visual vertical is determined jointly by visual and postural (gravitational) cues. He further argued that, in case of a discrepancy between these cues, the brain learns to use the reliable cues and to neglect the unreliable ones. 2.1. Multisensory Cues to Subjective Vertical Gibson’s hypothesis has been corroborated and refined by subsequent studies, and we now know that several types of visual and non-visual cues contribute to the subjective estimate of vertical direction (e.g., Angelaki et al., 2009; Harris et al., 2011; Howard, 1982; Lackner and DiZio, 2005; Mittelstaedt, 1983). The subjective visual vertical (SVV) is usually tested by asking subjects to align an initially tilted luminous bar with the estimated earth-vertical. In darkness, SVV of upright subjects deviates by 0.3 g) to be recognized as a reference for SVV (De Winkel et al., 2012). In general, the perception of orientation in a rich, naturalistic environment depends on visual and non-visual cues (Lacquaniti et al., 2014a). Harris et al. (2011) list the following visual cues to orientation: (a) the visual frame identified by vertical and horizontal contours (walls, ceilings, floors); (b) the visual horizon; (c) the assumption that light comes from above (although it has recently been shown that this assumption is weak, Morgenstern et al., 2011); (d) the spatial relationship between resting objects and their support; (e) the orientation of familiar polarized objects (e.g., trees, people, lamps, chairs); (f) movement of objects on the ground plane (corresponding to horizontal trajectories) or falling in air (vertical trajectories). Non-visual cues to orientation are provided by the otoliths of the vestibular system, as well as by the skin, muscle and tendon receptors, and by specialized visceral receptors (in the kidneys, vena cava, etc.). The otoliths respond to a tilt of the head relative to gravity, but in general they signal the net gravito-inertial acceleration, and cannot distinguish between gravitational and inertial components (Fernandez and Goldberg, 1976). However, gravito-inertial accelerations can be disambiguated by combining the otolith signals with the signals of the semicircular canals (Angelaki et al., 1999; Glasauer, 1992; Merfeld et al., 1999). Notice that, in addition to the SVV test, the subjective vertical can also be assessed haptically (e.g., Bortolami et al., 2006). In the latter task, blindfolded subjects manually align a rod with the estimated gravitational vertical. This approach has the advantage of being unaffected by the vestibulo-ocular reflexes. Moreover, the subjective vertical has been assessed studying selfpaced saccadic eye movements (Barnett-Cowan and Harris, 2008; Pettorossi et al., 1998). Thus, subjects asked to perform saccades along the direction of gravity in the dark are fairly accurate when upright, but they exhibit the Aubert-effect when tilted. 2.2. Modeling Multisensory Interactions for Subjective Vertical To determine the relative role of visual, gravity-related and body-related orientation cues, Dyde et al. (2006) presented the luminous bar of the SVV test against a highly polarized visual background. The visual background and body orientation could be tilted independently. Following Mittelstaedt (1983), they modeled the perceived vertical as a weighted vector sum of the different orientation cues, the weights depending on the relative reliability of each cue (Fig. 1). Dyde et al. (2006) found that the influence of vision in the SVV test is small, contributing only about 8% of the information, compared to 77% from gravity and 16% from the long axis of the observer’s body. This is very different from what is found if, instead of a luminous line, a more complex visual

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Figure 1. Model proposed by Dyde et al. (2006) for the subjective estimate of the upward direction. The vector sum of gravity, body orientation and visual cues corresponds to the estimated upward.

object is shown to probe the perception of upright. Thus, in the oriented character recognition test (OCHART), observers are asked to report whether they see the letter ‘d’ or the letter ‘p’ when the corresponding symbol is presented at various orientations (Dyde et al., 2006). Using this test, it has been found that vision contributes about 27% of the information needed to determine the perceptual upright, compared to about 13% from gravity and 60% from the body (Barnett-Cowan et al., 2013). OCHART has also been performed during parabolic flight (Harris et al., 2012) and during centrifuge tests simulating levels of gravity from zero to earth’s gravity along the long-axis of the body (Harris et al., 2014). In contrast with SVV (see above), low levels of gravity such as that of the moon (0.16 g) have been shown to be sufficient for maintaining a similar weighting as on ground of the cues determining the perceptual upright, i.e., vision, body and gravity-related cues (Harris et al., 2014). Statistically optimal Bayesian models have also been used to predict SVV responses (Clemens et al., 2011; De Vrijer et al., 2008; MacNeilage et al., 2007). Thus, the inputs to a Bayesian model are represented by the head orientation in space and the visual orientation of the luminous bar relative to the retina. While the visual signals are precise, the head tilt signals are noisy. However, these tilt signals are combined with a prior assumption that the head and the body are most likely oriented near the vertical, resulting in a statistically optimal estimate. This prior assumption is somewhat equivalent to the idiotropic component of the vectorial model of Mittelstaedt (1983). Visual– vestibular combination also contributes to the perception of heading direction, each cue contributing to the precision and accuracy of the estimates (Zaidel et al., 2013). Related to this point, representation of self-motion in threedimensional (3D) space has been shown to be non-uniform (Barnett-Cowan

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et al., 2012; see also Section 4.4), and it has been suggested that this perceptual anisotropy arises as a consequence of righting reflexes that tend to keep the head upright along with the prior assumption of the head being upright (Barnett-Cowan and Bülthoff, 2013). 3. Spatial Orientation Cues for the Recognition of Objects and People We typically interact more easily with objects when they are upright (the right way up). We already mentioned the issue of recognizing ambiguous characters at different orientations (OCHART). Here we briefly summarize other examples of object recognition problems. ‘Right-way-up’ can be defined relative to a variety of biologically relevant reference frames, such as the viewer-centered frame, the gravity-centered frame, and the visual frame (Howard, 1982; Lacquaniti, 1997). Thus, recognition of scenes, people and actions tends to be faster and more accurate when they are aligned with the observer, whether both the scene and the observer are upright or they are both tilted (e.g., Chang et al., 2010; Dyde et al., 2006; Köhler, 1940; Kushiro et al., 2007; Troje, 2003; Yin, 1969). For instance, when a digitally edited photograph of a face is presented upside-down relative to the observer, the ability to detect gross distortions and abnormalities is strongly impaired (Lobmaier and Mast, 2007; Thompson, 1980). Similar viewer-centered inversion effects have been described for the discrimination of static whole-body postures (Reed et al., 2003) and of biological motion in point-light walker stimuli (e.g., Chang et al., 2010; Pavlova and Sokolov, 2000; Sumi, 1984; Troje and Westoff, 2006). Even though a viewer-centered reference frame may allow optimal processing of object properties in the canonical perspectives and although egocentric cues dominate in the encoding of visual scenes, allocentric cues contribute as well. Thus, observers are sensitive to the artificial inversion of the visual effects of gravity on the motion of inanimate objects (Bingham et al., 1995; Indovina et al., 2005). Also, a role of orientation relative to gravity has been documented for processing global and local motion cues of point-light walker stimuli, presumably in connection with expectations about the dynamics of the body due to gravity (Chang and Troje, 2009; Shipley, 2003; Troje and Westhoff, 2006). It has also been shown that the view of a rotated photograph or video-clip with strong ‘up’ and ‘down’ polarization cues can alter the perceived direction of physical ‘up’ and ‘down’ directions (Dyde et al., 2006; Jenkin et al., 2004, 2011). Thus, perceptual biases have been documented in relation to the orientation of the stimuli relative to gravity (Chang et al., 2010; Lobmaier and Mast, 2007; Lopez et al., 2009) and to intrinsic visual references (Jenkin et al., 2004).

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Finally, allocentric visual cues can influence mental transformation of bodies. Preuss et al. (2013) used the York Tumbling Room to modulate the allocentric visual reference frame and the perceived orientation of the body relative to gravity. They found that body stimuli with a visual polarity relative to the environment were more accurately identified when the room and the body stimuli were aligned. Instead, this congruency did not facilitate identifying hand stimuli that do not have visual polarity relative to the environment. 4. Subjective Time Estimates Time information is analyzed across a wide range of intervals, from the microsecond timing of sound localization to the 24-h period of circadian rhythms. While an intriguing relationship between the macular receptors and the circadian timing system has been shown (Fuller and Fuller, 2006), here we concentrate on events unfolding over the scale of tens to hundreds of milliseconds, a time scale critical for rapid interactions with the environment. Time is not directly measured by the nervous system, but is estimated by integrating appropriate information over discrete intervals using internally generated and/or externally triggered signals (see Eagleman et al., 2005; Fraisse, 1963). Because of the complex, context-dependent interplay of internal and external factors, the estimates of elapsed time in the sub-second range can be distorted (Eagleman, 2008; Haggard et al., 2002; Lacquaniti et al., 2014b; Orgs et al., 2013; Zago et al., 2011a). Thus, the perceived duration of a generic moving stimulus is longer than that of a stationary stimulus with the same physical duration (Brown, 1995; Kanai et al., 2006), and it increases with increasing speed (Kaneko and Murakami, 2009). Moreover, a constant-speed motion appears to last longer than a decelerating motion, and the latter appears to last longer than an accelerating motion (Matthews, 2011). Also the predictive estimates of the time remaining before a collision (so called timeto-contact, or TTC) can be inaccurate in the case of generic accelerating or decelerating motion, as shown by the errors in interception (Port et al., 1997). Temporal biases in action and perception may actually fulfill a specific function, e.g., improving agency (temporal binding effect, Moore and Obhi, 2012), enhancing visual processing during action preparation (Hagura et al., 2012), support apparent movement perception (Orgs et al., 2013) and action discrimination (Carrozzo et al., 2010). On the other hand, accurate time estimates that reflect veridical physical duration are desirable in other circumstances, such as catching a ball or escape from an approaching predator. Therefore, there must co-exist distinct mechanisms that support cognition/perception by distorting subjective time in a principled and purposeful manner, and mechanisms that improve the accuracy of temporal estimates when timely reactions are needed.

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One specific mechanism that can keep time estimates calibrated takes advantage of the fact that objects’ motion under gravity represents a highly predictable event, with a fixed duration over a given path. Indeed, there is much evidence that prior knowledge about gravitational force is incorporated in the neural mechanisms computing elapsed time (e.g., Indovina et al., 2005; Lacquaniti et al., 1993; McIntyre et al., 2001; Moscatelli and Lacquaniti, 2011; Zago et al., 2004). In particular, an internal model of the effects of gravity has been shown to be applied to both automatic sensorimotor processes and some cognitive judgments of elapsed time. 4.1. Timing of Interceptive Movements It has been shown that the manual interception of a ball in vertical free-fall (e.g., Brenner et al., 2014; Lacquaniti and Maioli, 1989b; Zago et al., 2004; see Fig. 2), rolling down an inclined plane (La Scaleia et al., 2014a; Mijatovi´c et al., 2014; see Fig. 3), or in ballistic projectile motion (Bosco et al., 2012; Cesqui et al., 2012; D’Andola et al., 2013) is accurately timed, even in blindfolded subjects provided with an auditory cue on ball release (Lacquaniti and Maioli, 1989a). The effects of gravity are also taken into account in the oculomotor behavior necessary to track projectile motion (Delle Monache et al., 2014; Diaz et al., 2013). On the other hand, the interception of targets descending vertically under non-ecological conditions is generally inaccurate (Figs 2, 3). Thus, astronauts move their arm too early to catch a weightless approaching target, as if they still anticipated the effects of earth’s gravity (McIntyre et al., 2001). Similar results are obtained by simulating lack of gravity or reversed gravity on visual motion in the laboratory (Indovina et al., 2005; Zago et al., 2004). Interception timing under both normal and abnormal gravity conditions can be explained by assuming that visual on-line information about target position and velocity is combined with a prior of earth’s gravitational acceleration (Gómez and LópezMoliner, 2013; McIntyre et al., 2001; Zago and Lacquaniti, 2005a; Zago et al., 2004). This model is somewhat reminiscent of the Bayesian formulation of the SVV problem reviewed above, in so far as it involves statistical information derived from both current sensory inputs and past experience. However, the prior of gravitational acceleration appears to be surprisingly resistant to changes in the face of new sensory evidence. In fact, under conditions violating earth’s gravity, interception performance is improved by using sensory feedback and performance errors to adjust internal time-delay parameters, without modifying the prior of acceleration (McIntyre et al., 2003; Zago et al., 2005; Zago and Lacquaniti, 2005b, c).

Figure 2. Motor timing of punching movements. In the experiments of Zago et al. (2005), subjects intercepted a virtual sphere moving vertically downward on a screen by punching a real ball that fell under gravity hidden behind the screen (right panels). The virtual sphere and the real ball arrived in synchrony below the lower border of the screen. The virtual target descended either accelerated by gravity (1 g) or at constant speed (0 g). Wrist acceleration records are aligned relative to the arrival time of the target. Traces are ordered from the first to the last repetition from bottom to top in each panel. Notice that, for 1-g targets, the zero-crossing of acceleration occurred systematically close to target arrival, indicating that subjects generated maximum momentum to punch the ball at the right time. By contrast, for 0-g targets, hand movements were much more variable; they tended to start and to end too early, with the result that the hand arrived too soon and passed beyond destination before target arrival. With practice, performance improved with 0-g targets, but the responses often remained premature.

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Figure 3. Left column. (A) In the experiments of La Scaleia et al. (2014), a real ball rolled down an incline with a kinematics that differed as a function of the starting position and slope angle, and subjects had to punch it after its exit from the incline. (B) Timing errors (TE) for each condition (slope angle and duration of ball motion, nBMD). Responses were well within the theoretical margin of error for successful punching (grey area). Right column. (C) In the experiments of Mijatovi´c et al. (2014), subjects pressed a button to intercept a virtual target sliding along an inclined plane, either downwards under normal gravity or upwards under artificial reversed gravity. Target motion was occluded from view over the last segment. (D) Difference in timing error (DTE) between the reversed gravity and the normal gravity conditions. The responses in the condition with unnatural forces were systematically delayed relative to those with natural forces.

4.2. Multisensory Information for Timing Interceptions Interception timing is thus driven by an internal model of the effects of gravity, combined with sensory information. In addition to visual on-line signals

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about target motion, also proprioceptive neck and vestibular signals contribute. In one study, subjects intercepted a looming ball shown in a head-mounted stereoscopic display (Senot et al., 2005). They either pitched their head backwards looking up towards the ball descending from a virtual ceiling (‘above’ condition), or they pitched their head downwards looking down towards the ball rising from a virtual floor (‘below’ condition). The visual reference frame for up and down was therefore roughly aligned with physical gravity. Subjects generally responded earlier for ‘above’ than for ‘below’. Moreover, interception rate was higher when balls accelerated or decelerated in a manner congruent with the direction of movement. Indeed, the success rate for accelerating approaches was higher for ‘above’ than for ‘below’, and higher for decelerating balls for ‘below’ than for ‘above’. The same asymmetry of responses between ‘above’ and ‘below’ conditions was observed when subjects were lying down on the laboratory floor with their body axis orthogonal to gravity (Le Séac’h et al., 2010). In contrast, no asymmetry of responses was found in an experiment in which the visual conditions of ‘above’ and ‘below’ were reproduced while the subject held the head in a normal, horizontal posture, thus with the visual reference for virtual up and down roughly orthogonal to physical gravity (Senot et al., 2005). Overall, these results indicate that the adjustments of motor timing were based on vestibular and neck proprioception indicating the expected direction of ball motion with respect to gravity. Further evidence for a contribution of otolith sensors in the timing of visuomotor responses to accelerating/decelerating targets was obtained during parabolic flight (Senot et al., 2012). During each parabola, a weightless phase of about 20 s is preceded and followed by 20 s of hypergravity. During the transition from hyper- to hypogravity, saccular afferents in the otoliths briefly overshoot the 0-g-level, as if they sensed a negative gravity, i.e., a gravitational pull in the upward direction. Consistent with this reversal of the otolith responses, the timing of the interceptive responses in the virtual environment described above (Senot et al., 2005) also reversed sign during the weightless phases compared with the responses at normal gravity (Senot et al., 2012). As in the case of the perception of subjective vertical, also the definition of ‘up’ and ‘down’ for timing an interception is a multimodal process that can involve both allocentric and egocentric information. The experiments of Senot et al. (2005, 2012) involved a reduced visual scene, resulting in a predominant contribution of cues aligned with physical gravity. Instead, Miller et al. (2008) used a richer, more strongly polarized visual scene, and found that response timing was systematically better for downward accelerating versus downward decelerating balls even when subjects lied on their back and the vertical of the visual scene was aligned with the body and orthogonal to physical gravity

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(Fig. 4). The bias for visual gravitational motion disappeared with a blank scene. Therefore, when the visual scene is naturalistic and strongly polarized, the scene vertical can predominate, driving the perceived direction of freefall away from physical gravity when this deviates from the visual vertical (a winner-take-all mechanism). Zago et al. (2011b) manipulated the alignment of visual gravity effects and structural visual cues between each other, and relative to the orientation of the observer and physical gravity (Fig. 5). A factorial design assessed the effects of the scene orientation (normal or inverted) and the direction (normal or inverted) of virtual gravity affecting target motion. They found that the success rate of interception was significantly higher when the orientation of the scene was concordant with the direction of the gravity that affected target motion, irrespective of whether both directions were upright or inverted. These results show that the visible influence of virtual gravity and pictorial cues can outweigh both physical gravity and viewer-centered cues; subjects tend to rely on the congruence of the apparent physical forces acting on people and objects in the scene. 4.3. Perceptual Estimates of Free-Fall Duration Just as in the case of sensorimotor processes involved in interception, also cognitive judgments of elapsed time can engage an internal model of the effects of gravity (see Zago et al., 2011a). Grealy et al. (2004) showed that blind-folded subjects throwing a ball in the air can accurately indicate when the ball will hit the floor. Their results on the estimated temporal durations were well accounted for by a tau-guide model (Lee, 1998) that takes gravity into account (Georgopoulos, 2002). Similar results were reported for the indication of the time of landing of a computer-animated target that rolls off a horizontal surface and falls hidden from view (Huber and Krist, 2004). Moscatelli and Lacquaniti (2011) showed that perceptual time discriminations are systematically better when the linear motion of an object complies with gravitational constraints than when it artificially violates such constraints. Thus, the duration of a target accelerating downwards was discriminated more precisely than that of the same target accelerating upwards, rightwards, or leftwards, irrespective of whether target motion was embedded in a pictorial scene including several metric cues (familiar size, linear perspective, shading, and texture gradient) or it was embedded in a blank scene lacking any metrics. However, the gravityrelated anisotropy was more pronounced in the former than in the latter case. The same study addressed the issue of whether the sensitivity to gravitational constraints is tied to egocentric coordinates, Earth’s gravity, or visual references intrinsic to the scene. To this end, the same stimuli as before were used, but the observer was tilted by 45° relative to the monitor and earth’s gravity in one experiment, while the observer was upright and the monitor was tilted by

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Figure 4. In the experiments of Miller et al. (2008), a virtual ball was launched vertically from the red box, rebounded at the trajectory apex, and returned to the starting point where it had to be intercepted. In g trials, target acceleration was consistent with natural gravity, that is, the target decelerated while moving up and accelerated while moving down. In rg trials, instead, target acceleration was reversed relative to natural gravity, that is, the target accelerated while moving up and decelerated while moving down. Target motion was embedded in a pictorial context (top left) or in a blank scene (top right). Bottom panel: Response timing errors (RTE) as a function of target motion (g vs. rg) and visual context (pictorial vs. non-pictorial). Responses were timed systematically better for downward accelerating (white bar) versus downward decelerating (black bar) balls with the pictorial scene, but this facilitation disappeared with the non-pictorial scene.

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Figure 5. Effect of visual congruence between background and gravity orientation. Top panels: In the experiments of Zago et al. (2011b), the virtual ball was launched vertically from the launcher, hit the opposite surface and bounced back. The target decelerated from launch to bounce (blue trajectory), and it accelerated after bounce (red trajectory). When subjects pressed the button, the standing person in the scene shot a bullet toward the interception point (crosshair). The direction of the scene (‘s’) and the direction of virtual gravity acting on the target (‘g’) were varied in different blocks of trials: (A) normal scene and gravity, (B) normal scene and inverted target gravity, (C) inverted scene and gravity, (D) inverted scene and normal target gravity. Bottom panel: Success rate for each condition. Success rate was significantly higher for the congruent scenes (A and C) than for the incongruent ones (B and D).

45° in another experiment. In both experiments, the pictorial downward was tilted relative to the retinal vertical meridian. It was found that the discrimination precision was still higher for targets directed downwards relative to the pictorial vertical, although the size of the effect decreased with tilting. By contrast, the anisotropy essentially disappeared with the non-pictorial scene when

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target motion was oblique. The difference in precision between downward and upward motion varied in a graded manner as a function of the conditions, being highest when both the observer and the pictorial scene were upright, and being lowest when the target direction in the non-pictorial scene was tilted by 45° relative to an upright observer. The results were modeled using a linear combination of pictorial cues, orientation of the observer, and orientation of target motion relative to the physical vertical (reminiscent of the approach of Dyde et al., 2006, mentioned above). The resulting weighing coefficients were 43, 37, and 20% for observer orientation, target motion orientation, and pictorial cues, respectively. The fact that the weight of egocentric cues specifying the observer’s orientation was highest in this task is in line with previous work on the perceptual discrimination of scenes, people and actions (e.g., Chang et al., 2010). Also, the substantial contribution of visual references intrinsic to the scene, such as the direction of target motion and the presence of additional pictorial cues, agrees with the previous observation that viewing a picture with strong polarization cues (indicating relative up and down directions in the picture) affects the perceived direction of up and down directions in the real world (Jenkin et al., 2004). 4.4. Time-to-Passage During Passive Self-Motion The visual effects of gravity also contribute to time estimates during selfmotion in the vertical direction. In the studies by Indovina et al. (2013a, b), stationary subjects experienced virtual rides on a roller-coaster in a firstperson perspective (Fig. 6). These visual stimuli provide an immersive sense of presence in the virtual environment, compatible with forward self-motion (Baumgartner et al., 2008; Indovina et al., 2013a, b). The roller-coaster vehicle moved along vertical or horizontal rectilinear sections, connected by curves. Acceleration/deceleration was coherent with gravity for vertical motion, whereas the same acceleration/deceleration was unnatural for horizontal motion. In one experiment, the vehicle traveled in the open, through various mountain landscapes. In a second experiment, the vehicle traveled within dark tunnels during the final part of the path to eliminate visual cues. Subjects pressed a button when they thought the vehicle passed through a given reference point. The results showed that gravitational acceleration was taken into account, for both visible and occluded conditions. In particular, timeto-passage was indicated earlier when the vehicle accelerated downward at 1 g (as during free fall), as compared to when the same acceleration occurred along the horizontal direction. Since the motion law was the same for the two conditions, this difference must be related to the visual context that defines the orientation of the motion, vertical or horizontal. Moreover, the precision in time-to-passage estimates was higher during accelerated falls than constant speed motion along vertical tracks (Indovina et al., 2013a). This result is

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Figure 6. Time-to-passage during passive self-motion. In the experiments of Indovina et al. (2013a), subjects riding a virtual roller-coaster pressed a button at the time at which they thought the rollercoaster car passed through a reference point. Left: Still frames from animated visual stimuli simulating the roller-coaster ride. Vertical and horizontal tracks are shown at the onset of the trial and at about 2 m before crossing the passage reference point. Right: Difference between time-to-passage (DTTP) during vertical motions and that during horizontal motions, plotted as a function of motion law. Va, vertical accelerated; Vc, vertical constant speed; Vd, vertical decelerated; Ha, horizontal accelerated; Hc, horizontal constant speed; Hd, horizontal decelerated. The results show a significant anticipation in the time-to-passage estimate during the vertically accelerated downward motion (free fall) when compared with accelerated horizontal motion.

consistent with a lower noise in time estimates when the motion complies with the gravitational constraint as compared to when the motion violates the constraint, consistent with the results obtained by Moscatelli and Lacquaniti (2011). Notice that perceptual asymmetries for self-motion have also been reported for physical self-motion, in this case the sensitivity for vertical translations being lower than that for horizontal translations and sensitivity for downward motion being higher than for upward motion (Nesti et al., 2014). 4.5. Perceptual Judgments of Periodic Events In general, the timing of periodic events is highly predictable because a regular time interval can be used as a predictive template (Huron, 2006). While the temporal reference in an auditory rhythm typically corresponds to the ‘beat’

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(Large, 2008), a periodic visual motion contains time-varying spatial information and the reference may be defined by several different parameters in the trajectory identifying a visual ‘beat’ (Luck and Sloboda, 2007). Su (2014) considers that visual motion can be perceptually segmented using velocity peaks and distinct spatial positions, such as path reversals. Both path reversals and the velocity profile can be used when judging the period of oscillation of a pendulum, another familiar example of gravitational motion. Several inanimate and animate (biological) motions are described approximately as a pendulum. For instance, the body and limbs oscillate as a multi-jointed pendulum during walking. Indeed, gravitational information contributes to the recognition of walking movements (Maffei et al., 2015; Shipley, 2003; Troje and Westoff, 2006). There is considerable evidence that pendulum motion is perceptually salient, inasmuch as artificial deviations from the normal relation between pendulum period and pendulum length are visually detected (Bozzi, 1958; Frick et al., 2005; Pittenger, 1990). Thus, in experiments in which a pendulum is made artificially to oscillate faster or slower than normal, the observers rate the oscillations violating the physical length-period relation as less natural than the oscillations complying with physics (Pittenger, 1990). Moreover, observers discriminate between the patch-light display of a freely swinging pendulum and that of a hand-moved pendulum with the same period and amplitude. However, discrimination is impaired when the pendulum is shown upside-down (Bingham et al., 1995). One psychophysical approach to discover an implicit bias toward gravitational motion when viewing an oscillating pendulum is based on the idea that the brain takes into account the statistics of environment stimuli, and in particular it is biased toward events that occur more frequently, relying on a statistical prior model of the natural environment (Barlow, 1959; Simoncelli and Olshausen, 2001). Runeson (1974) developed this argument further and proposed that the speed of a visual stimulus is estimated with reference to a natural motion with a compatible trajectory. Whenever speed changes are consistent with a natural dynamic event, they are not taken into account, and speed is perceived as approximately constant. Consistent with Runeson’s hypothesis, La Scaleia et al. (2014b) showed that the quasi-harmonic motion of a point-light target oscillating like a simple pendulum is perceived as uniform, but this bias disappears when the stimuli are incompatible with a pendulum (Fig. 7). 5. Discussion We argued that the brain is endowed with mechanisms that exploit the effects of gravity to estimate spatial orientation and time. These mechanisms

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Figure 7. Implied gravity in a pendulum motion biases the visual perception of speed (experiments of La Scaleia et al., 2014b). (A) In one experiment, the target oscillated back-and-forth along a circular arc around an invisible pivot (leftmost and middle panels). The imaginary segment from the pivot to the midpoint of the trajectory could be oriented vertically downward (consistent with an upright pendulum, leftmost panel), or vertically upward (upside-down, middle panel). In another experiment, the target moved uni-directionally, anticlockwise on a circular trajectory, being visible only in the bottom and top quadrants (rightmost panel). In all experiments, the target shifted according to one of 21 different kinematic conditions, including both harmonic and constant speed motion, and the observers were asked to choose the profile that appeared most uniform. (B) Distribution histograms of the responses (pooled over all participants) for the conditions illustrated in A. Abscissae: motion conditions: −1 g corresponds to a target moving under reverse gravity; 0 g, constant-speed motion, 1 g, motion under natural gravity; 2 g and 3 g, motions with maximum velocity twice and three times as large as 1 g, respectively. Ordinates: number of responses. Blue (black) bars: 0 g; red (grey) bars: 1 g. (C) Cumulative distribution functions for each participant (black) and for the population (red). The results show that, for both pendulum orientations (leftmost and middle columns), the responses clustered around the kinematic profile simulating the effects of a virtual gravity (1 g) acting

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are built so as to match environmental structure. For instance, visual images of natural scenes are anisotropic, with more image structure at orientations parallel or orthogonal to the direction of gravity (e.g., Hansen and Essock, 2004). These image anisotropies are matched by corresponding anisotropies in perceptual responses. Thus, line and motion directions are discriminated better when they are oriented vertically or horizontally (cardinal directions) than when they are oriented obliquely (Appelle, 1972; Ball and Sekuler, 1987). As reviewed in a previous section, anisotropy related to the direction of motion has been described also in a task of time perception, the discrimination of temporal duration being better for vertical downward motion that for other directions of motion (Moscatelli and Lacquaniti, 2011). By taking advantage of a structured environment, not only does the brain improve spatial and temporal estimates about current events, but it is also able to shape accurate expectations about forth-coming events. Predictive behavior can improve perception by anticipating the ‘what’, the ‘when’ and the ‘where’ of probable stimuli (Huron, 2006), and can facilitate more appropriate motor responses (Zago et al., 2009). Considerable sensory-motor delays are involved in neural transmission, muscle force generation and effector inertia. In particular, vestibular conscious perception of motion is strikingly slow as compared to visual, auditory or tactile perception (Barnett-Cowan, 2013). In general, sensory-motor delays would result in motor responses too sluggish to be effective unless they were compensated by predictive components. If there is a consensus about the existence of predictions about the effects of gravity, the nature of these predictions is still controversial (Zago et al., 2008, 2009). The controversy revolves around the more general inverse problem of perception, that is, how the brain can recover the external source of stimulation and generate adequate responses starting from under-determined, ambiguous sensory signals. For instance, although objects are accelerated by gravity at a constant rate, the corresponding acceleration of the retinal image is not constant at all, but is inversely related to the viewing distance. In line of principle, retinal motion information might be scaled by viewing distance to estimate target motion in world coordinates. However, viewing distance is hard to estimate, especially when it is time-varying as in the case of an approaching target, such as a projectile. In line of principle, eye vergence, accommodation, stereodisparity and motion parallax may contribute to estimates of viewing distance of target motion in 3D space, but these cues are ineffective when the

Figure 7 (Continued). downwards (leftmost column), or upwards (middle column), although the responses were much less variable in the former than the latter case. In contrast, the responses for unidirectional motion along the circle (rightmost column) clustered close to the constant speed profile.

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target is distant or when it is animated on a 2D video display. Pictorial information from the moving target or the background of the visual scene also may help recovering an environmental reference and scale (Distler et al., 2000). However, there is no evidence that the brain keeps perceptual constancy of gravitational acceleration at varying viewing conditions. Moreover, perception and motor responses do not necessarily share a common neural estimate of viewing distance (Wei et al., 2003). Different solutions to the inverse problem have been proposed. According to the ecological theory of perception championed by Gibson (1979), sensory stimuli derived from organism-environment interactions (‘affordances’) are sufficient to recover the external source of stimulation under natural conditions, because the physical laws constrain a potentially under-determined problem, excluding all solutions that are ecologically impossible and are therefore irrelevant to perception. However, there are intrinsic limitations in the sensory signals that preclude perfect compensation of sensori-motor delays. Thus, because the visual system is essentially insensitive to target acceleration over short time epochs (e.g., Brouwer et al., 2002; Calderone and Kaiser, 1989; Werkhoven et al., 1992), the timing of interception responses as well as the perceptual judgment of elapsed time are often based on first-order algorithms including target position and velocity, but not acceleration (Kaiser and Hecht, 1995; Port et al., 1997; Senot et al., 2003). Such first-order algorithms are clearly inadequate to cope with the strong gravitational acceleration (see Zago et al., 2008). Purves et al. (2014) revisited the Gibsonian approach, and proposed that the brain does not even try to solve the inverse problem, but simply links the frequency of occurrence of biologically determined stimuli to useful perceptual and behavioral responses without recovering real-world properties. However, neither Gibson’s nor Purves’s hypotheses offer satisfactory accounts for the observation that the same visual stimuli can generate completely different responses depending on the cognitive context. Thus, subjects tend to respond too early when a target descends at constant speed vertically when the target is expected to move under the effects of earth’s gravity, while the same type of target motion is intercepted at the right time if it is not expected to be subject to gravity (Zago et al., 2004). In contrast with the ecological theory, the constructivist theory posits that sensory information is inherently ambiguous and insufficient to solve the inverse problem, and must be augmented by making ‘unconscious inferences’ about the world, constructed on past experience (Helmholtz, 1925; Shepard, 1984). The hard version of constructivism assumes complementarity in the correspondence between psychological structures and environmental structures (Shepard, 1984, 1994). Accordingly, internal representations would mirror the actual physical principles that govern the environment. For instance,

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neural anticipation of a gravitational motion would ideally be based on exact Newton’s laws. However, because cognitive judgments often appear to be inconsistent from Newtonian mechanics, psychologists have suggested that people’s intuitive physics is based on a set of shortcuts or heuristics rather than realistic models of physics (e.g., McCloskey, 1983). Nevertheless, when people’s responses are provided under naturalistic dynamic perceptual and action contexts, they are often in accord with physics as we reviewed in this article. Currently, the most plausible and general account of the experimental evidence reviewed in this article is provided by soft versions of the constructivist theory that assume either approximate models of physics (Zago et al., 2008) or exact models combined with noisy observations (Sanborn et al., 2013). Thus, probabilistic accounts have been proposed for both the estimate of vertical orientation and that of time passage. With regards to the former, Battaglia et al. (2013) validated a model that uses approximate, probabilistic simulations of mechanics to make robust and fast inferences in complex natural scenes where crucial information is missing. One of their tasks involved subjective judgments of stability under the perturbing influence of gravity of virtual towers of stacked blocks of bricks presented on a monitor. Their results provided support to the idea that human judgments are driven by rich physical simulations. At the same time, the results supported the idea that these simulations are probabilistic, by showing in some cases systematic deviations of people’s judgments from true physics, as well as the existence of stability illusions. The conceptual architecture of their model is reminiscent of that of computer graphics engines that are now used in realistic videogames. With regards to estimates of time passage, Ahrens and Sahani (2011) argued that observed biases in perceived time may ultimately derive from an adaptive use of stochastically evolving dynamic stimuli to help refine estimates derived from internal time-keeping mechanisms, essentially a process of Bayesian inference based on expectations of change in the natural environment. Finally, we note that potentially common neural regions may be involved in the weighting of multisensory cues for the perception of verticality and for estimates of the timing of physical events affected by gravity, in parallel with the observation that similar probabilistic models may account for both temporal and spatial orientation estimates. Thus, functional neuroimaging and trans-cranial magnetic stimulation have shown that several areas (such as the posterior insula and supramarginal gyrus) of multisensory network at the junction of frontal-parietal-temporal lobes engaged in the processing of timing information for visual stimuli congruent with the effects of gravity (Bosco et al., 2008; Indovina et al., 2005, 2013b; Maffei et al., 2010, 2015; Miller et al., 2008) also contribute to accurate perception of upright (Kheradmand et al., 2013). Moreover, electrophysiological studies in the monkey showed that

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Purkinje cells in the caudal cerebellar vermis encode head tilt, reflecting an estimate of the direction of gravity based on vestibular information (Laurens et al., 2013). Functional neuroimaging in humans showed that the posterior cerebellar vermis (a putative human homologue region of that studied in monkeys by Laurens et al., 2013) and vestibular nuclei are involved in combining pictorial information with the internal model of gravity to extract gravitational motion from visual scenes (Miller et al., 2008). Overall, the neuroimaging studies mentioned above (Indovina et al., 2005, 2013b; Maffei et al., 2010, 2015; Miller et al., 2008) show that the effects of gravity on visual motion are encoded in a highly distributed cortical-subcortical network. Several regions of this network co-localize with the regions independently activated by vestibular caloric stimuli (Indovina et al., 2005). These regions belong to the multi-modal vestibular network that responds to visual and neck proprioceptive stimuli, in addition to vestibular stimuli (Bense et al., 2001; Bottini et al., 2001). Lesions of vestibular cortex often lead to a tilt of SVV and rotational vertigo/unsteadiness (Brandt and Dieterich, 1999), and conversely focal electrical stimulation or epileptic discharges in these regions elicit sensations of self-motion or altered gravity (Nguyen et al., 2009). Although there is some evidence for the existence of common substrates for the perception of verticality and for the estimate of timing of gravitational motion, we cannot rule out the alternative possibility that these two sets of estimates are processed in partially segregated pathways. In this vein, VentreDominey (2014) has recently argued for distinct speed and inertial processing pathways in the vestibular cortex. According to this hypothesis, self-motion speed would be mainly processed in a pathway linking MST with the vestibular nuclei, whereas integration of inertial motion for space perception would be mainly processed in a pathway linking the parietal cortex with the vestibular nuclei complex responsible for velocity storage integration. In conclusion, we reviewed several pieces of evidence arguing that the brain is endowed with mechanisms that exploit the effects of gravity to estimate spatial orientation and time. These mechanisms are based on the combination of multisensory cues (visual, vestibular, haptic, proprioceptive) and prior assumptions about the orientation and effects of gravity. Overall, these mechanisms provide rich physical simulations that rely on probabilistic information, giving rise to either accurate performance or systematic deviations from true physics, depending on the context. Acknowledgements Our work was supported by the Italian Ministry of Health (RC and RF10.057), Italian Ministry of University and Research (PRIN grant

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Contribution of Bodily and Gravitational Orientation Cues to Face and Letter Recognition Michael Barnett-Cowan 1,2,∗ , Jacqueline C. Snow 1,3 and Jody C. Culham 1 1

3

The Brain and Mind Institute, Department of Psychology, The University of Western Ontario, London, ON N6A 3K7, Canada 2 Present address: Department of Kinesiology, University of Waterloo, Waterloo, ON N2L 3G1, Canada Present address: Department of Psychology, University of Nevada, Reno, NV 89557, USA

Abstract Sensory information provided by the vestibular system is crucial in cognitive processes such as the ability to recognize objects. The orientation at which objects are most easily recognized — the perceptual upright (PU) — is influenced by body orientation with respect to gravity as detected from the somatosensory and vestibular systems. To date, the influence of these sensory cues on the PU has been measured using a letter recognition task. Here we assessed whether gravitational influences on letter recognition also extend to human face recognition. 13 right-handed observers were positioned in four body orientations (upright, left-side-down, right-side-down, supine) and visually discriminated ambiguous characters (‘p’-from-‘d’; ‘i’-from-‘!’) and ambiguous faces used in popular visual illusions (‘young woman’-from-‘old woman’; ‘grinning man’-from-‘frowning man’) in a forced-choice paradigm. The two transition points (e.g., ‘p-to-d’ and ‘d-to-p’; ‘young woman-to-old woman’ and ‘old woman-to-young woman’) were fit with a sigmoidal psychometric function and the average of these transitions was taken as the PU for each stimulus category. The results show that both faces and letters are more influenced by body orientation than gravity. However, faces are more optimally recognized when closer in alignment with body orientation than letters — which are more influenced by gravity. Our results indicate that the brain does not utilize a common representation of upright that governs recognition of all object categories. Distinct areas of ventro-temporal cortex that represent faces and letters may weight bodily and gravitational cues differently — possibly to facilitate the specific demands of face and letter recognition.

*

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_006

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Keywords Face perception, gravity, letter recognition, multisensory, object recognition, perceptual upright, vestibular, visual

1. Introduction The vestibular system is traditionally known as a contributor to our sense of balance, self-motion and orientation. It is now well appreciated that sensory signals from the vestibular system are integrated early on with information from the other senses to facilitate these processes (see Goldberg et al., 2012, for review). It is not surprising then that the vestibular system and its multisensory connections are recently being implicated in a wide array of cognitive processes (Gurvich et al., 2013; Seemungal, 2014). One such process is object recognition, where sensory information about gravity’s direction relative to the body serves as a readily available reference on Earth for the ability to recognize objects. A reference orientation direction is fundamental to perception and action because knowing one’s orientation and the orientation of surrounding objects in relation to gravity affects the ability to maintain postural stability (Kluzik et al., 2005; Wade and Jones, 1997) as well as the ability to identify (Barnett-Cowan et al., 2013; Dyde et al., 2006), predict the behaviour of (Barnett-Cowan et al., 2011; Lupo and Barnett-Cowan, in press) and interact with surrounding objects (McIntyre et al., 2001) and people (Lopez et al., 2009). Here we further implicate the role of the vestibular system in cognition by demonstrating that the ability to discriminate ambiguous faces, which change their identity when inverted, relies less on gravitational cues (vestibular signals of upright) than the ability to discriminate ambiguous letters, suggesting that vestibular information can be differentially recruited to suit the needs of recognizing different classes of objects. The orientation at which objects are most easily recognized — the perceptual upright (PU) — is influenced by body orientation with respect to gravity as detected from the somatosensory, visual and vestibular systems (Dyde et al., 2006). To date, the influence of these sensory cues on the PU has been measured using the Oriented CHAracter Recognition Test (OCHART) where participants indicate whether the symbol ‘p’ visually presented in various orientations is the letter character ‘p’ or ‘d’. This technique has been particularly useful in identifying group (Barnett-Cowan et al., 2010a), neurological (Barnett-Cowan et al., 2010b), and environmental (Harris et al., 2012, 2014) differences in the relative role that multisensory cues have in recognizing objects. Here we sought to assess whether gravitational influences on letter recognition is similar or different from influencing other, common object categories, such as human faces by using a within-participants design.

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Objects such as trees, letters, and faces can be slow to detect and can even become unfamiliar and unrecognizable when viewed upside down (Jolicoeur, 1985; Mack et al., 2002; Thompson, 1980). Faces in particular seem to be optimally recognized when aligned with an observer’s orientation (Kohler, 1940; Rock, 1988; Troje, 2003), however more recently it has been shown that there are gravitational influences on recognizing faces even while they seem to predominantly be processed egocentrically (Chang et al., 2010; Lobmaier and Mast, 2007). In the present study we chose to measure the perceptual upright for ambiguous letters and faces for the first time using a within-participants design so that we could directly compare the contribution of bodily and gravitational orientation cues to face and letter recognition. If the brain recognizes objects of different categories with reference to a common representation of upright, we would expect letter character and face recognition to be equally influenced by body and gravitational cues. Alternatively, if the relative weighting of these cues differ across object categories, this would suggest separate category specific representations of upright. Two experiments were conducted. The first experiment assessed the general effect of body orientation relative to gravity on recognizing ambiguous letter and face stimuli as well as modeling the relative weighting of body and gravity cues on the perceptual upright for these object categories. The second experiment was a control condition to assess whether asymmetries in the direction that the ambiguous line drawings of faces looked in may have bearing on the general effects observed in the first experiment. 2. Experiment 1 2.1. Methods 2.1.1. Participants 13 right-handed participants (seven males) between the ages of 21 and 41 (mean age: 23.8, SD: 5.5) took part in the experiment. All participants were tested with the body upright, and when lying supine and left-side-down (LSD) and right-side-down (RSD). All participants had normal or correctedto-normal vision and reported no history of vestibular dysfunction. All participants gave their informed written consent. Experiments were approved by the Psychology Research Ethics Board at The University of Western Ontario and conformed to the 1964 Declaration of Helsinki. 2.1.2. Convention The orientation of all stimuli is defined with respect to the body mid-line of the participant where 0° refers to the orientation of the longitudinal axis of

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Figure 1. Stimulus probes used to measure the perceptual upright. Characters ‘p’ and ‘i’ and faces ‘young woman’ and ‘grinning man’ shown in their upright orientation (0°; top row). Inverted characters yield ‘d’ and ‘!’ and faces ‘old woman’ and ‘frowning man’ in their upside down orientation (180°; bottom row). Each probe stimulus was shown independently through a circular aperture.

the body. Positive orientations are clockwise (‘rightwards’) from this reference point, negative orientations are counter-clockwise (‘leftwards’). Thus the gravity defined ‘up’ is at +90° when the participant is lying on their left side. The letter character probes (‘p–d’, ‘i–!’) used in the OCHART test (see below) are described as being 0° when the vertical shaft of the symbol is aligned with the body axis; for the ‘p’ character with the letter bowl to the right (i.e., the symbol appears as an upright ‘p’), for the ‘i’ character with the dot on top (i.e., the symbol appears as an upright ‘i’). These are shown in Fig. 1. Figure 1 also shows the face probes which are shown in their 0° (‘grinning man’, ‘young woman’) and 180° orientations (‘frowning man’, ‘old woman’). 2.1.3. Stimulus Presentation Participants sat upright or lay on a foam mattress supine, on their right or on their left side with their head supported by foam blocks to ensure that their head was comfortably aligned with the body. Participants observed images presented in their fronto-parallel plane on an Apple MacBook Pro laptop computer with a resolution of 52 pixels/cm (31 pixels/°). The screen was masked to a circle subtending 33.7° when viewed at 30 cm by a black circular shrouding tube that obscured all peripheral vision. The laptop was mounted in an aluminum frame and fixed to a mount to maintain the screen at a fixed orientation relative to the observer (the top of the screen corresponded to the top of the participant’s head) and to hold the shroud. Participants responded by pressing one of two buttons using a gamepad held in the right hand. The buttons were pressed always with the same right (dominant) hand and the exact instruction was to “press the left button if you think you see the (letter d/i/young woman/grinning man) or the right button if you think you see the (letter p/!/old woman/frowning man)” depending on the relevant test condition.

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2.1.4. Test for Perceptual Upright (OCHART Probe) The Oriented CHAracter Recognition Test (OCHART — Dyde et al., 2006) is an indirect measure of the PU. The OCHART has the observer discriminate between the letter ‘p’ and the letter ‘d’. As the letter ‘p’ when rotated 180° becomes the letter ‘d’, the transitions from p-to-d and d-to-p when averaged define the PU. The advantage of this technique is that observers are not asked to make judgements with respect to any frame of reference, but rather only identify the character. Here we extend the use of the OCHART to another character ‘i’ which appears as an ‘!’ when upside down. This is the first time to our knowledge that the OCHART has been used and published with letters other than ‘p’ and ‘d’, although the letters ‘b’ and ‘q’ have been compared to the letters ‘p’ and ‘d’ from Dyde et al. (2006) in pilot testing (unpublished data). We used the same technique with illusory faces which can appear as a ‘young woman’ or a ‘grinning man’ in one orientation or as an ‘old woman’ and a ‘frowning man’ in the opposite orientation (Fig. 1). Using the method of constant stimuli, each probe stimulus (‘p’: 4.5° × 7.2°; ‘i’: 1.2° × 7.2°; ‘young woman’: 6.1° × 7.2°; ‘grinning man’: 5.7° × 7.2°) was presented rotated around its geometric centre in one of 24 static orientations 0°–345° in 15° increments. Each probe was presented for 500 ms as a white probe on a neutral grey background (Fig. 1). After 500 ms, stimuli were replaced with a neutral grey screen with a black central fixation point (0.3° diameter). The order of the four body orientations was selected randomly for each participant. Within each body orientation, participants were randomly assigned the order of the four probe stimuli to ensure that the instructions for each probe stimulus were clearly assigned (‘p’ or ‘d’; ‘i’ or ‘!’; ‘young woman’ or ‘old woman’; ‘grinning man’ or ‘frowning man’). Thus for each probe stimulus there were 192 trials (24 probe orientation × 8 repeats) presented in a random order. Probes were independently tested in random order within each body orientation, resulting in a total of 768 trials (192 × 4 probe types) for each randomly assigned body orientation and a total number of 3072 trials (768 × 4 body orientations) for the entire experiment. Testing took approximately 1.5 h to complete. No feedback as to participant performance was given. 2.1.5. Analysis The percentage of presentations that participants identified the probe as its veridical upright (i.e., as a ‘p’, ‘i’, ‘young woman’, or ‘grinning man’) was plotted as a function of each probe’s orientation. Two sigmoidal cumulative Gaussian functions (Eq. (1)) were fitted to the participants’ response rate to determine each of the probe transitions (e.g., ‘p-to-d’ and ‘d-to-p’, ‘young

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Figure 2. Polar plot illustrations of how the PU was measured. Observers chose whether they thought the probe stimulus was a ‘p’ (coded as a 1) or ‘d’ (0) (a), an ‘i’ (1) or ‘!’ (0) (b), a ‘young woman’ (1) or an ‘old woman’ (0) (c), or a ‘grinning man’ (1) or a ‘frowning man’ (0) (d). Typical psychometric functions fit to data obtained from such responses from a representative participant (solid lines). The two 50% points were averaged to give the PU (arrows). The angle between the LSD PU and RSD PU was taken as the BE (dashed arc).

woman-to-old woman’ and ‘old woman-to-young woman’) for each body orientation (Fig. 2). y=

100 1+e

x−x0 σ

%,

(1)

where: x0 corresponds to the 50% point and σ is the standard deviation. The average of the orientations at which these two transitions occurred was taken as the PU for each stimulus probe in body coordinates, expressing the PU for each probe in gravitational coordinates was obtained by subtracting or adding 90° to the LSD and RSD conditions, respectively. Uncertainty for each task was taken as the average of the two standard deviations estimated from the slope of the psychometric function.

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PU and uncertainty values for each probe were submitted to separate oneway repeated measures ANOVA. The Friedman repeated measures ANOVA was performed in instances of unequal variance or non-normally distributed data. A ‘body effect’ (BE), representing the total angular range between the left- and right-side-down PUs (see Fig. 2) was calculated by subtracting the LSD PU from the RSD PU, such that a larger BE represents a greater influence of the body than gravity. Analogous to measuring the overall magnitude of visual cues on the perceptual upright in coarsely sampled visual orientation cues to upright (i.e., visual effect; Barnett-Cowan et al., 2010a, b; Dyde et al., 2009; Haji-Khamneh and Harris, 2010) BE values were calculated in order to assess the effect of tilting the body relative to gravity on object recognition irrespective of possible previously reported directional biases in object recognition (Barnett-Cowan et al., 2013). BE values for each of the four probe stimuli were submitted to a one-way repeated measures ANOVA and Fisher’s least squares difference test was used to assess mean BE differences. A paired t-test between pooled BE values for letter character and face stimuli was used to assess difference between these object categories. Finally, as the letter stimuli contain less complex and ambiguous visual content of lower spatial frequency compared to faces, response times (RT) were recorded to assess whether potential differences in gravity’s influence on processing letter versus face stimuli can be accounted for by the visual complexity of the two object categories. Here a 2 (object) × 4 (body orientation) repeatedmeasures ANOVA was performed on both mean and median RT values. The Pearson product–moment correlation coefficient was also calculated between BEface –BEletter values and mean and median RTface –RTletter values to assess whether there is a relationship between RT and BE differences between face and letter stimuli. 2.2. Results In order to obtain the relative influence of the body and gravity on the perception of upright (PU) for letter characters and faces, we first obtained the direction of the PU with the directions signalled by body and gravity separated with the person upright, and laying LSD, RSD, and supine. The average directions of the PU found for each body orientation and probe stimulus are shown in Fig. 3, where a significant effect of body orientation is found for each probe (p–d: χ 2 [3] = 35.68, p < 0.001; i–!: F [12] = 37.32, p < 0.001; young–old: χ 2 [3] = 25.52, p < 0.001; grin–frown: F [12] = 35.18, p < 0.001). Here, when the body was tilted to the left, the PU shifted to the right (relative to the body, i.e., towards the direction of gravitational up) and vice versa. Analysis of the average uncertainty of the PU only found a significant effect of body orientation for the p–d stimulus (F [12] = 42.97, p = 0.011), driven by

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Figure 3. The variation of the average perceptual upright in response to body posture for each probe stimulus. The Body Effect (RSD PU–LSD PU) is shown as the magnitude of the effect of body orientation on object recognition. Note that PU values are plotted in body coordinates, where less deviation from zero suggests more bodily influence on the PU. Errors are standard errors.

Figure 4. The magnitude of the effect of the body on object recognition (left — Body Effect for each probe stimulus). Pooled BE values confirm that face recognition is more influenced by the body than letter recognition (right). Errors are standard errors.

greater uncertainty when supine compared to RSD (Holm–Sidak t = 3.11, p = 0.022). Significant differences were found in the BE among probe stimuli (F [12] = 4.12, p = 0.013; Fig. 4), whereby face stimuli were approximately 9% more

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Figure 5. A weighted vector sum model of how gravity and body orientation cues are summed to generate an estimate of perceptual upright. The prediction is shown by the direction of the dotted line representing the vector sum.

Figure 6. Model fits for the weighting of the body relative to gravity (fixed to 1; dashed line) for each of the probe stimuli (left). Model fits to the pooled letter and face stimuli confirm that face recognition is more influenced by the body than letter recognition (right). Errors are standard errors.

influenced by the body (mean BE = 144.9, s.e. = 5.2) than letter stimuli (mean BE = 132.8, s.e. = 4.6; t[12] = 3.28, p = 0.007), while there were no differences in BE values within object categories. To further assess the role of bodily and gravitational cues to letter and face recognition, the full dataset for all body orientations (LSD, upright, RSD, supine) was fit using a simplified model of Dyde et al. (2006) and the Marquardt–Levenberg optimization algorithm technique (Press et al., 1988) in which the PU is modeled as the simple linear sum of two weighted vectors corresponding to the body and gravity cues (see Eq. (2); Fig. 5). −−→ P U = b × b + g × g, (2) where b (body) and g (gravity) are the directions signalled by each cue, weighted by factors b and g respectively, such that the relative length of each vector indicates the extent to which the PU is influenced by each factor. The results, shown in Fig. 6, closely confirm those of the BE analysis (Fig. 4) wherein face recognition is approximately 6.3% more influenced by the body

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(body:gravity = 3.16:1, s.e. = 0.55, 75.9%) than letter stimuli (body:gravity = 2.29:1, s.e. = 0.34, 69.6%). The relative contribution of the body to gravity for letter stimuli is comparable to that previously reported by Dyde et al. (2006) (2.61:1, 72%); however it should be noted that these authors also simultaneously measured visual influences on the perceptual upright for letters. Finally, no significant effects of object type (letters vs faces), body orientation or their interaction was found using both mean RT (object: F [12] = 0.25, p = 0.626; body: F [3, 36] = 0.6, p = 0.619) and median RT (F [12] = 3.66, p = 0.08; body: F [3, 36] = 0.94, p = 0.43). No significant Pearson product– moment correlation coefficients were found between BEface –BEletter values and mean and median RTface –RTletter values (mean: r[13] = −0.011, p = 0.972 median: r[13] = −291, p = 0.335). 3. Experiment 2 As the ambiguous line drawings of faces used in the first experiment are not mirror symmetric (i.e., the young woman is portrayed looking to her right, whereas the old woman is portrayed as looking to her left; Fig. 7), a control condition was conducted to assess whether this view-dependent difference in the ambiguous figures could influence the general effects reported in the first experiment. Here, if body position is the determining factor, then the portrayed view in the line-drawing faces should have little or no effect. To assess this we presented a second group of observers with the original images or left–right mirror inversions of these images mixed within the same testing session when the body was oriented LSD, upright, or RSD.

Figure 7. Stimulus probes used to measure the perceptual upright also used in the first experiment (a) and mirror flipped control stimuli (b). Faces ‘young woman’ and ‘grinning man’ shown in their upright orientation (0°; top row). Inverted faces ‘old woman’ and ‘frowning man’ in their upside down orientation (180°; bottom row). Each probe stimulus was shown independently through a circular aperture.

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3.1. Methods 3.1.1. Participants Nine right-handed participants (five males) between the ages of 18 and 35 (mean age: 23.6, SD: 4.9) took part in the experiment. All participants were tested with the body upright, and when lying left-side-down (LSD) and rightside-down (RSD). All participants had normal or corrected-to-normal vision and reported no history of vestibular dysfunction. All participants gave their informed written consent. Experiments were approved by the Psychology Research Ethics Board at The University of Western Ontario and conformed to the 1964 Declaration of Helsinki. 3.1.2. Procedure We used the same convention, method of stimulus presentation, and analysis of the PU as outlined in the first experiment using only the face probes which were either shown in the same manner as the first experiment (‘young woman’ and ‘grinning man’ both looking leftward at 0°; Fig. 7a) or their mirror opposite (‘young woman’ and ‘grinning man’ both looking rightward at 0°; Fig. 7b). Using the method of constant stimuli, each probe stimulus was presented rotated around its geometric center in one of 24 static orientations 0°–345° in 15° increments. The order of the three body orientations was selected randomly for each participant. Within each body orientation, participants were randomly assigned the order of the two face stimuli to ensure that the instructions for each probe stimulus were clearly assigned (‘young woman’ or ‘old woman’; ‘grinning man’ or ‘frowning man’). Original (Fig. 7a) and mirror flipped stimuli (Fig. 7b) were randomly mixed within a face type in the same testing session. Thus for each probe stimulus there were 192 trials (24 probe orientation × 8 repeats) presented in a random order. Probes were independently tested in random order within each body orientation, resulting in a total of 768 trials (192 × 4 probe types) for each randomly assigned body orientation and a total number of 3072 trials (768 × 4 body orientations) for the entire experiment. Testing took approximately one hour to complete. No feedback as to participant performance was given. PU and uncertainty values for each probe were submitted to separate oneway repeated measures ANOVA. A ‘body effect’ (BE), representing the total angular range between the left- and right-side-down PUs was calculated by subtracting the LSD PU from the RSD PU, such that a larger BE represents a greater influence of the body than gravity. BE values for each of the four probe stimuli were submitted to a one-way repeated measures ANOVA and Fishers least squares difference test was used to assess mean BE differences. A paired t-test between pooled BE values for original and mirror flipped face stimuli was used to assess difference between probe orientations.

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3.2. Results A replication of the main effects found for the relative influence of the body and gravity on the PU for faces used in the first experiment is shown in Fig. 8 (white bars) as well as their mirror images (grey bars), where a significant effect of body orientation is found for each probe (young–old: F [2, 16] = 6.79, p = 0.007; grin–frown: F [2, 16] = 24.37, p < 0.001). While there was a significant effect found for mirror flipping each probe (young–old: F [16] = 22.17, p = 0.002; grin–frown: F [16] = 49.76, p < 0.001), original and mirror flipped PU values were much restricted in range compared to letter PU values observed in experiment 1 (Fig. 8; dashed lines). Analysis of the average uncertainty of the PU found no significant effects of body orientation or image orientation for any of the probe stimuli. Significant differences between original and mirror flipped probe stimuli can be explained by biases in the PU independent of the BE. Figure 9 shows the BE among probe stimuli where although a difference in the BE was found between the two face types (F [3, 24] = 4.64, p = 0.011), no difference was found between original and mirror flipped probes (t[8] = 0.94, p = 0.374).

Figure 8. The variation of the average perceptual upright in response to body posture for each probe stimulus. Original (white) and mirror-flipped (grey) PU values were more restricted in range compared to letter PU values observed in experiment 1 (dashed lines). Note that PU values are plotted in body coordinates, where less deviation from zero suggests more bodily influence on the PU. Errors are standard errors.

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Figure 9. The magnitude of the effect of the body on object recognition (left — Body Effect for each probe stimulus). Pooled BE values confirm that mirror flipping the face probes does not significantly affect the BE (right). Normal and flipped face stimuli BE values well exceed those obtained for letter stimuli in the first experiment (Fig. 4; dashed line). Errors are standard errors.

3.3. Discussion We found that while both letters and faces are strongly influenced by egocentric cues (body orientation), faces are more optimally recognized when they are aligned with the body when compared to letters — which are comparatively more influenced by gravity. The difference in the magnitude of the body effect for the two types of stimuli suggests that letters and faces are represented by the central nervous system in a slightly different manner. In agreement with previous experiments that have found a small but still significant role of gravitational cues to face recognition (Chang et al., 2010; Lobmaier and Mast, 2007), our results confirm an influence of gravity on the ability to discriminate ambiguous face stimuli. Importantly, we found no evidence suggesting that the difference in gravitational effects on letter versus face recognition is based on the complexity of the stimuli. Our results indicate that the brain does not utilize a common representation of upright that governs recognition of all categories of objects. Rather, upright appears to be defined locally within an object category. Spatio-temporal differences in processing faces, words, and other objects have been repeatedly reported in the literature, suggesting that the processing of information in the human object recognition system is divided into functionally independent networks each specialized for processing certain types of visual form information (Bentin et al., 1996). Activation differences between faces and objects in the regions of the inferior occipital gyrus and middle fusiform gyrus (e.g., Kanwisher et al., 1997; Puce et al., 1996; Sergent et al., 1992; see Haxby et al., 2000), and in the left fusiform gyrus for letter strings com-

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pared to numbers and shapes (the ‘Visual Word Form Area’, McCandliss et al., 2003), although the two regions are thought to be homotopic and share some functionality (Behrmann and Plaut, 2013). A large number of imaging studies have shown that compared to other objects, pictures of faces activate the occipito-temporal cortex (posterior and middle fusiform gyrus) bilaterally, with a right-hemisphere advantage (e.g., Hasson et al., 2002; Puce et al., 1996; Sergent et al., 1992). In contrast, letters evoke activation that is primarily restricted to the left lateral fusiform gyrus and occipitotemporal sulcus (Hasson et al., 2002; Polk et al., 2002; Puce et al., 1996; Sergent et al., 1992). As the current study only focused on letter and face stimuli, future work could also assess other objects (e.g. animals, cars, plants) in order to confirm whether differences between letters and faces reported here is associated rather with complex objects in general or is specific to faces. Given the rather diffuse connectivity of vestibular projections to the cortex (Hitier et al., 2014), we speculate that distinct areas of ventro-temporal cortex that represent faces and letters may weight bodily and gravitational cues differently whereby different sensory weightings possibly reflect the facilitation of the specific demands of face and letter recognition in the presence of conflicting frames of reference. A possible, not mutually exclusive, alternative explanation for our results could be that faces are processed differently in terms of cognitive mechanisms, which is reflected in the different brain areas and networks listed above. For example, it has been shown that words are not processed as holistically as faces (Puce et al., 1996; Richler et al., 2011). Another explanation could be that different image statistics in daily life such as the frequency with which faces and words are seen in different orientations could generate prior expectations and image processing efficiencies for optimally processing faces when upright, as faces are most often upright relative to the observer, as opposed to letters which are more likely to assume nonupright orientations relative to the observer such as when reading and writing.

Acknowledgements MB-C was supported by a Banting Postdoctoral Fellowship from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Ontario Ministry of Economic Development and Innovation. The project was funded in part by an NSERC Discovery Grant (249877-2006-RGPIN) and Discovery Accelerator Supplement to JCC. The authors thank Derek Quinlan for building equipment as well as Paul Armstrong, Stephan Poirier, and Scott Squires who helped with data collection.

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Internal Models, Vestibular Cognition, and Mental Imagery: Conceptual Considerations Fred W. Mast 1,2,∗ and Andrew W. Ellis 1,2 1

Department of Psychology, University of Bern, Fabrikstrasse 8, 3012 Bern, Switzerland 2 Center for Cognition, Learning and Memory, University of Bern, Switzerland

Abstract Vestibular cognition has recently gained attention. Despite numerous experimental and clinical demonstrations, it is not yet clear what vestibular cognition really is. For future research in vestibular cognition, adopting a computational approach will make it easier to explore the underlying mechanisms. Indeed, most modeling approaches in vestibular science include a top-down or a priori component. We review recent Bayesian optimal observer models, and discuss in detail the conceptual value of prior assumptions, likelihood and posterior estimates for research in vestibular cognition. We then consider forward models in vestibular processing, which are required in order to distinguish between sensory input that is induced by active self-motion, and sensory input that is due to passive self-motion. We suggest that forward models are used not only in the service of estimating sensory states but they can also be drawn upon in an offline mode (e.g., spatial perspective transformations), in which interaction with sensory input is not desired. A computational approach to vestibular cognition will help to discover connections across studies, and it will provide a more coherent framework for investigating vestibular cognition. Keywords Vestibular, mental imagery, subjective vertical, modeling, Bayes, forward model, psychophysics, anticipation

1. Introduction The term vestibular cognition has made a relatively recent appearance. In the absence of a clear definition, there is much room for interpretation about what it could actually mean. At what point does the processing of vestibular information enter the realm of cognition? Why has this cognitive connection not *

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_007

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been pointed out much earlier? Does all vestibular science belong to the field of vestibular cognition? If not, when is vestibular research cognitive, and when is it not? Interestingly, it has been shown that lower-level reflex arcs, such as the vestibular–ocular reflex (VOR), are susceptible to top-down influences. Hine and Thorn (1987) showed that the gain of the VOR adjusts as a function of imagined target distance. Imagined targets do not stimulate the retina, and thus, there is no direct sensory input that is responsible for the change in VOR gain. Therefore, vestibulo-ocular mechanisms do not operate in a purely reflexive manner; they are interfaced with higher cognitive processes. Indeed, the gain of the VOR is malleable by top-down processes (see also Nigmatullina et al., 2015). How sensorimotor and cognitive processes are nested and intertwined still needs to be elaborated, and we present in this contribution some conceptual considerations as to how these interactions could manifest themselves. In particular, basic and clinical vestibular science has for a long time emphasized the rather reflexive and automatic parts of the processing of vestibular information. We focus on how the brain computes predictions of vestibular stimuli, and how this network can be used in an offline mode in the service of mental imagery. At first glance, there seems to be no obvious connection between predictions and mental imagery. However, Moulton and Kosslyn (2009) proposed that visual mental imagery should be conceived of as a mechanism that enables anticipation of future sensory signals (perceptual anticipation hypothesis). Referring to the example with the adaptation of the VOR gain, imagined targets can be considered to function similarly to predicted targets, and this allows for flexible adjustments of the oculomotor system to incoming visual stimuli. This perspective is rather new to the vestibular domain but there are several compelling demonstrations in vision research. For example, Laeng and Sulutvedt (2014) were able to show that pupil diameter changes as a function of the luminance of imagined stimuli, and that these changes were similar to changes due to the luminance of actually perceived stimuli. In light of the perceptual anticipation hypothesis, the pupil diameter can be adjusted in advance when bright visual input is expected. We will see further below to which extent we can emphasize the similarities between predicted sensory input and imagined sensory experience, and what kind of conceptual considerations need to be taken into account. 2. Internal Models The brain is able to generate guesses about the state of the world and expected sensory input by combining information from previous sensory measurements and internal models of the world. Internal models represent physical properties or statistical regularities of the world, and they can improve the estimate of the

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state of the world. In vestibular research, many models have been suggested, ranging from relatively simple models aimed at explaining optimal behavior in psychophysical tasks to more complex dynamic models (see MacNeilage et al., 2008, for a summary). A fundamental property of dynamic models is that they combine prior information and sensory signals in order to estimate a current state of the world, and they then use the current state in order to generate predictions for future sensory signals. It is important to point out that most modeling approaches in vestibular science include a top-down or a priori component and are therefore a promising way to stimulate the emerging field of vestibular cognition. In order to investigate vestibular cognition, it is advantageous to attempt a synthesis between low-level models, such as Karmali and Merfeld (2012), which are successful at explaining experimental findings at the level of sensory processing, and the field of vestibular cognition, where so far only few attempts have been made at understanding processing at a computational level. In essence, we can see two conceivable ways to investigate vestibular cognition: (1) How is vestibular information involved in different cognitive tasks or, in the reverse direction, (2) how cognitively penetrable is the processing of vestibular information? Can the perception of vestibular stimuli be manipulated by cognitive factors, such as task requirements, instructions, expectations or beliefs? We focus on the second question. A first example was provided above; the gain of the VOR is malleable by cognitive information (imagined target distance). In the following we will consider two further vestibular tasks in more detail: the subjective visual vertical (SVV), and the problem of disambiguating tilt from translational movement. We will particularly focus on the SVV task because it serves the purpose of a suitable entry point for vestibular cognition. 3. The Subjective Visual Vertical There is no doubt that sensory signals from the otoliths are involved in the SVV task. Numerous clinical studies demonstrate that the SVV is sensitive to the side of the lesion (e.g., Böhmer and Mast, 1999). Besides the clinical applications, the SVV is a compelling perceptual phenomenon, and it can be observed outside the laboratory. When one is in a darkened room, lying in bed with the right or left ear down (horizontal position), with light entering the room only through the crack in the door, the orientation of the light appears to be tilted. This happens despite the fact that we know that it must be upright; the crack in the door does not appear in its true vertical orientation but rather tilted opposite to the direction of head tilt. Many psychophysical studies have assessed the SVV over a wide range of body positions, and typical deviations like the A- and E-effect have been observed as a function of body tilt (A-effect: the SVV is set toward the orientation of the body axis; E-effect:

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the SVV is set opposite to the orientation of the body axis). What is the cause of these inaccurate estimations of the vertical? It has long been believed that in complete darkness, extra-retinal sensory data do not provide adequate information about body orientation with respect to gravity. Therefore, A- and E-effects were considered to occur as a result of erroneous gravity-receptive information (Van Beuzekom et al., 2000; van Beuzekom and Van Gisbergen, 2001). However, this conclusion cannot be supported. While there is absolutely no doubt that sensory signals from the otoliths are inherently noisy, this fact cannot account for the inaccuracy of the SVV, as demonstrated by Mast and Jarchow (1996). In this experiment, participants adjusted themselves to the subjective horizontal position (SHP) in darkness (i.e., the body position in which they felt perfectly horizontal). The performance demonstrated that participants were neither accurate (mean SHP: 96.3°) nor precise (SD: 19.7°). Importantly, and this is the crux of the matter, the authors were able to show that the subjective visual horizontal (SVH) cannot be derived from measurements of the SHP. The participants were asked to align a visual line to the perceived horizontal. Since they positioned themselves to the SHP one might assume that it would suffice to simply adjust the visual line to one’s own body axis (as shown by Haustein and Mittelstaedt, 1990). Indeed, participants could have solved the task by logical reasoning: They felt perfectly horizontal, and thus, a visual horizontal line could be set in line with their body axis. But this is not what participants did. On average, they adjusted the visual line further down by 27.4° with respect to their body axis (i.e., 0° would have resulted if the participants had adjusted the SVH in line with their body axis). The SVH was roughly orthogonal to the expected SVV. Taken together, there is inaccurate sensory information about the position with respect to gravity (SHP), but this inaccuracy cannot explain the SVH. How do the two tasks differ? For the SHP, the participants have to adjust their own body orientation with respect to the gravitational vertical, and for the SVV, they have to adjust an external indicator (usually a luminous line) to the gravitational vertical (or horizontal for the SVH). Evidently, gravity is used as the external reference in both tasks, but the external indicator to map the vertical in world-fixed coordinates introduces a difference between the tasks. The example of the SVV shows that sensory processes alone cannot account for perceptual judgments. A convincing solution to this problem was proposed by Mittelstaedt (1983). 4. Prior Guesses In order to explain the characteristic errors in the SVV task, Mittelstaedt (1983) introduced an internal bias signal (idiotropic vector). The concept of the idiotropic vector had a huge impact on subsequent research. It is modeled as a head-fixed vector that is added to the sensory measurements provided by

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the otoliths. The idiotropic vector is aligned with the body’s long axis and is independent of the body’s orientation with respect to gravity. The idiotropic vector can explain the A-effect, and its length varies between individuals to account for individual differences in SVV measurements. It is of non-sensory origin, and it can be seen as a top-down mechanism that may not need to reach conscious awareness. Mittelstaedt’s research inspired subsequent interpretations of the idiotropic vector; Eggert (1998) showed that it could be interpreted as a prior guess that the head is closely aligned with the gravitational vertical. In order to compensate for the noise in the sensory signals from the otoliths, the brain assumes that the head is aligned with the direction of gravity, and then the otolith signal is merely a deflection from that headfixed signal. The body tilt angle is not measured, but constructed, using prior knowledge about the expected position of the head with respect to gravity. This effectively reduces the noise when the assumption is valid, that is, when the head is near upright, but leads to errors when the assumption is violated, thus explaining the A-effect. Clemens et al. (2011), building on a previous model formulated by De Vrijer et al. (2008, 2009), presented a Bayesian optimal observer model that explained behavioral data in the SHP and SVV tasks described above, and the differences between the tasks. In particular, the characteristic A-effects in the SVV are explained in terms of the brain optimally combining noisy sensory measurements with a prior belief that the head’s tilt position is usually aligned with gravity. In a Bayesian model, all signals are modeled as probability distributions, rather than as single values. If the prior assumption is appropriate, i.e., the prior is unbiased, the resulting estimate of the head’s tilt position, obtained by combining sensory measurements and prior belief according to Bayes’ theorem, is accurate and more precise than if the measurements had been used alone. The prior belief that the head is usually upright can be expressed by letting the prior estimate be a normally distributed random variable with an expected value of 0. The variance of the prior distribution reflects the certainty of belief in the prior assumption. If the sensory measurements (or likelihood in Bayesian inference) are also normally distributed, with a mean given by the actual tilt angle, then the posterior estimate is also a normally distributed variable. The posterior estimate is adjusted toward the mean of the sensory measurements, according to the level of noise in the measurement. The posterior precision (the inverse of variance), is equal to the sum of the prior and likelihood precisions, and is therefore never less than the precision of the data alone. In fact, for a given set of measurements and a prior distribution with a fixed mean, an increase in prior precision leads to an increase in posterior precision, and the posterior mean will be pulled toward the prior mean. This dual effect on the posterior estimates is illustrated in Fig. 1, for the case that the prior assumption about the position of the head

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Figure 1. The effect of the prior precision for a fixed prior mean and a given set of sensory measurements. The example represents data from a human observer lying at a tilt angle of 96°. The sensory measurements are shown as grey histograms (adapted from Mast and Jarchow, 1996). Rather than relying on the data alone to estimate head tilt, the observer incorporates prior knowledge. This prior, shown as a solid black curve, reflects the fact the observer assumes that the upright position is more frequent than other body positions. The uncertainty of the prior distribution is expressed as the standard deviation. Each subplot shows a different prior with a different standard deviation. Panel A: 25°, panel B: 12°, panel C: 6°. The posterior estimate of the tilt angle is shown as a dashed line. When using a prior with a standard deviation of 25° (upper panel), the posterior estimate is centered close to the mean of the data sample, and the uncertainty regarding the posterior estimate is less than that of the sensory measurement. In the middle panel, the observer is using a prior with a standard deviation of 12°, and the effect of this is twofold: due to the higher certainty, the prior carries more weight, and thus the mean of the posterior is biased towards the prior. In addition to this, also as a consequence of the higher certainty in the prior, the observer is also slightly more certain of his posterior estimate. In the lower panel, the influence of the prior on the posterior estimate is even more exaggerated.

with respect to gravity is inappropriate. Previous modeling approaches inspire new questions that go beyond the explanation of the SVV under static conditions. For example, Clemens et al. (2011) assume that the prior estimates of the head tilt position are drawn from a normal distribution with a fixed mean, which cannot be adjusted. Consequently, it is not possible for the model to take into consideration the recent history of head tilt position (Schöne and LechnerSteinleitner, 1978), the awareness of body tilt information (Barra et al., 2012) or other contextual information.

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While it is true that direction and magnitude of the gravity vector remain constant on earth, this is not necessarily evident from a perceptual point of view. The direction of gravity with respect to head or body coordinates varies as a function of the body’s motor actions. The estimated direction of gravity requires constant updating, and thus, prior beliefs can unfold their effect on the posterior estimate. In a previous study we were able to demonstrate that not only perceived (e.g., Asch and Witkin, 1948) but also imagined visual information can bias the SVV (Mast et al., 1999). The participants had to imagine a tilted grating while judging the vertical. The gratings contained parallel lines and induced a cue for horizontality. Mast et al. (1999) showed that imagined gratings exert a similar influence on the SVV as actually perceived gratings. Depending on its orientation, the visual context can influence the SVV. This demonstrates that the SVV is malleable by cognitive processes; the lines are purely imagined and there is no visual stimulus to be processed. Imagined lines can alter the way we perceive where up and down is. On the one hand, this may appear surprising. How we perceive the direction of gravity is vital and undesired interference should be minimal. On the other hand, however, it is absolutely evident that the non-sensory influence of the prior is necessary for a useful estimate of gravity (see Fig. 1). These seemingly contradictory statements can be reconciled in a conceptual model that we will introduce and discuss below. The finding of Mast et al. (1999) means that imagined lines can be seen as a prediction about the status of the world. Mental imagery serves to anticipate future events. This means that a prior belief about the state of the world is built up, and it exerts an influence on the SVV. Malleability by predictions is functional even in a relatively simple task like the SVV. In this case, the prior assumption is based on expected visual regularities in the real world (perceived or imagined), and the posterior estimate changes depending on the prior expectations. This input adds more flexibility to the system. 5. Tilt Translation Ambiguity In order to estimate the SVV, the brain needs to have an estimate of the position of the body relative to gravity. To obtain this information it is not possible to rely solely on sensory information. Due to Einstein’s equivalence principle, a measurement device cannot distinguish between inertial and gravitational force. In order to determine whether the gravitoinertial force (GIF) measured by the otoliths is due to translational movement, or due to a tilt of the head with respect to gravity, the brain must make additional a priori assumptions. Merfeld et al. (1999) and Angelaki et al. (2004) proposed models in which sensory information from the semi-circular canals is combined with otolith information in order to obtain an estimate of the inertial component of the GIF.

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MacNeilage et al. (2007) introduced a Bayesian model, which makes use of information from the visual system in order to disambiguate the sensory input. This model also incorporates prior assumptions, one of which corresponds to the idiotropic prior assumption in Clemens et al. (2011). Taken together, a common theme to all these models described above is that they make use of an internal model that reflects physical properties of the world. The internal model usually comprises two separate parts. One part is a forward model, which receives the input signal and generates predictions of sensory data. In order to achieve this, the forward model receives an efference copy of a motor command from a motor center and computes as output a prediction of the sensory state (Von Holst and Mittelstaedt, 1950). The second part is an inverse model, which is used in order to estimate the internal states and the actions that would need to be made in order to bring about desired outcomes. An intuitively obvious use for such a forward model in vestibular processing is when the brain has to distinguish between sensory activity that is induced by active self-motion, and activity that is due to passive self-motion. Cullen et al. (2009, 2011) show that neurons in the vestibular nuclei are less sensitive to active motion as compared to passive motion even though the sensory input is identical. They propose that a forward model, which provides the sensory predictions used to attenuate vestibular signals due to active motion, is implemented in the vestibular cerebellum. Laurens et al. (2013) demonstrated that neurons in the monkey cerebellum reflect the output of a forward model that provides predictions with respect to perceived motion rather than the physical motion profile. Thus, the monkeys in this study are experiencing a perceptual illusion, in which the forward model erroneously estimates a rotation, and it is claimed that the monkeys perceive rotation despite the absence of any appropriate signal from the semicircular canals. We will later see that the fundamental distinction between self-generated vs. passive movements can be reconsidered outside the context of motor behavior. 6. Mental Imagery In previous paragraphs, we have focused on basic vestibular perception, and it became evident that prior guesses of non-sensory origin and forward models contribute to simple tasks in spatial orientation and self-motion perception. Now, we will focus on mental imagery. This is an area of research that is seemingly remote from the contents of the previous chapters, and we will elaborate on the links between mental imagery, and sensorimotor processing. Indeed, it is not at all uncommon to simulate motion or tilt in the absence of the corresponding sensory input, and vestibular imagery is an integral part of imagined spatial body transformations (Falconer and Mast, 2012; Grabherr et al., 2011;

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Kessler and Thomson, 2010; Lenggenhager et al., 2008; Van Elk and Blanke, 2014). We can voluntarily imagine movement of our bodies through space, or being tilted when we are in fact perfectly upright. For example, picture yourself standing upright at a bus station, patiently waiting for the next bus. You have recently returned from a summer vacation by the seaside, and — while you are waiting — you get lost in fond memories of lying on the beach. You are vividly imagining the relaxing feeling of lying on your back on the beach, snuggled happily to the sandy surface, your legs are stretched out, and you feel a cool breeze on your toes. When the bus arrives, all of a sudden you are pulled back into reality. Luckily, however, your first reaction is not to attempt to stand up, even though you were fully immersed in your inner world, in which you were actually lying on your back. What happens in this example? It is possible that two estimations of the vertical are simultaneously active. One is used for controlling upright stance, and the other is used in the service of mental imagery. Evidently, the two verticals are not aligned but rather deviate by roughly 90°. Referring to the example given above, imagined tilts are necessary for creating vivid images that simulate a perceptual state. It is as if the estimate of gravity, usually used for assessing the SVV, were copied, and the copy (and only the copy) is mentally rotated independently to a new target orientation (90° in the example above). This shift in imagined orientation enables us to vividly imagine body tilts while still upright (and vice versa, for example imagine yourself in an upright position while actually still lying in bed). How can we create in our mind the quasi-sensorial experience of being tilted while the body remains physically upright? Given that the brain uses sophisticated forward models that generate sensory predictions, it is by all means conceivable that the same mechanisms are used in generating mental simulations, such as mental imagery of vestibular sensations. For example, in order to predict sensory signals that are due to a rotation of the head about the yaw axis, the brain must possess are very detailed model of how actual physical rotation would affect the signals from the semicircular canals. In other words, the brain must posses a detailed model of the effect of physical movement on its afferent sensory signals. It seems a small step to assume that in order to perform cognitive tasks requiring mental self-rotations (i.e., mental imagery or spatial perspective taking) the brain reuses this knowledge of the body’s sensorimotor interactions with the physical world (i.e., its internal model of spatial transformations). Therefore, vestibular cognition can be viewed as the phenomenon of the brain flexibly ‘reusing’ the knowledge of its sensorimotor interactions with the physical world in the service of many different tasks, in an offline manner (in the sense that the brain is then disengaged from actual sensorimotor interactions with the environment). Figure 2 illustrates how we may incorporate cognitive processes such as mental imagery into a general model of motor control (Karmali and Mer-

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Figure 2. Standard dynamical system used in models of motor control. Motor intentions are converted into motor commands. These are implemented by the motor system (referred to as the plant) and affect the states of the body (its sensory systems) and the environment. Noisy measurements of the environment are transmitted to be compared with predictions from a forward model. The difference between actual and predicted sensory signals is then passed through a gain control mechanism, which regulates the system’s sensitivity to predictions errors. The predicted sensory signals are computed by a forward model, which receives an efference copy of the motor commands sent to the motor plant. Both motor commands and efference copy are represented by thick dashed lines. If the sensitivity is set accordingly, prediction error signals are fed back into the internal model. The internal model can then be improved, in order to make more useful predictions. Additionally, feedback signals can be sent to higher centers, which can adjust intentions and motor behavior (overt mode). Additions to the standard model are shown as thick solid lines. If the system is to be used in covert mode, i.e. for offline processing, including mental imagery, the forward model must receive signals from higher centers, but these signals cannot be sent as motor commands to the motor plant. Furthermore, we propose that the brain must be able to regulate its sensitivity to incoming sensory signals, as during covert processing, any comparison between actual and fictive sensory signal would be undesirable.

feld, 2012). This follows an approach taken by models in cognitive robotics in which a covert mode is implemented besides overt action execution (see for example Chersi et al., 2013). It is exactly the covert mode that is of crucial importance; it is the prerequisite for mental imagery that can happen outside of ongoing interactions with the external world. However, the covert mode engages the same mechanisms used for online control of behavior. We first explain the components involved in the online mode. As explained above in the context of the tilt-translation ambiguity, the brain makes use of internal models of sensorimotor processes. The forward model as part of the inter-

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nal model uses an input signal received from a higher-level center in order to predict the sensory measurements of the controlled system. These predictions are vital in normal online operation, for example in order to counteract delayed incoming sensory signals. The predicted sensory signals, also known as ‘corollary discharge’, are constantly compared to the reafferent signals in order to compute a prediction error signal. This prediction error represents aspects of the external world that the model was unable to predict. Note that the sensory stimulus is processed in the sensory buffer. The prediction error is fed back into the internal model, in an ongoing cycle of prediction and model checking. Changes to the internal model can inform the higher-level centers through a feedback loop, resulting in eventual changes of intentions and goals. An essential component is the gain control. This parameter determines the influence that sensory prediction has on the correction of the internal model, and thus controls the system’s sensitivity to, for example, incoming sensory signals. It is important that the gain depends on the estimated noise levels in the sensory signal. If the sensory signals are considered unreliable, then any prediction error made by the system will not lead to a great adjustment of the internal model. Exactly this type of model can be used to explain how the brain may distinguish between actively generated and passive self-motion signals by using an efference copy from the motor commands that initiate the movement as input to a forward model, and then predict the expected vestibular motion signals. Cullen et al. (2009) show that vestibular signals due to active self-motion, which can be predicted by the organism, are greatly attenuated relative to unpredictable motion, which are the result of passive motion. We suggest that mental imagery could be understood as the offline application of forward models, in which the predictive, top-down component is used, but without engaging the usual sensorimotor interaction with the external world. This is exactly what is meant by the covert mode. Interestingly, much current research in functional magnetic resonance imaging lends support to the idea that mental imagery draws on — to a considerable extent — the same circuitry that is also involved in perception (Cichy et al., 2012; Slotnick et al., 2005, 2012). A logical next step is to claim that this strong top-down activation of sensory areas through imagery is related to the prediction mechanism. This would essentially mean that the large overlap between mental imagery and perception might be explained by the common use of predictive mechanisms. Based on the conceptual model illustrated in Fig. 2, we claim that predictive mechanisms are engaged in mental imagery and perception, and this leads to another yet more fundamental question: If the internal model, especially the forward model can be used in online and offline mode, how can the system differentiate between predictions due to overt sensorimotor interactions, and predictions made as a result of covert top-down signals?

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A possible solution to this problem might lie in the gain control mechanism. This gain control is adjusted according to the estimated noise levels of incoming sensory signals in online mode. However, the prediction error signal plays an entirely different role in offline mode. During mental imagery, the prediction error signal is not of interest. Importantly, in the covert mode, the brain needs to regulate the gain control mechanism, in order to ensure that imagined information remains disengaged from the external world. In statistical terms, the online mode could be a hypothesis generating and testing mode (Gregory, 1980), whereas during offline processing, the brain is merely trying to generate hypotheses, without testing them on the world. This is similar to an idea recently proposed by Hobson et al. (2014), in which they discuss the role of dreaming and its relationship to online sensory processing within the context of active inference (Friston et al., 2012). Taken together, it has to be pointed out that imagery is based on sensory predictions (predicted reafference) and it is thus an integral part of the brain’s general operation mode. We suggest that sensory predictions can be either of covert or overt origin. The latter allows for the distinction between active and passive self-motion whereas the former provides the possibility to access forward models in an offline mode. That is, for example, a representation of the body can be rotated mentally while the physical body remains upright. This is exactly the case in spatial perspective transformations. There is strong behavioral evidence that speaks to the account in which body movements are emulated during spatial perspective transformations (e.g., Kessler and Thomson, 2010). So far, however, only very few studies have addressed the role of vestibular information in spatial perspective transformations (Falconer and Mast, 2012; Lenggenhager et al., 2008; Van Elk and Blanke, 2014). The use of different techniques makes it difficult to compare the results from these studies, but they all suggest involvement of the vestibular network in an offline mode. There is a need for more research to better understand the link between the processing of vestibular information and spatial perspective transformations. At this point, we can only speculate about the neuronal implementation that would distinguish between predictions that are due to either the overt or the covert mode. Pickering and Clark (2014) state that is currently an unanswered question whether the brain actually uses distinct circuitry for forward models, or whether the required predictions are generated using the same circuits that represent sensorimotor activity (e.g., using a different temporal code). 7. Further Experiments The conceptual model as it is currently conceived entails that the offline mode produces signals (covert predictions) that propagate all the way down the hierarchy. It is likely that this will lead to interference effects. With respect

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to the conceptual model outlined above, interference effects imply that predicted sensory signals produced by the covert mode are not fully cancelled by gain control mechanisms. Mast et al. (1999, 2001) provide evidence that imagining static lines or moving dots influences the estimate of gravity. These experiments were first empirical demonstrations, and they are based on visual imagery. More specific experiments are needed to test the role of vestibular imagery and how it interferes with vestibular perception. An example is Mertz and Lepecq (2001), who found that imagined roll tilt position induced E-like effects in an SVV task. The cause of this is attributed to shared mechanisms between imagery and perception. Given the fact that the field of vestibular cognition is new and only few investigations have been carried out to address the underlying mechanisms, the conceptual model can be backed up by several other findings. For example, bilateral vestibular patients have impaired performance in spatial perspective transformations (but not in object-based mental rotation tasks, which rely on a different cognitive operation; Grabherr et al., 2011). This suggests that the forward model no longer produces appropriate covert or overt predictions. In a broader sense, the field of motor imagery is an area of research that has brought forward compelling evidence that motor imagery involves some of the same mechanisms engaged during the execution of actual movements. The inhibition process proposed by Jeannerod (2001) has been proposed to prevent covert action from being executed, and this suggests a connection with the gain control mechanism. This could account for clinical cases such as a patient reported by Schwoebel et al. (2002). The patient with a bilateral posterior parietal lesion was unable to imagine a sequence of finger movements without simultaneous execution of the movements. There was no doubt that the patient understood the instructions to imagine the movements. To what extent an active inhibition of overt motor behavior takes place during motor imagery is still an open question, and would go beyond the scope of this contribution with a particular focus on vestibular information. In order to more specifically address the role of vestibular information, we introduce two possible experimental paradigms. They might serve to explore the involvement of vestibular information in higher cognitive functions, and in particular, to explore the relationship between spatial perspective transformations and sensory predictions: (1) Using the tilt/translation problem to explore interactions between imagery and perception: Based on the equivalence principle, the brain must use additional information in order to estimate the body’s tilt angle with respect to gravity. We propose that it should be possible to use models of how the brain solves this problem (Merfeld et al., 1999) in order to investigate interactions between mental imagery and sensory processing. A participant is seated in a reclined position (pitched back by 45°) on a motion platform. If the participant

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remains stationary, the direction of the GIF and gravity are aligned. Based on the sensory information from the otoliths alone this position is indistinguishable from an upright position with forward acceleration. Therefore, the brain must use additional information to decompose the measured GIF into tilt relative to gravity and translational acceleration. When the participant is instructed to imagine him or herself being upright, this would effectively mean that the participant’s imagined direction of gravity would point downwards (i.e. in line with the body axis). In order to achieve an imagined upright position, we suggest that the participant will (involuntarily) simulate a forward acceleration, in order to account for the change in GIF. Specifically, if the participant performs a forward/backward motion discrimination task while imagining an upright body tilt, it is possible that performance would be enhanced for forward motion (facilitation), but impaired for backward motion (interference), resulting in a bias for forward motion. We would expect to find no effect in a left/right discrimination task (control condition), other than potential costs due to switching between covert and overt modes. The switching costs would not be specific to the direction of motion. This experiment would demonstrate the involvement of a forward model and that vestibular signals are predicted during imagery as illustrated in Figure 2. The error signal is not completely suppressed by the gain control mechanism, and thus spills over to the online mode. Studies inducing a mismatch between imagined and perceived direction of gravity could be informative to clinical disorders, such as paroxysmal room tilt illusion or sensations of disembodiment (Bonnier, 1905). (2) Offline use of forward models: In order to explore the relationship between sensory anticipation and higher vestibular processing, we propose to use a motion discrimination task, for which the vestibular afferent signals are relatively well understood, such as rotation about the earth’s vertical axis. Detailed forward models of semi-circular canal afferent signals have been developed (see Karmali and Merfeld, 2012); the fact that this problem can be described at this level of detail would make self-motion an ideal task to build upon. In order to test our claims that mental imagery and cognitive processes, such as spatial perspective taking, are based on the offline usage of forward models, it is necessary to first determine the effect of expectation, for example in a leftward/rightward rotation discrimination task. This can be achieved by manipulating frequency of occurrence of physical motion, and measuring both choices and response times. Choices and response times can be analyzed jointly using cognitive process models, such as drift diffusion models (DDM) (Gold and Shadlen, 2001; Ratcliff and McKoon, 2008; Ratcliff and Rouder, 1998). In particular, manipulations of stimulus frequency have been shown to selectively influence parameters of the DDM (Leite and Ratcliff, 2011). In a further experimental condition, participants could be instructed to imagine self-motion prior to performing the same discrimination task, and using the

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same method of data analysis, it could be determined to what extent imagery has similar effects to expectation; this effect on sensory processing can be operationalized as an effect on parameters of the DDM model. A similar kind of experiment could be performed using a task requiring a spatial perspective transformation prior to the self-motion discrimination task. Differences between imagined self-rotations and expected self-rotations could be due to the gain control mechanism that helps to make a distinction between processing in the covert and overt mode. 8. Outlook We are convinced that a combined approach of using forward models and the concept of mental imagery will open up interesting new avenues in vestibular cognition, and will introduce novel methods for addressing open issues in how the brain uses forward modeling in order to generate sensory signals. For example, Tian and Poeppel (2010) demonstrated that the brain generates expected sensory consequences, even if speech production is merely imagined. It is an advantage that vestibular science provides an abundance of modeling approaches, which can be used to provide new insight into the question of how the brain generates mental imagery. In our view, the future of research in vestibular cognition will benefit from computational approaches. To date, research on vestibular cognition is rather fragmented, and numerous and yet quite different empirical demonstrations have been provided (see Mast et al., 2014 for an overview). However, there has not been enough emphasis on understanding the findings at a computational level, and previous experiments have not necessarily been carried out with regard to computational modeling. For example, in mental imagery research, shared mechanisms are often invoked as an explanation for experimental findings. However, postulating shared mechanisms does not provide sufficient constraints on experimental work; seemingly opposite results can be equally well accommodated under this hypothesis. The conceptual model we outline in this manuscript takes the important idea of shared mechanisms one step further. We focus on the mechanisms that generate sensory predictions, and we claim that not only are they drawn upon during overt motor control and perception, but also covertly during mental imagery. Future research in vestibular cognition should therefore take into account forward models, which are traditionally concerned with issues of motor control and low-level sensory processing. Vestibular cognition might also benefit greatly from considering research in cognitive robotics. In a recent study, Di Nuovo et al. (2013) implemented the ability to perform imagery training in robots in order to improve its sensorimotor skills during offline operation. The ability to implement specific models in robots could greatly add to our understanding of how and when mental imagery may en-

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hance cognitive processes through mental training. Moreover, there is still a paucity of knowledge in how cognitive approaches can aid rehabilitation of vestibular patients (Lopez et al., 2011). Acknowledgements This research is supported by the Swiss National Science Foundation. References Angelaki, D. E., Shaikh, A. G., Green, A. M. and Dickman, J. D. (2004). Neurons compute internal models of the physical laws of motion, Nature 430(6999), 560–564. Asch, S. E. and Witkin, H. A. (1948). Studies in space orientation. 1. Perception of the upright with displaced visual fields, J. Exp. Psychol. 38, 325–337. Barra, J., Pérennou, D., Thilo, K. V., Gresty, M. A. and Bronstein, A. M. (2012). The awareness of body orientation modulates the perception of visual vertical, Neuropsychologia 50, 2492– 2498. Böhmer, A. and Mast, F. (1999). Chronic unilateral loss of otolith function revealed by the subjective visual vertical during off center yaw rotation, J. Vestib. Res. 9, 413–422. Bonnier, P. (1905). L’Aschématie, Rev. Neurol. Paris 12, 605–609. Chersi, F., Donnarumma, F. and Pezzulo, G. (2013). Mental imagery in the navigation domain: a computational model of sensory-motor simulation mechanisms, Adapt. Behav. 21, 251– 262. Cichy, R. M., Heinzle, J. and Haynes, J.-D. (2012). Imagery and perception share cortical representations of content and location, Cereb. Cortex 22, 372–380. Clemens, I. A., De Vrijer, M., Selen, L. P., Van Gisbergen, J. A. and Medendorp, W. P. (2011). Multisensory processing in spatial orientation: an inverse probabilistic approach, J. Neurosci. 31, 5365–5377. Cullen, K. E., Brooks, J. X. and Sadeghi, S. G. (2009). How actions alter sensory processing: reafference in the vestibular system, Ann. N. Y. Acad. Sci. 1164, 29–36. Cullen, K. E., Brooks, J. X., Jamali, M., Carriot, J. and Massot, C. (2011). Internal models of self-motion: computations that suppress vestibular reafference in early vestibular processing, Exp. Brain Res. 210, 377–388. De Vrijer, M., Medendorp, W. P. and Van Gisbergen, J. A. M. (2009). Accuracy–precision trade-off in visual orientation constancy, J. Vis. 9, 1–15. De Vrijer, M., Medendorp, W. P. and Van Gisbergen, J. A. M. (2008). Shared computational mechanism for tilt compensation accounts for biased verticality percepts in motion and pattern vision, J. Neurophysiol. 99, 915–930. Di Nuovo, A. G., Marocco, D., Di Nuovo, S. and Cangelosi, A. (2013). Autonomous learning in humanoid robotics through mental imagery, Neural Netw. 41, 147–155. Eggert, T. (1998). Der Einfluss orientierter Texturen auf die subjektive visuelle Vertikale und seine systemtheoretische Analyse, PhD Thesis, München, Germany. Falconer, C. J. and Mast, F. W. (2012). Balancing the mind: vestibular induced facilitation of egocentric mental transformations, Exp. Psychol. 59, 332–339.

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The Effects of Complete Vestibular Deafferentation on Spatial Memory and the Hippocampus in the Rat: The Dunedin Experience Paul F. Smith ∗ , Cynthia L. Darlington and Yiwen Zheng Dept. Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand

Abstract Our studies conducted over the last 14 years have demonstrated that a complete bilateral vestibular deafferentation (BVD) in rats results in spatial memory deficits in a variety of behavioural tasks, such as the radial arm maze, the foraging task and the spatial T maze, as well as deficits in other tasks such as the five-choice serial reaction time task (5-CSRT task) and object recognition memory task. These deficits persist long after the BVD, and are not simply attributable to ataxia, anxiety, hearing loss or hyperactivity. In tasks such as the foraging task, the spatial memory deficits are evident in darkness when vision is not required to perform the task. The deficits in the radial arm maze, the foraging task and the spatial T maze, in particular, suggest hippocampal dysfunction following BVD, and this is supported by the finding that both hippocampal place cells and theta rhythm are dysfunctional in BVD rats. Now that it is clear that the hippocampus is adversely affected by BVD, the next challenge is to determine what vestibular information is transmitted to it and how that information is used by the hippocampus and the other brain structures with which it interacts. Keywords Vestibular, hippocampus, rat, spatial memory, place cells, theta rhythm

1. Introduction One way of understanding the contribution that a sensory system makes to higher cognitive function is to remove its influence completely and immediately in experimental animals. In the context of the vestibular system, and most other sensory systems, this can be a questionable approach because so *

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_008

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many vestibular disorders, such as vestibular neuritis and Meniere’s disease, can be unilateral, chronic conditions that result in a partial loss of vestibular function rather than a sudden and complete loss. Therefore, the use of ‘simultaneous’ (i.e., sequential under anaesthesia) surgical deafferentation of both the left and right vestibular systems (‘bilateral vestibular deafferentation’ or ‘BVD’) seems at odds with clinical reality when complete bilateral vestibular loss is a relatively rare condition. Nonetheless, as a first step to understanding the various contributions that the vestibular sensory system might make to medial temporal lobe function, it has an attractive simplicity even if it falls short on clinical relevance. This is the approach that we have taken since 2001. Our focus has been on the contributions of vestibular input to spatial memory and the hippocampus, in particular. We have studied the effects of BVD in rats on performance in classical spatial memory tasks such as the radial arm maze, the Whishaw foraging task, the spatial T maze, as well as other tests such as the object recognition memory task and the five-choice serial reaction time tasks. We have examined the effects of BVD on hippocampal place cell function and theta rhythm as well as hippocampal volume and neuronal number, and glutamate receptor expression. In all of these studies, a critical issue has been to try and separate the effects of complete bilateral vestibular loss on cognitive and hippocampal function, from the direct reflex deficits that occur, i.e., the oscillopsia and ataxia resulting from the loss of the vestibulo-ocular and vestibulo-spinal reflexes (VORs and VSRs) (see Curthoys and Halmagyi, 1995 for a review). This is very difficult to do and may be impossible to achieve completely. Nonetheless, we believe that some of our studies have isolated a vestibular contribution to cognitive function that cannot be explained simply by reflex deficits. The aim of this paper is to review and critically appraise our studies using complete surgical BVD in rats, over the last 12 years. Because other reviews have evaluated the literature on the effects of vestibular loss on cognitive function more broadly, including unilateral and bilateral vestibular dysfunction in animals and humans (e.g., Hitier et al., 2014; Smith and Zheng, 2013a), this review will focus on our BVD studies in rats and their implications. 2. BVD and Spatial Memory in Rats: Radial Arm Maze, Foraging Task, and Spatial T Maze Task There is a long history of animal studies of the effects of vestibular loss on spatial navigation, which has been reviewed in detail previously (Smith and Zheng, 2013a). Some of them have used chemical lesions, some surgical, some unilateral and others bilateral lesions and most of them have suggested that vestibular dysfunction interferes with spatial memory (e.g., Besnard et al., 2012; Chapuis et al., 1992; Horn et al., 1981; Machado et al., 2012; Os-

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senkopp and Hargreaves, 1993; Stackman and Herbert, 2002; Wallace et al., 2002). Our studies began with an eight-arm radial maze task, in which rats were trained to find the food target arm of the maze, which was always located in a constant position relative to the extra-maze environment (the ‘reference memory version’ of the radial arm maze task) (Russell et al., 2003a). The task was performed in light and the animals received either bilateral surgical labyrinthectomies (which involved opening the vestibule above the ampullae of the anterior and horizontal semi-circular canals, aspirating the labyrinthine fluids and rinsing the labyrinth with ethanol through the ventral portion of the oval window and the vestibule), or a sham surgical procedure (in which the vestibular organ is not opened), at least five weeks previously. The animals were required to reach a criterion of one error or less, averaged across seven trials for three consecutive days of training. While all of the control rats achieved the criterion by day 21, only 50% of the BVD rats had managed to do so. Furthermore, the control rats reached the criterion at a significantly faster rate than the BVD rats. Importantly, although the number of errors exhibited by the BVD rats was greater than for the controls, the latency to locate the bait was similar, indicating that the BVD animals were hyperkinetic (see also Goddard et al., 2008a; Stiles et al., 2012). On the final four days of testing, during which the criterion was met, there was no significant difference in the number of errors between the BVD and control animals, indicating that some of the BVD animals could eventually acquire the task (Russell et al., 2003a). Several important aspects of this study are that: (1) the animals were at least five weeks post-BVD, therefore the acute effects of the surgery were unlikely to be responsible for the poor performance and there was no obvious difference in the degree of ataxia exhibited by the rats that reached the criterion by day 21 and those that did not; (2) fifty percent of the BVD animals did eventually acquire the task, demonstrating that ataxia did not prevent them from doing so; (3) the BVD animals were hyperkinetic, rather than hypokinetic, therefore inability to move was not the problem; (4) the availability of visual cues in light did not prevent the BVD animals from performing more poorly than the control animals, although this was probably partly attributable to oscillopsia. We used the food foraging task to investigate the effects of BVD on the ability of rats to return to a hidden home cage after collecting food randomly located on a foraging table (Zheng et al., 2009a). This time the animals were tested at five months following a complete surgical BVD or sham surgery, and the sham surgery included the removal of the tympanic membrane in order to create transmission deafness and to partially control for the sensory deafness in the BVD rats. They were first trained on this task in light for ten days, with the home cage in the same place each trial, and then tested with a probe trial in light with the home cage moved to a novel location. Following one day of

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pre-training, the animals were then trained again in the dark for 14 days, with the home cage located at a different position each day. Some of the animals in each of the BVD and sham groups had been trained in a T maze task previously, in order to determine whether this spatial experience would enhance their performance in the foraging task. However, there were no significant differences between the T maze-trained and non-trained animals in either the BVD or sham groups. During the initial pre-training in light, by the eighth session, both the sham and BVD animals had achieved a pre-set criterion of three or more food retrievals per session; however, the time taken to return to the home cage (the ‘homing time’) was significantly greater for the BVD animals compared to the sham controls. In the light probe test, both the sham and BVD animals took longer to find the new home base, and most animals made the old home cage location their first choice, with their second choice randomly distributed around the table; however, there was no difference between sham and BVD animals in the number of errors that they made before reaching the correct home cage or in the number of visits to the old home cage. Therefore, when visual cues were available, BVD rats had no problems returning back home. However, when trained in the dark, the BVD animals searched for a longer distance before finding the food compared to the sham animals, and exhibited a longer homing distance and time. While the sham animals’ first home choices were concentrated around the correct home location in every session in the dark, the BVD animals’ choices indicated no preference for the correct home (Fig. 1). Having made an incorrect first home choice, the BVD animals’ second home choice was randomly distributed around 360 degrees; the heading angles for the BVD animals were consistently larger than those for the sham animals (Fig. 2). Not surprisingly, the BVD animals made significantly more errors than sham animals before the correct home was reached (Fig. 2). This suggests that when the visual cues are not available and the animals have to rely on the egocentric cues (i.e., vestibular and proprioceptive information) generated on their outward food-searching path for homing, BVD animals are significantly impaired. In this case, oscillopsia could not be an explanation, since no visual cues were present. The seemingly random nature of the BVD animals’ heading angle and first home choice appeared to confirm that they were missing vestibular sensory input that they would normally have used to direct their choice to the correct home location. These findings were very similar to those reported by Wallace et al. (2002); however, in our study the degree of vestibular damage was more consistent because of the use of surgical lesions rather than chemical lesions with sodium arsanilate; and the length of time since the lesion was much longer (five months compared to two weeks). In a related study (Zheng et al., 2007), rats were tested in a spatial forced alternation task in an elevated T maze in light at three weeks, three months and five months following a BVD or sham surgery (the sham surgery was the

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Figure 1. The first and second home choices on the first and the last dark sessions. The big circle represents the foraging table and the eight medium-sized circles equally distributed on the periphery of the table represent the potential home bases. The closed circle represents the old home location, and the striped circle represents the novel home location on the probe trial. The small circle outside the table represents individual sham (open circle) or BVD (closed circle) rats’ first or second home choices. The direction and the length of the arrow in the middle of the table represent the mean direction and tendency of the first or second home choices for sham (open arrow) and BVD (closed arrow) rats. Reproduced with permission from Zheng et al. (2009a).

Figure 2. Number of errors (A) and heading angles (B) for the sham and BVD rats during the dark sessions. Data reflect a block of two sessions and are presented as mean ± SEM. Reproduced with permission from Zheng et al. (2009a).

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same as in the Zheng et al. [2009a] study). The animals were given a sample run in which they were forced to enter a pre-selected arm of the maze and eat food there. In the choice run, after a delay of ten seconds (sessions 1–10) or no delay (sessions 11–20), the animals were allowed a free choice between the two arms of the maze. If the animal entered the arm not previously entered on the sample run, it was rewarded for a correct response by being allowed to eat food there. If it entered the arm visited previously (i.e., an incorrect response), it was confined to that arm for 10 s and then returned to its cage. The sham rats achieved a 90% correct response rate on the second session at three weeks post-operative. By contrast, the BVD rats’ performance was significantly worse and remained around chance level (Fig. 3). Although their performance improved at three and five months post-operative, it remained significantly worse than that of the sham animals (Fig. 3). We re-visited the foraging task with rats that were 14 months post-BVD and this time attempted to determine whether their spatial memory deficits could be exacerbated by the administration of the cannabinoid receptor agonist, WIN55,212-2 (Baek et al., 2010). The design, in terms of pre-training, light probe test and training in the dark, was the same as in the Zheng et al. (2009a) study, except that the dark training continued for 21 days, with the

Figure 3. Percentage of correct choices in the T maze task for bilateral vestibular deafferentation (BVD) and sham surgery control animals at three weeks (A), three months (B), and five months (C) post-op. Symbols represent means and bars one SE of the mean. Reproduced with permission from Zheng et al. (2007).

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home cage location changed each day. Once again, the sham surgery included the removal of the tympanic membrane in order to partially control for hearing loss. In pre-training in light, the BVD animals exhibited a longer searching time than the sham controls until the last two days, when there was no significant difference. Although the BVD animals had to be trained for a longer period of time to reach the criterion, the number of sessions required was not significantly different between the BVD and the sham animals. This indicated that the BVD animals could acquire the task. However, the BVD animals exhibited a significantly longer homing time. In the light probe trial, there were no significant differences in the searching or homing distance, time, velocity or number of errors between the BVD and sham animals. However, while the sham animals had a significant preference for the old home location, the BVD animals did not (Fig. 4). The sham animals made significantly more visits to the old home location compared to the BVD animals. Drug treatment with the cannabinoid agonist made no difference to the performance of either group of animals. During the dark training, the BVD animals searched for a significantly longer distance, and at a higher velocity, although the searching time was not significantly different. During homing in the dark, the BVD animals travelled a significantly longer distance and exhibited a longer homing time; however, there was no difference in homing velocity. After finding the food, the sham animals exhibited a heading angle that indicated a clear sense of home direction; however, the BVD animals’ heading angles were distributed around 360 degrees (Fig. 5). The BVD animals made significantly more errors before reaching the correct home (Fig. 6). Although there was no significant drug effect overall, WIN55,212-2 actually reduced the number of errors in the

Figure 4. The mean number of visits to the old home for sham-vehicle, sham-WIN, BVDvehicle, and BVD-WIN animals in the light probe trial. The data are represented as means. Reproduced with permission from Baek et al. (2010).

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Figure 5. The frequency of the different initial heading angles for the sham and BVD animals for the dark training. Note that while the angles for the sham animals cluster around 0 and 360 degrees of the circle representing the correct home location on the circular foraging table, the BVD animals are distributed around 360 degrees, indicating that they have no clear sense of direction. Reproduced with permission from Baek et al. (2010).

Figure 6. The mean area under the curve (AUC) for the number of errors for the sham and BVD animals to show the effect of surgery and drug treatment during the dark training. Data are represented as mean ± 95% confidence interval. Reproduced with permission from Baek et al. (2010).

BVD group. Similar to the Zheng et al. (2009a) study, these results indicated that the BVD animals could perform the foraging task in light, but that their performance was substantially poorer than the sham animals in darkness. This study also demonstrated that the spatial deficits of the BVD animals did not recover over time, and that at 14 months post-operative they were just as severe

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Figure 7. Scatter graph illustrating the simple regression analysis performed to predict the AUC values for the number of errors made by the sham or BVD animals from the AUCs for their searching velocities. The AUC values were used to perform the regression analysis. Note that there is no relationship between the errors and the searching velocities, as an index of the animals’ hyperactivity. Reproduced with permission from Baek et al. (2010).

if not more so, than at five months post-operative. Baek et al. (2010) considered the possibility that the poor performance in the foraging task could have been related to the hyperactivity that the BVD animals exhibited; however, a regression analysis suggested that there was no relationship between the animals’ spatial memory performance and locomotor hyperactivity (Fig. 7). This is a result that has also been obtained in later studies (Smith et al., 2013). Zheng et al. (2012a) returned to the use of the spatial T maze task in light in order to investigate spatial memory performance of rats at 16–19 weeks post-operative. Once again, the BVD animals were shown to have very poor performance compared to the sham animals (Fig. 8; see also Neo et al., 2012). One of the objectives to this study was to determine whether anxiolytic or anxiogenic drugs might affect these spatial memory deficits. The drug treatments had no significant effect on performance in the spatial T maze, although they had very little effect on performance in tasks designed to test anxiety (e.g., elevated plus maze and elevated T maze). Machado et al. (2012) also found that diazepam administration had no effect on the spatial memory deficits exhibited by BVD rats in a radial arm maze, suggesting that these deficits are independent of anxiety. In an attempt to investigate the effects of BVD on attention, Zheng et al. (2009b) used an automated five-choice serial reaction time (5-CSRT) task, a task commonly used to assess attentional performance in humans. The animals were five months post-operative, with the same surgical controls as in Zheng et al. (2009a), and the task was performed in light. The rats were confronted

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Figure 8. Mean % correct responses in the spatial T maze task for the BVD and sham animals over eight days ± 95% CI. Reproduced with permission from Zheng et al. (2012a).

with a series of five apertures. When a light appeared above one of them, the rat had to insert its nose into that aperture, which broke a photo-beam. A correct response was defined as performing this behaviour within 5 s, after which the rat was rewarded with a sucrose pellet in a magazine. Responses in a non-illuminated aperture were defined as an incorrect response and failure to respond within 5 s was defined as an omission. Compared to sham controls, the rats with BVD made significantly fewer correct responses, more incorrect responses, but with no more omissions (Fig. 9); they also responded with a reduced latency. The fact that the BVD rats performed worse but with no more omissions indicated that their poor performance was not attributable to a failure to respond, but to reduced attention. Few studies have examined object recognition memory in rats with BVD. Zheng et al. (2004) used an object recognition memory task in which rats that were three or six months post-BVD were first exposed to four similar objects, and then, on the test day, one of the familiar objects was replaced with a novel object. The location of the novel object was carefully counterbalanced across the groups with the spatial position controlled, in order to exclude spatial effects. Rats with BVD spent significantly less time exploring the novel object compared to sham controls (Fig. 10). The only other study to investigate the effects of BVD on object recognition memory failed to find any significant effect (Besnard et al., 2012). While the results of the studies using the radial arm maze, the foraging task and the spatial T maze suggest that BVD results in hippocampal dysfunction, deficits in the 5-CSRT task and the object recognition memory task suggest that BVD may have more widespread effects on brain structures other than the hippocampus (Table 1), since deficits in the 5-CSRT are often related to

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Figure 9. Percentage of correct responses (A), incorrect responses (B) and omissions (C) for sham (open square) and BVD (closed square) rats after the animals reached the criterion. Data are expressed as mean ± SEM. Asterisks indicate significant differences. Reproduced with permission from Zheng et al. (2009b).

Figure 10. Mean time spent exploring familiar and novel objects in control, unilateral vestibular deafferentation (UVD) sham, UVD, BVD sham and BVD groups three (A) and six (B) months following the surgery. Data are expressed as mean ± SEM. Reproduced with permission from Zheng et al. (2004).

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Table 1. Behavioural studies of the effect of bilateral vestibular deafferentation (BVD) on cognitive function in rats at different time points following the surgery. w = weeks; m = months Task

Time point

Species

Literature

Radial arm maze Foraging task Foraging task Spatial T maze task Spatial T maze task Spatial T maze task 5-CSRT task Object recognition task

5 w post-BVD 5 m post-BVD 14 m post-BVD 3 w, 3 m and 5 m post-BVD 16–19 w post-BVD 6 w post-BVD 5 m post-BVD 3 and 6 m post-BVD

rat rat rat rat rat rat rat rat

Russell et al. (2003a) Zheng et al. (2009a) Baek et al. (2010) Zheng et al. (2007) Zheng et al. (2012a) Neo et al. (2012) Zheng et al. (2009b) Zheng et al. (2004)

the prefrontal cortex (Zheng et al., 2009b) and deficits in the object recognition memory task have been related to the perirhinal cortex (Zheng et al., 2004). It is notable that many of these studies involved long-term time points (up to 14 months post-operative) and yet the performance deficits were severe. Furthermore, while the radial arm maze, spatial T maze, 5-CSRT and object recognition memory tasks took place in light, where oscillopsia due to the absence of the VORs could be partly responsible for the poor performance, the deficits in the foraging task were evident in darkness, where oscillopsia could not be responsible. Because of the long-term time points, ataxia is a less obvious explanation for poor performance. The BVD animals could perform these various tasks; however, they made incorrect choices. It is difficult to exclude the possibility that the hyperactivity associated with BVD is partly responsible. However, our statistical analyses in different studies suggest that a direct relationship is unlikely (Baek et al., 2010; Smith et al., 2013). At present, the best evidence that anxiety is not a major factor underlying the spatial memory deficits is the study by Machado et al. (2012) in which diazepam did not alter the poor performance of BVD rats in the radial arm maze, even though it caused anxiolytic effects. Finally, although it is difficult to completely exclude hearing loss as a contributor to the poor performance of BVD rats in these various tasks, we have used partial auditory control groups (i.e., the tympanic membrane removed in the sham surgical controls) in many of these studies (foraging task: Baek et al., 2010; Zheng et al., 2009a; spatial T maze task: Zheng et al., 2007, 2012a; 5-CSRT: Zheng et al., 2009b). Even if the sham controls had some remaining auditory function with the tympanic membrane removed, the performance of the BVD animals was substantially and significantly worse. This is consistent with the results of animal studies in which rats treated with streptomycin, which lesioned the auditory and the vestibular systems, exhibited impaired working memory in a radial arm maze task; how-

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ever, rats treated with neomycin, which lesioned the auditory system only, did not (Schaeppi et al., 1991). 3. Effects of BVD on the Hippocampus It must be emphasised at the outset that the hippocampus is only one part of an extremely complex circuit involving the limbic system and neocortex, to which vestibular information is transmitted. As reviewed elsewhere (Hitier et al., 2014; Lopez and Blanke, 2011; Shinder and Taube, 2010), there is a complex network of vestibular cortical regions that is responsible for the three-dimensional representation of the body in space, that includes the parieto-insular vestibular cortex and temporo-parietal junction, the anterior parietal cortex, the posterior parietal and medial superior temporal cortex, the cingulate gyrus and the retrosplenial cortex. There are complex species differences that still impede a detailed understanding of some of these brain regions (Hitier et al., 2014). There is also evidence that, in addition to the hippocampus, the parahippocampal regions such as the entorhinal, perirhinal and postrhinal cortices all receive vestibular input (Hitier et al., 2014). Nonetheless, our studies have focussed on the hippocampus, in an effort to understand its role in this complex system and with a view to extending our studies to other areas. In 2001, we began to investigate the effects of BVD on the activity of place cells in the rat hippocampus (Russell et al., 2003b; Table 2). This study was related to the radial arm maze study by Russell et al. (2003a) and used the same method of lesioning the vestibular labyrinth. Recording began in the Table 2. Electrophysiological and neurochemical studies of the effect of bilateral vestibular deafferentation (BVD) on hippocampal function in rats at different time points following the surgery. LTP: long-term potentiation. GRs: glutamate receptors. w = weeks; m = months Hippocampal variable

Time point

Species

Literature

Hippocampal place cells Hippocampal theta Hippocampal theta Hippocampal LTP Hippocampal volume Hippocampal neuron no. Hippocampal GRs

8.5 w post-BVD 8.5 w post-BVD 6 w post-BVD 6 w and 7 m post-BVD 16 m post-BVD 16 m post-BVD 24, 72 h, 1 w, 1, 6 m post-BVD 6 m post-BVD 6 m post-BVD

rat rat rat rat rat rat rat

Russell et al. (2003b) Russell et al. (2006) Neo et al. (2012) Zheng et al. (2010) Zheng et al. (2012b) Zheng et al. (2012b) Zheng et al. (2013)

rat rat

Goddard et al. (2008a) Goddard et al. (2008b)

Hippocampal synapses Hippocampal amines

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CA1 of alert behaving rats at a minimum of 8.5 weeks following the BVD. Compared to sham controls, the overall average firing rate was significantly higher in BVD animals. The firing fields of complex spiking cells (i.e., putative place cells) were significantly larger in BVD rats, with significantly lower infield/outfield firing ratios (Fig. 11). Measurements of spatial information and spatial coherence indicated lower values for place cells from BVD animals compared to sham controls. The instability of the place cell firing in the BVD animals was similar in light and darkness (Fig. 12), suggesting that oscillopsia was not a contributing factor to their abnormal activity. Some neurons were recorded over a period of six weeks and the lack of spatial selectivity persisted in neurons from BVD animals. Stackman et al. (2002) had published a similar result in rats; however, intratympanic tetrodotoxin injections were used to inactivate the bilateral vestibular labyrinths. One intriguing aspect of this study was that they recorded over 24 h after the injections and it was evident that the disruption to place cell firing patterns was immediate, but it recovered over time, as the effect of the injections wore off. This result indicated that longterm changes in hippocampal structure, such as atrophy (Brandt et al., 2005), were unnecessary for the changes in place cell function to develop. In a related study, Russell et al. (2006) examined the effects of surgical BVD on theta rhythm in the hippocampus of the rat. The recordings were made from the same animals used for place cell recordings in Russell et al. (2003b); therefore, the animals were at least 8.5 weeks post-BVD. They found that the power of theta was significantly reduced following BVD, but also the quasi-sinusoidal nature of the waveform was degraded (Figs 13 and 14). The BVD animals were hyperactive, and theta is modulated by locomotor activity (Jeewajee et al., 2008; Lever et al., 2009); however, theta was consistently abnormal across the entire range of locomotor velocities exhibited by the BVD animals (Fig. 15). We obtained similar results in rats that were six weeks postBVD (Neo et al., 2012). Tai et al. (2012) recently reported that rats exhibited a reduction in theta power following bilateral intratympanic administration of sodium arsanilate. Neo et al. (2012) attempted to reverse the spatial memory deficits caused by BVD by electrically stimulating the septum in order to provide an artificial theta rhythm; however, this was not successful. One reason might have been that theta power and frequency has to be modulated during different behaviours rather than maintained at a fixed level (Neo et al., 2012). An early study showed a decrease in the population spike amplitude, somal field excitatory post-synaptic potential (EPSP) and field EPSP slope, in the CA1 in brain slices from rats with unilateral vestibular deafferentation (UVD), compared to sham controls (Zheng et al., 2003). This led to an investigation of the effects of BVD on field EPSPs, population spikes and long-term potentiation (LTP) in both the CA1 and dentate gyrus of freely moving rats up to 43 days post-BVD, and anesthetised rats at seven months post-BVD (Zheng

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Figure 11. (A) Firing rate maps for the cells recorded over a six-week period. Control complex spiking cell. (B) Lesion complex spiking cell. Reproduced with permission from Russell et al. (2003b).

et al., 2010). Compared to sham controls, BVD had no effect on baseline field potentials or LTP in either condition, at least at the level of resolution of field potential recording. Whether smaller effects might be detected using patch clamp recording remains to be seen.

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Figure 12. Firing rate maps recorded in the light–dark-light protocol in control (A) and lesioned (B) animals. The changes to the firing field that occurred in the dark were no greater than those in the light, for either control or lesioned animals. Therefore the observed changes to the lesioned animal’s firing field in the dark cannot be attributed to the absence of vision. Reproduced with permission from Russell et al. (2003b).

Hitier et al. (2014) have recently reviewed the evidence relating to how vestibular information reaches the hippocampus. There are several postulated routes via various parts of the thalamus, and the pedunculopontine tegmental nucleus and supramammillary nucleus, as well as other possible pathways via the cerebellum and basal ganglia (see also Shinder and Taube, 2010 and Lopez and Blanke, 2011 for reviews). At the moment, the available studies have shown that electrical stimulation of the vestibular labyrinth evokes acetylcholine release in the hippocampus (Horii et al., 1994); that selective stimulation of the labyrinth evokes field potentials in CA1 (Cuthbert et al., 2000); and that electrical stimulation of the vestibular nucleus evokes the firing of single CA1 neurons that appear to be complex firing cells (i.e., putative place cells) (Horii et al., 2004). These are obviously long-latency pathways and it is probable that several different ones are involved. In 2005, Brandt et al. reported that patients with BVD exhibited a bilateral atrophy of the hippocampus, which correlated with spatial memory impairment measured using a virtual Morris water maze task. Cutfield et al. (2014) failed to find a similar hippocampal atrophy in patients with bilateral vestibular loss, although other studies of unilateral vestibular neuritis have reported complex changes in hippocampal volume (e.g., zu Eulenburg et al., 2010). One difference between the studies was that while the patients in Cutfield et al. (2014) were ‘more than nine months’ post-lesion, those in Brandt et al. (2005) were 5–10 years post-lesion. In Cutfield et al. (2014), six patients had

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Figure 13. Power spectrum analysis of EEG from control and vestibular-lesioned animals. (A) Mean power spectral density (PSD) for each animal in the control and lesioned groups. The EEG recorded from the lesioned animals has relatively more broadband power at lower frequencies but a smaller peak at the theta frequency (8 Hz) relative to this background activity. (B) Mean normalized power and mean frequency relative to underlying broadband EEG at the energy peaks within the 6–9.5 and 9.5–13 Hz bands. Reproduced with permission from Russell et al. (2006).

bilateral vestibular loss due to aminoglycoside ototoxicity and six due to idiopathic vestibular failure; in Brandt et al. (2005), all of the patients had bilateral vestibular loss associated with neurofibromatosis type 2. We sought to investigate whether hippocampal atrophy might occur in rats with BVD. Zheng et al. (2012b) used rats at 16 months post-BVD and could find no significant change in hippocampal volume or in the number of neurons in different hippocampal subregions, quantified using stereology. Besnard et al. (2012) also found no significant change in hippocampal volume using MRI, following a sequential chemical BVD procedure. However, in unpublished studies using Golgi staining, we have found a significant decrease in the dendritic length of neurons in the CA1 of BVD rats (Fig. 16). Of note is that we have recently demonstrated that one hour of galvanic vestibular stimulation under anaesthesia caused a

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Figure 14. (A) Distributions of the correlation coefficients generated by fitting a 6–9-Hz sinusoidal wave to all 1-s epochs of EEG for animals in the control and lesioned groups. A distribution was determined for each 10-min recording session and then averaged across all sessions to create a single distribution for each animal. EEG epochs tended to be less sinusoid-like in the lesioned animals. (B) Examples of 1-s epochs of ‘theta’ rhythm that had correlation coefficients of 0.1, 0.2, 0.4, 0.6, and 0.8 with a sine wave of 6–9 Hz (actual coefficients are displayed next to each waveform). Control group animals were almost four times more likely to generate an EEG epoch with a correlation of 0.6 or higher than were lesioned animals. Calibration bar: 0.2 mV. Reproduced with permission from Russell et al. (2006).

significant decrease in neurogenesis in the rat dentate gyrus, although spatial memory was not affected (Zheng et al., 2014). There have been few studies of neurochemical changes in the hippocampus following BVD (Table 2). Following earlier studies of glutamate receptor and nitric oxide synthase changes following UVD, we examined the expression of the NR1, NR2A and NR2B subunits of the NMDA receptor, and the GluR1, GluR2, GluR3 and GluR4 subunits of the AMPA receptor, at 24 h, 72 h, one week, one month and six months following BVD (Zheng et al., 2013). Despite clear changes in receptor expression in different subregions of the hippocampus due to T maze exposure, there were no significant changes in the expression of these subunits in BVD rats compared to sham controls. However, principal component analysis did demonstrate subtle changes in the relationship between the different NMDA receptor subunits (Smith and Zheng, 2013b). By contrast, Besnard et al. (2012) reported an increase in NMDA receptor density and a decrease in affinity, in the hippocampi of BVD rats. However, the two studies are difficult to compare because Besnard et al. (2012) used a sequential chemical UVD procedure (i.e., sodium arsanilate) and they used autoradioradiography with beta imaging, whereas Zheng et al. (2013)

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Figure 15. Representative EEG recordings from each of the control (C) and lesioned group (L) animals. Each continuous 30-s EEG recording is split into 2 15-s traces (top and bottom of each pair). Below each trace is a representation of the animal’s velocity at the corresponding time as a grey scale. The velocity trace is smoothed with a 1-s running average and darker regions indicate higher velocities. Note that theta rhythm is present in most of the EEG traces from the control animals, but less obvious or absent in the recordings from lesioned-group animals. Reproduced with permission from Russell et al. (2006).

employed a simultaneous surgical BVD and western blotting. It is possible that the results of Besnard et al. (2012) reflect functional NMDA receptors rather than the total receptor pool, due to their use of beta imaging. Goddard et al. (2008a) investigated the effects of BVD on the expression of four synaptic markers: synaptophysin, SNAP-25, drebrin and neurofilament-L in the rat hippocampus. At six months following BVD, there were no significant differences in synaptophysin; however, there was a significant increase

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Figure 16. Example of a significant decrease (p  0.0001) in the number of basal dendritic intersections in the CA1 from rats with bilateral vestibular deafferentation (BVD) compared to sham-lesioned rats and control rats which did not undergo surgery. Unpublished preliminary data from Balabhadrapatruni, Zheng, Napper and Smith.

in SNAP-25 expression in the dentate gyrus. In a further study, Goddard et al. (2008c) examined the expression of several biogenic amine enzymes and transporters in the hippocampi of BVD rats at six months post-lesion. They found a significant decrease in the expression of the serotonin transporter in the CA1 in BVD rats, as well as a significant increase in the expression of tryptophan hydroxylase in the CA2/3 and the dentate gyrus. These findings remain to be further explored.

4. Future Directions One of the problems in interpreting the cognitive effects of vestibular loss is separating the effects on behaviours that are needed to express cognitive performance, such as locomotion, from those that reflect changes in, for example, memory. We and others have tried to do this by using different post-operative time points, since ataxia decreases over time following BVD, and measuring motor activity to determine whether it is a possible explanation for what appear to be cognitive deficits. A more difficult issue is to isolate the effects on cognition that are mediated by the consequences of vestibular loss for the hippocampus itself, as opposed to those mediated by the many other parahippocampal and neocortical structures that are affected. It is well established that performance in behavioural tasks such as the foraging task, radial arm maze and spatial T maze do involve the hippocampus; however, it is impossible to

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know, at this stage, to what extent the effects of vestibular loss on other brain structures might have contributed to the observed deficits. From our electrophysiological studies and those of others we know that the function of the hippocampus is affected by BVD; however, the extent to which this is due to functional deficits in others areas is poorly understood. It is assumed that all of the structures comprising the polysynaptic pathways from the vestibular nucleus to the hippocampus, function abnormally following BVD; however, many of these pathways have not been studied in detail as yet (Hitier et al., 2014). It is predictable that the entorhinal cortex, as an area containing grid cells that are likely to be necessary for the generation of hippocampal place fields, would be affected by BVD, and there is recent evidence to support this idea (Jacob et al., 2014). However, it is likely that many parahippocampal and neocortical regions become abnormal following BVD. It will be important for future studies to examine these areas in detail. The fact that hippocampal place cells and theta rhythm exhibit deficits following BVD seems inconsistent with the apparent lack of effect on LTP. However, it must be remembered that in that single study LTP was measured by recording field potentials only, and it is possible, even likely, that any changes that occur in LTP following BVD might be reflected in more subtle ways that are below the resolution of field potential recording and may require the study of LTP at single synapses using intracellular recording and patch clamping. The changes induced in place cells and theta rhythm by BVD have now been reported in several studies (Neo et al., 2012; Russell et al., 2006; Stackman et al., 2002; Tai et al., 2012) and, more recently, abnormal theta has been reported in the entorhinal cortex following bilateral intratympanic tetrodotoxin injections (Jacob et al., 2014). Therefore, there is substantial evidence that the hippocampus functions abnormally following BVD, whether or not LTP is affected. To what extent do these changes reflect sensory loss in general as opposed to loss of vestibular input specifically? There is reason to think that these changes are specific to the loss of vestibular input, even though the hippocampus uses many different sensory inputs to generate place cells. For example, in our studies, the place fields of control and BVD rats were not changed by subjecting the rats to darkness (Russell et al., 2003a). Although acute high intensity sound exposure has been reported to alter the responses of hippocampal place cells (Goble et al., 2009), these changes were variable and consisted mostly of shifting the location-specific firing of the neurons, as opposed to the indiscriminant firing reported for place cells following vestibular loss (Russell et al., 2003b; Stackman et al., 2002). Finally, in our studies of acoustic trauma-induced tinnitus, we have not observed the kinds of spatial memory deficits seen in BVD rats (Zheng et al., 2011).

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5. Conclusions The studies that others and we have conducted over the last 14 years have demonstrated that a complete BVD in rats results in spatial memory deficits that manifest in a variety of behavioural tasks, such as the radial arm maze, the foraging task and the spatial T maze. BVD rats may also be impaired on other cognitive tasks, such as the 5-CSRT task and object recognition memory tasks. These deficits persist long after the BVD, in some cases as long as 14 months, and are not obviously attributable to ataxia, anxiety, hearing loss or hyperactivity. In tasks such as the foraging task, the spatial memory deficits are evident in darkness when there can be no oscillopsia; therefore, although oscillopsia may contribute to impairment in some tasks such as the radial arm maze, the spatial T maze, the 5-CSRT task and object recognition memory tasks, it cannot explain the severely impaired performance in the foraging task in darkness. The deficits in the radial arm maze, the foraging task and the spatial T maze, suggest hippocampal dysfunction following BVD, and this is supported by the finding that both hippocampal place cells and theta rhythm are dysfunctional in BVD rats. Despite this, LTP appears to be normal. It appears to date as if the hippocampal atrophy that has been documented in humans with bilateral vestibular loss by Brandt et al. (2005) does not occur in rats; whether this is due to the hyperactivity that occurs in BVD rats is unknown, but more subtle changes in dendritic length appear to occur. At present, there are too few studies of neurochemical changes in the hippocampus following BVD to be certain of how glutamate receptors and other receptors are affected. Now that it is clear that the hippocampus is adversely affected by BVD, the next challenge is to determine what vestibular information is transmitted to it and how that information is used by the hippocampus and the other brain structures with which it interacts. Acknowledgements This research has been supported by grants from the New Zealand Neurological Foundation and the Royal Society of New Zealand Marsden Fund. YZ was a recipient of the Health Research Council Sir Charles Hercus Fellowship. References Baek, J.-H., Zheng, Y., Darlington, C. L. and Smith, P. F. (2010). Evidence that spatial memory deficits in rats following bilateral vestibular loss is probably permanent, Neurobiol. Learn. Mem. 94, 402–413. Besnard, S., Machado, M. L., Vignaux, G., Boulouard, M., Coquerel, A., Bouet, V., Freret, T., Denise, P. and Lelong-Boulouard, V. (2012). Influence of vestibular input on spatial and nonspatial memory and on hippocampal NMDA receptors, Hippocampus 22, 814–826.

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Brandt, T., Schautzer, F., Hamilton, D. A., Bruning, R., Markowitsch, H., Kalla, R., Darlington, C. L., Smith, P. F. and Strupp, M. (2005). Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans, Brain 128, 2732–2741. Chapuis, N., Krimm, M., de Waele, C., Vibert, N. and Berthoz, A. (1992). Effect of post-training unilateral labyrinthectomy in a spatial orientation task by guinea pigs, Behav. Brain Res. 51, 115–126. Curthoys, I. S. and Halmagyi, G. M. (1995). Vestibular compensation: a review of the ocular motor, neural and clinical consequences of unilateral vestibular loss, J. Vest. Res. 5, 67–107. Cutfield, N. J., Scott, G., Waldman, A. D., Sharp, D. J. and Bronstein, A. M. (2014). Visual and proprioceptive interaction in patients with bilateral vestibular loss, Neuroimage Clin. 4, 274–282. Cuthbert, P. C., Gilchrist, D. P., Hicks, S. L., MacDougall, H. G. and Curthoys, I. S. (2000). Electrophysiological evidence for vestibular activation of the guinea pig hippocampus, NeuroReport 11, 1443–1447. Goble, T. J., Møller, A. R. and Thompson, L. T. (2009). Acute high-intensity sound exposure alters responses of place cells in hippocampus, Hear. Res. 253, 52–59. Goddard, M., Zheng, Y., Darlington, C. L. and Smith, P. F. (2008a). Locomotor and exploratory behaviour in the rat following bilateral vestibular deafferentation, Behav. Neurosci. 122, 448–459. Goddard, M., Zheng, Y., Darlington, C. L. and Smith, P. F. (2008b). Synaptic protein expression in the medial temporal lobe and frontal cortex following chronic bilateral vestibular loss, Hippocampus 18, 440–444. Goddard, M., Zheng, Y., Darlington, C. L. and Smith, P. F. (2008c). Monoamine transporter and enzyme expression in the medial temporal lobe and frontal lobes following chronic bilateral vestibular loss, Neurosci. Lett. 437, 107–110. Hitier, M., Besnard, S. and Smith, P. F. (2014). Vestibular pathways involved in cognition, Front. Integr. Neurosci. 8, 59, 1–16. Horii, A., Takeda, N., Mochizuki, T., Okakura-Mochizuki, K., Yamamoto, Y. and Yamatodani, A. (1994). Effects of vestibular stimulation on acetylcholine release from rat hippocampus: an in vivo microdialysis study, J. Neurophysiol. 72, 605–611. Horii, A., Russell, N., Smith, P. F., Darlington, C. L. and Bilkey, D. K. (2004). Vestibular influences on CA1 neurons in the rat hippocampus: an electrophysiological study in vivo, Exp. Brain Res. 155, 245–250. Horn, K. M., DeWitt, J. R. and Nielson, H. C. (1981). Behavioral assessment of sodium arsanilate induced vestibular dysfunction in rats, Physiol. Psychol. 9, 371–378. Jacob, P. Y., Poucet, B., Liberge, M., Save, E. and Sargolini, F. (2014). Vestibular control of entorhinal cortex activity in spatial navigation, Front Integr. Neurosci. 8, 38. Jeewajee, A., Barry, C., O’Keefe, J. and Burgess, N. (2008). Grid cells and theta as oscillatory interference: electrophysiological data from freely moving rats, Hippocampus 18, 1175– 1185. Lever, C., Jeewajee, A., Burton, S., O’Keefe, J. and Burgess, N. (2009). Hippocampal theta frequency, novelty and behavior, Hippocampus 19, 409–410. Lopez, C. and Blanke, O. (2011). The thalamocortical vestibular system in animals and humans, Brain Res. Rev. 67, 119–146.

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Machado, M. L., Lelong-Boulouard, V., Smith, P. F., Freret, T., Philoxene, B., Denise, P. and Besnard, S. (2012). Influence of anxiety in spatial memory impairments related to the loss of vestibular function in rat, Neuroscience 218, 161–169. Neo, P., Carter, D., Zheng, Y., Smith, P. F., Darlington, C. L. and McNaughton, N. (2012). Septal elicitation of hippocampal theta rhythm did not repair the cognitive and emotional deficits resulting from vestibular lesions, Hippocampus 22, 1176–1187. Ossenkopp, K. P. and Hargreaves, E. L. (1993). Spatial learning in an enclosed eight-arm maze in rats with sodium arsinilate-induced labyrinthectomies, Behav. Neur. Biol. 59, 253–257. Russell, N., Horii, A., Smith, P. F., Darlington, C. L. and Bilkey, D. (2003a). Effects of bilateral vestibular deafferentation on radial arm maze performance, J. Vestib. Res. 13, 9–16. Russell, N., Horii, A., Smith, P. F., Darlington, C. L. and Bilkey, D. (2003b). The long-term effects of permanent vestibular lesions on hippocampal spatial firing, J. Neurosci. 23, 6490– 6498. Russell, N., Horii, A., Smith, P. F., Darlington, C. L. and Bilkey, D. (2006). Lesions of the vestibular system disrupt hippocampal theta rhythm in the rat, J. Neurophysiol. 96, 4–14. Schaeppi, U., Krinke, G., FitzGerald, R. E. and Classen, W. (1991). Impaired tunnel-maze behavior in rats with sensory lesions: vestibular and auditory systems, Neurotoxicology 12, 445–454. Shinder, M. E. and Taube, J. S. (2010). Differentiating ascending vestibular pathways to the cortex involved in spatial cognition, J. Vestib. Res. 20, 3–23. Smith, P. F. and Zheng, Y. (2013a). From ear to uncertainty: vestibular contributions to cognitive function, Front. Integr. Neurosci. 7, 84. Smith, P. F. and Zheng, Y. (2013b). Principal component analysis suggests subtle changes in glutamate receptor subunit expression in the rat hippocampus following bilateral vestibular deafferentation in the rat, Neurosci. Lett. 548, 265–268. Smith, P. F., Haslett, S. J. and Zheng, Y. (2013). A multivariate statistical and data mining analysis of spatial memory-related behavior following bilateral vestibular deafferentation in the rat, Behav. Brain Res. 246, 15–23. Stackman, R. W., Clark, A. S. and Taube, J. S. (2002). Hippocampal spatial representations require vestibular input, Hippocampus 12, 291–303. Stackman, R. W. and Herbert, A. M. (2002). Rats with lesions of the vestibular system require a visual landmark for spatial navigation, Behav. Brain Res. 128, 27–40. Stiles, L., Zheng, Y., Darlington, C. L. and Smith, P. F. (2012). The D2 dopamine receptor and locomotor hyperactivity following bilateral vestibular deafferentation in the rat, Behav. Brain Res. 227, 150–158. Tai, S. K., Ma, J., Ossenkopp, K. P. and Leung, L. S. (2012). Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation, Hippocampus 22, 914–925. Wallace, D. G., Hines, D. J., Pellis, S. M. and Whishaw, I. Q. (2002). Vestibular information is required for dead reckoning in the rat, J. Neurosci. 15, 10009–10017. Zheng, Y., Kerr, D. S., Darlington, C. L. and Smith, P. F. (2003). Peripheral vestibular damage causes a lasting decrease in the electrical excitability of CA1 in hippocampal slices in vitro, Hippocampus 13, 873–878. Zheng, Y., Darlington, C. L. and Smith, P. F. (2004). Bilateral vestibular deafferentation impairs object recognition in rat, NeuroReport 15, 1913–1916.

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Zheng, Y., Goddard, M., Darlington, C. L. and Smith, P. F. (2007). Bilateral vestibular deafferentation impairs performance in a spatial forced alternation task in rats, Hippocampus 17, 253–256. Zheng, Y., Goddard, M., Darlington, C. L. and Smith, P. F. (2009a). Long-term deficits on a foraging task after bilateral vestibular deafferentation in rats, Hippocampus 19, 480–486. Zheng, Y., Balabhadrapatruni, S., Munn, O., Masumura, C., Darlington, C. L. and Smith, P. F. (2009b). Evidence for deficits in a 5 choice serial reaction time task in rats with bilateral vestibular deafferentation, Behav. Brain Res. 203, 113–117. Zheng, Y., Mason-Parker, S. E., Logan, B., Darlington, C. L., Smith, P. F. and Abraham, W. C. (2010). Hippocampal synaptic transmission and LTP in vivo are intact following bilateral vestibular deafferentation in the rat, Hippocampus 20, 461–468. Zheng, Y., Hamilton, E., Begum, S., Smith, P. F. and Darlington, C. L. (2011). The effects of acoustic trauma that can cause tinnitus on spatial performance in rats, Neuroscience 186, 48–56. Zheng, Y., Cheung, I. and Smith, P. F. (2012a). Performance in anxiety and spatial memory tests following bilateral vestibular loss in the rat and effects of anxiolytic and anxiogenic drugs, Behav. Brain Res. 235, 21–29. Zheng, Y., Balabhadrapatruni, S., Chung, P., Gliddon, C. M., Zhang, M., Napper, R., Baek, J.-H., Brandt, T., Strupp, M., Darlington, C. L. and Smith, P. F. (2012b). The effects of bilateral vestibular loss on hippocampal volume, neuronal number and cell proliferation in rats, Front. Neuro-Otol. 3, 20. Zheng, Y., Wilson, G., Stiles, L. and Smith, P. F. (2013). Glutamate receptor subunit and calmodulin kinase II expression in the rat hippocampus, with and without T maze experience, following bilateral vestibular deafferentation, PLoS One 8(2), e54527. DOI:10.1371/journal. pone.0054527. Zheng, Y., Geddes, L., Sato, G., Stiles, L., Darlington, C. L. and Smith, P. F. (2014). Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory, Hippocampus 24, 541–552. zu Eulenburg, P., Stoeter, P. and Dieterich, M. (2010). Voxel-based morphometry depicts central compensation after vestibular neuritis, Annal. Neurol. 68, 241–249.

Making Sense of the Body: the Role of Vestibular Signals Christophe Lopez ∗ Laboratoire de Neurosciences Intégratives et Adaptatives, Aix Marseille Université, CNRS, NIA UMR 7260, 13331, Marseille, France

Abstract The role of the vestibular system in posture and eye movement control has been extensively described. By contrast, how vestibular signals contribute to bodily perceptions is a more recent research area in the field of cognitive neuroscience. In the present review article, I will summarize recent findings showing that vestibular signals play a crucial role in making sense of the body. First, data will be presented showing that vestibular signals contribute to bodily perceptions ranging from low-level bodily perceptions, such as touch, pain, and the processing of the body’s metric properties, to higher level bodily perceptions, such as the sense of owning a body, the sense of being located within this body (embodiment), and the anchoring of the visuo-spatial perspective to this body. In the second part of the review article, I will show that vestibular information seems to be crucially involved in the visual perception of biological motion and in the visual perception of human body structure. Reciprocally, observing human bodies in motion influences vestibular self-motion perception, presumably due to sensorimotor resonance between the self and others. I will argue that recent advances in the mapping of the human vestibular cortex afford neuroscientific models of the vestibular contributions to human bodily self-consciousness. Keywords Vestibular system, body’s metric properties, body ownership, embodiment, mirror neuron system, biological motion, first-person perspective, bodily consciousness

1. Introduction Current research in neuroscience and experimental psychology has accumulated a large body of data showing that the most crucial sense of self stems from the integration of exteroceptive, interoceptive and muscular proprioceptive signals (review in Blanke, 2012; Blanke and Metzinger, 2009; Serino et al., 2013). While a strong emphasis has traditionally been put on the role *

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of visual and somatosensory information in constructing the bodily self, recent neuroscientific investigations aimed at unraveling the contributions of the more ‘hidden’ and covert senses such as the vestibular and interoceptive senses. In the present review article, I argue that vestibular information is crucially involved in bodily self-consciousness. For the sake of clarity, I propose that vestibular signals contribute to perceiving bodies ‘from within’ as well as ‘from the outside’ (following a distinction proposed by Tsakiris et al., 2011). Perceiving bodies from within refers to the fact that the vestibular sense is often referred to as a ‘personal sense’ similarly to interoceptive and muscular proprioceptive senses (Craig, 2009; Lenggenhager and Lopez, 2015a, 2015b; Seth, 2013). Data will be presented showing that vestibular signals interact with somatosensory, muscular proprioceptive and interoceptive signals in various brainstem, thalamic and cortical structures to modulate the sense of the bodily self. I will summarize findings showing that artificial vestibular stimulations influence various bodily perceptions ranging from low-level sensations, such as touch and pain detection, the internal models of the body’s metric properties (the perceived width and length of one’s own body parts), to higher level bodily perception and cognition, including the sense of owning a body, the sense of being located within the physical body, and the anchoring of the first-person perspective to this body. Perceiving bodies from the outside refers to the influence of vestibular signals on the interpretation of visual information about our conspecifics’ bodies, for example the interpretation of the motion and posture of another body. However, perceiving other bodies also plays a role in the perception of our own body. This line of research has been very productive during the past few years, demonstrating that the observation of other bodies strongly modulates self perception and consciousness (e.g., Faivre et al., 2015; Maister et al., 2015; Rizzolatti and Craighero, 2004; Serino et al., 2008). 2. Perceiving Bodies ‘from within’ This first part describes how vestibular signals modulate processing of somatosensory signals and complex bodily perceptions. To understand how vestibular signals influence the perception of the body from within we shall first examine how somatosensory, muscular proprioceptive and interoceptive signals are integrated with vestibular signals in the brain. Electrophysiological investigations in animals have demonstrated convergence of vestibular and somatosensory signals in several brain structures along the vestibulothalamo-cortical pathway, including the vestibular nuclei in the brainstem, several thalamic nuclei and multiple cortical areas (reviews in Angelaki and Cullen, 2008; Dieterich and Brandt, in press; Lopez, 2015; Lopez and Blanke, 2011; Ventre-Dominey, 2014).

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Regarding multisensory convergence in the brainstem, bimodal neurons that respond to stimulation of muscular proprioceptive, tactile and vestibular receptors have been identified in the vestibular nuclei (Roy and Cullen, 2004). Vestibular nuclei neurons also respond to the observation of visual patterns moving coherently (optokinetic stimulation: Waespe and Henn, 1978) and to eye movements signals (Tomlinson and Robinson, 1984). In addition, vestibular signals project to other brainstem structures involved in interoceptive and nociceptive processing and in autonomic regulation, including the parabrachial nucleus and nucleus of the solitary tract (review in Balaban, 1999, 2004). A contribution of the parabrachial nucleus in perceiving the body from within is very likely because parabrachial nucleus neurons not only respond to natural vestibular stimulation (McCandless and Balaban, 2010), but are also involved in nociceptive and cardiovascular pathways to the cerebral cortex and amygdala (Herbert et al., 1990; Moga et al., 1990). In the thalamus, vestibular responses have been recorded in the ventral posterior group of nuclei (for reviews on the human ‘vestibular’ thalamus, see Conrad et al., 2014; Lopez and Blanke, 2011): vestibular-responding neurons in these nuclei respond to proprioceptive signals from joints and muscles and code for passive movements of the neck, shoulders, legs and vertebral column (Blum and Gilman, 1979; Deecke et al., 1977). Tactile stimulation applied to a cat’s paws also activate thalamic vestibular-responding neurons (Sans et al., 1970). Vestibular thalamic neurons also respond to the motion of visual patterns. For example, about half of the vestibular neurons of the lateral geniculate nucleus respond to optokinetic stimulation and most of them are activated by saccadic eye movements (Magnin and Putkonen, 1978). In the cerebral cortex, convergence of vestibular, somatosensory and visual signals has been reported in several areas. A main region of multisensory convergence is the parieto-insular vestibular cortex located at the posterior end of the lateral sulcus in several monkey species, at the junction of the insula with the retroinsular and somatosensory cortex (Grüsser et al., 1990a, 1990b; Guldin and Grüsser, 1998). Neurons responding to both vestibular and somatosensory stimulations have also been recorded in the intraparietal sulcus (e.g., in the ventral intraparietal area) and primary somatosensory cortex in monkeys (areas 2v and 3av in the hand/arm and neck/trunk representations), and vestibulo-somatosensory integration has been shown in the secondary somatosensory cortex in humans (Bottini et al., 1995, 2001, 2005; Bremmer et al., 2002; Fasold et al., 2008; Guldin and Grüsser, 1998; Schwarz and Fredrickson, 1971). Visual-vestibular convergence has also been reported in the extrastriate visual area MST, a region responding to optic flows and crucially implicated in self-motion perception (Bremmer et al., 1999; Gu et al., 2006).

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There is a severe lack of studies in humans concerning how vestibular signals are integrated with other sensory signals at the neural level, mainly due to the difficulty in providing natural vestibular stimulation during electrophysiological recordings in humans (i.e., electroencephalography and magnetoencephalography). In the past few years, several studies have shown that caloric and galvanic vestibular stimulation can modulate detection of simple tactile and nociceptive stimuli (Bottini et al., 1995, 2005; Ferrè et al., 2011, 2012, 2013a, 2013c; Vallar et al., 1990, 1993), but it remains difficult to provide a definite opinion on how the vestibular information acts on the processing of tactile and nociceptive information. Related studies on the interactions between the pain and touch systems have shown that multimodal interactions are characterized by several mechanisms, including ‘multimodal convergence’ and ‘multimodal modulation’ (see Fig. 2 in Haggard et al., 2013). There is multimodal convergence when two sensory signals are “integrated by simple feedforward convergence onto a single higher-order neuron”, that is when this neuron sums excitatory and inhibitory postsynaptic potentials from, e.g., tactile and nociceptive afferents (Haggard et al., 2013). This form of multisensory integration allows the integration of different stimulus features. By contrast, there is multimodal modulation when one sensory signal (e.g., vestibular signal) changes the synaptic connection of another sensory pathway (e.g., nociception) through projection to an interneuron. The action of one sensory modality on another can be excitatory or inhibitory and this type of multisensory integration modifies the gain of a sensory modality without adding new information (Haggard et al., 2013). A recent study measured the influence of caloric vestibular stimulation on tactile and pain thresholds (Ferrè et al., 2013a) and allows speculating on the type of multisensory integration involved. The authors found that caloric stimulation decreased tactile thresholds, but increased pain thresholds. That opposite effects were found for tactile and pain processing speaks against a general and unspecific effect of vestibular stimulations on attention and awareness (see also Bottini et al., 2013). Thus, the authors proposed that such effects were compatible with an independent modulation of touch and pain processing by vestibular signal, suggesting that vestibular signals modulate synaptic connections in both the pain and tactile afferent pathways, but in opposite directions. Because the effects of caloric vestibular stimulation were found to be long lasting, the authors proposed that caloric vestibular stimulation might evoke long-term potentiation in the tactile pathways, and long-term depression in the pain pathways. According to Ferrè et al. (2013a), it is unlikely that the reported effects were due to multimodal convergence of vestibular and tactile/pain signals on bimodal neurons. This mechanism implies that vestibular stimulation evokes excitatory postsynaptic potentials in the touch pathways and inhibitory postsynaptic potentials in the pain pathways. Given the short-

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term effect of postsynaptic potentials, they cannot account for the long-lasting effects of the caloric vestibular stimulation. If the hypothesis of a vestibular modulation of the synaptic gain of touch and pain pathways is confirmed, a vestibular modulation of multisensory events could also explain other changes in the conscious experience of touch (‘somatosensation’) and the temporary remission of hemianesthesia in braindamaged patients, and several forms of depersonalization in patients with peripheral vestibular disorders. Similarly, I propose that multimodal modulation by the vestibular signals is also responsible for the vestibular influence on higher-order body representations, such as the perceived shape and size of the body (body’s metric properties), the experience of owning the body, and the experience of perceiving the world from an embodied first-person perspective. 2.1. Body’s Metric Properties A contribution of vestibular signals to internal models of the body is evident from observations in patients with peripheral vestibular disorders. In the late 19th century and early 20th century, clinicians already noted that vestibular disorders may result in perceiving body parts as enlarged (Bonnier, 1893, 1905; Schilder, 1935) or may induce more complex distortions of the body image and self-consciousness (Menninger-Lerchenthal, 1946; Skworzoff, 1931). In particular, Pierre Bonnier scrupulously reported distortions of the perception of the body shape and size in vestibular patients. One of his patients “felt his head became enormous, immense, losing itself in the air; his body disappeared and his whole being was reduced to only his face” while for another patient “her vertigo gave her the sensation that she no longer existed ‘as a body”’. A third patient “experienced a short acute episode of vertigo with the inability to perceive space, then it seemed to him that he was divided into two persons, one who had not changed posture, and another new person on his right, looking somewhat outwardly. Then the two somatic individuals approached each other, merged, and the vertigo disappeared” (Bonnier, 1905, 2009). Bonnier coined the term ‘aschématie’ to name these disorders (1905), indicating that their common feature was a ‘loss of the (body) schema’ (reviews in Lopez, 2013; Vallar and Papagno, 2003; Vallar and Rode, 2009). It is notable that these disorders are reminiscent of neurological symptoms of asomatognosia (Dieguez et al., 2007), but seem to be evoked by pure peripheral vestibular dysfunction, devoid of damage to the central nervous system. The relation between vestibular signals and body schema has only recently been put under neuroscientific scrutiny using caloric and galvanic vestibular stimulations and well-controlled psychophysical paradigms in healthy participants. In a study by Lopez et al. (2012c), participants had their left hand placed on a table and covered by a digitizing tablet. Using a stylus held in their right hand, participants were asked to repeatedly point to the tablet at the position

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above four anatomical landmarks (the tip of the middle finger, the wrist, the knuckle of the little finger and the knuckle of the index finger). The perceived length of the hand was calculated as the distance between the tip of the middle finger and the wrist; the width of the hand was calculated as the distance between the knuckles of the little finger and index finger. Results indicated that right warm/left cold caloric vestibular stimulation significantly increased the perceived length and width of the hand when compared to sham stimulation (air at body temperature in both ears). This data is compatible with reports by vestibular patients that their ‘neck swells during dizziness’, ‘extremities had become larger’ or ‘feet seem to elongate’ (Schilder, 1935). Another study by Ferrè and colleagues (2013c) used low-intensity galvanic vestibular stimulation to manipulate bodily awareness. The authors found no influence of galvanic vestibular stimulation on the model of the shape of the hand (perceived length and width), in contrast with the study by Lopez et al. (2012c). The discrepancy between both studies may be accounted for by the methods used to stimulate the vestibular receptors since caloric stimulation used by Lopez et al. (2012c) usually induces stronger vestibular sensations than the 1 mA galvanic vestibular stimulation used by Ferrè et al. (2013c). Although Ferrè and colleagues (2013c) did not find an influence of galvanic vestibular stimulation on the body model, they reported the interesting finding that galvanic vestibular stimulation significantly modulated the localization of tactile stimuli applied to the dorsum of the hand. They found that tactile stimuli applied to the dorsum of the hand were perceived as shifted towards the participant’s wrist. Thus, vestibular stimulation influenced somatoperception, i.e., “the processes of constructing percepts and experiences of somatic objects and events” (Ferrè et al., 2013c; Longo et al., 2010), very likely by modulating integration of tactile and proprioceptive signals at the level of the primary somatosensory cortex, posterior parietal cortex and temporo-parietal junction. As noted above, all these brain regions integrate vestibular and somatosensory signals and are involved in localizing tactile events on the body as well as in localizing body parts (Blanke et al., 2002; Bremmer et al., 2002; CorradiDell’Acqua et al., 2008, 2009; Felician et al., 2004; Schwarz and Fredrickson, 1971; Schwarz et al., 1973; Seyal et al., 1997; Wolpert et al., 1998; Zu Eulenburg et al., 2013a). 2.2. Body Ownership After having described the influence of vestibular signals on body’s metric properties, I shall now describe the influence of vestibular signals on the sense of owning a body, which is considered one of the main constituents of human self-consciousness (Blanke, 2012; Blanke and Metzinger, 2009; De Vignemont, 2007; Tsakiris, 2010; Tsakiris and Haggard, 2005). Traditionally, a strong emphasis has been put on the role of visual and somatosensory signals

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in body ownership. This is because self-attribution of body parts strongly relies on the synchrony between visual feedback from one’s own actions and the somatosensory feedback from this action, or it relies on the synchrony between the vision and experience of a tactile stimulus applied to the skin (Botvinick and Cohen, 1998; Jeannerod, 2003; Tsakiris and Haggard, 2005). Recent neuroscientific approaches have induced illusory ownership over a rubber hand by applying synchronous tactile stimulation on a fake hand presented in the participant’s field of view and on the participant’s (hidden) hand. This rubber hand illusion has become a widely used experimental paradigm to investigate the multisensory foundations of body ownership (Botvinick and Cohen, 1998; Costantini and Haggard, 2007; Kammers et al., 2009; Moseley et al., 2008; Tsakiris and Haggard, 2005). More recently, the question has arisen as to whether other sensory signals, such as vestibular and interoceptive signals, could play a significant role in body ownership (Aspell et al., 2013; Brugger and Lenggenhager, 2014; Lopez et al., 2008; Suzuki et al., 2013; Tsakiris et al., 2011). Regarding the vestibular contribution to body ownership, clinical observations in patients with right-brain damage suggested that vestibular signals modulate activity in brain regions involved in body ownership. In patients suffering from somatoparaphrenia — who fail to recognize their left hand as belonging to their own body (e.g., one patient claimed: ‘It’s my mother’s [hand]. . . I found it in my bed’; Bisiach et al., 1991) — caloric vestibular stimulation (cold water in the left ear) temporarily suppressed somatoparaphrenic delusions, improving self-attribution of their hand (Bisiach et al., 1991; Rode et al., 1992; Schiff and Pulver, 1999). There is also recent evidence that caloric vestibular stimulation reduced somatoparaphrenia for the right hand in a patient with a left-brain damage (Ronchi et al., 2013). Injection of cold water in the right ear suppressed the delusional belief that the patient owned only one hand (the left hand). Lopez et al. (2010b) applied galvanic vestibular stimulation during the rubber hand illusion in healthy participants. They found that galvanic vestibular stimulation (right cathodal/left anodal stimulation) significantly increased illusory ownership for the rubber hand and the intensity of illusory touch, i.e., the experience that touch originates from the rubber hand, measured by questionnaires (Fig. 1A). Yet, this effect was irrespective of the synchrony between the touch applied to the participant’s hand and the touch seen on the rubber hand. The authors interpreted this finding as an increase in visual capture, a mechanism by which visual signals dominate tactile signals in some experimental conditions (Pavani et al., 2000). This hypothesis was confirmed by the application of caloric vestibular stimulation during a non-visual variant of the rubber hand illusion (Lopez et al., 2012a). In this variant, an experimenter holds the participant’s right hand and uses the participant’s right index finger

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Figure 1. Methods to create illusory ownership of a rubber hand. (A) In the visual variant of the rubber hand illusion, participants observe a rubber hand (RH) placed in front of them while their physical hand (PH) is hidden. The synchronous application of a tactile stimulation on the rubber and physical hands (using two similar paintbrushes) can evoke the sensation that the rubber hand feels like the participant’s own hand (Lopez et al., 2010b). (B) In the non-visual variant of the rubber hand illusion, the experimenter moves the participant’s right hand to touch the rubber hand (RH) while at the same time the experimenter applies a tactile stimulation on the participant’s left physical hand (PH). Participants report that it feels as if they were touching their left hand (instead of the rubber hand) with their right index finger and that it seems like the rubber hand belonged to them (Lopez et al., 2012a).

to stroke the rubber hand on its dorsal surface (Fig. 1B). The experimenter also strokes with her own index finger the dorsal surface of the participant’s left hand to create the corresponding tactile input. Caloric vestibular stimulation did not modulate the intensity of illusory hand ownership, suggesting that vestibular signals do not interfere with the tactile-proprioceptive mechanisms underlying ownership for body parts when visual feedback from the body surface is absent. In none of their studies the authors (Lopez et al., 2010b, 2012a) found that vestibular stimulation changed the amplitude of the proprioceptive drift, that is the error of localization of the participant’s index finger towards the rubber hand. By contrast, a recent study (Ferrè et al., 2015) showed that low-intensity galvanic vestibular stimulation modulated the amplitude of the proprioceptive drift: right cathodal/left anodal stimulation decreased the proprioceptive drift with respect to that measured after left cathodal/right anodal stimulation. While it is difficult to reconcile results from these studies, it is notable that illusory hand ownership (as measured by questionnaires in Lopez et al., 2010b) and the proprioceptive drift (as measured in Ferrè et al., 2015) are two independent aspects of the rubber hand illusion (Rohde et al., 2011). Results from the studies about the influence of vestibular stimulation on illusory body ownership (Ferrè et al., 2015; Lopez et al., 2010b, 2012a) are also helpful to understand how vestibular stimulation influences somatoparaphrenic delusion (Bisiach et al., 1991; Rode et al., 1992; Schiff and Pulver, 1999). In three clinical studies showing that caloric vestibular stimulation abolishes somatoparaphrenia for the left arm, the arm was visually presented

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to the patient — for example, “when the examiner brought [the patient’s] left arm in her good visual field, she recognized it as hers and no longer claimed it was the examiner’s” (Rode et al., 1992). Thus, the influence of vestibular stimulation on abnormal sense of ownership in these patients could be due to the influence of vestibular signals on visual processing and visual neglect (e.g., Cappa et al., 1987; Rubens, 1985). An additional direct modulation of tactile, proprioceptive and motor signals processing by vestibular stimulations in these patients is also very likely, as demonstrated by other behavioral studies (Bottini et al., 2013; Bresciani et al., 2002; Ferrè et al., 2011, 2012, 2013a, b, 2015; Rode et al., 1992). More work is now needed in this rare clinical condition to establish whether remissions of somatoparaphrenic delusion during caloric vestibular stimulation are supported by visuo-vestibular interactions, vestibulo-somatosensory interactions, or both. To conclude this section I note that vestibular contributions to other bodily disorders involving abnormal forms of body ownership have been proposed. Ramachandran and McGeoch (2007) proposed that caloric vestibular stimulation could be used to treat patients with a desire for amputation of healthy body parts, a disorder known as body identity integrity disorder (BIID) or xenomelia. A recent study endeavored to test this hypothesis during the application of caloric vestibular stimulation in 13 participants suffering from BIID (Lenggenhager et al., 2014). The authors found that neither left nor right cold caloric vestibular stimulation reduced in those patients the subjective evaluation of ‘degree of estrangement’ for their limb. This negative result indicates that the underlying mechanisms may differ in BIID and somatoparaphrenia. While BIID is a long-term condition that has often been consolidated since childhood (Brugger et al., 2013), somatoparaphrenia can be observed during the acute phase after brain injury and may be more prone to modulations by vestibular stimulation. 2.3. Embodiment and First-Person Perspective A relation between vestibular processing and embodiment — the experience of self-location within the physical body — has been proposed on the basis of observations in patients with peripheral vestibular disorders and epileptic patients. Patients suffering from peripheral vestibular disorders may report being detached from their body and experience symptoms of depersonalization, the experience that the body and self appear strange or unreal (Bonnier, 1905, 1893; Jauregui-Renaud et al., 2008; Lopez, 2013; Schilder, 1935; Yen Pik Sang et al., 2006). In some instances, vestibular patients may even report seeing or feeling the presence of their own double (Bonnier, 1905; Skworzoff, 1931). Epileptic patients may also report out-of-body experiences, characterized by the feeling that their self is located outside their physical body (disembodiment), and that the environment is experienced from this extra-

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corporeal location (disembodied perspective). It is interesting to note here that such disembodied experiences are frequently associated with vestibular sensations, such as the feeling of levitation, lightness and floating in the room (Blanke and Mohr, 2005; Blanke et al., 2004; Heydrich et al., 2011; Lopez et al., 2010a). Thus, a triple misintegration of vestibular signals with somatosensory and visual information regarding self-location in space has been proposed to explain illusory sensations of disembodiment (Blanke, 2012; Blanke et al., 2002, 2004; Lopez et al., 2008). Recent data indicate that the temporo-parietal junction and the posterior insula, which are considered two main vestibular regions, may be involved in the sense of embodiment and first-person perspective (Bense et al., 2001; Dieterich et al., 2003; Heydrich and Blanke, 2013; Ionta et al., 2011; Lopez and Blanke, 2011; Lopez et al., 2012b; Mazzola et al., 2014; Pfeiffer et al., 2014; for recent reviews, see: Lenggenhager and Lopez, 2015a, b). On the basis of these clinical observations we can propose that one of the main functions of vestibular signals could be to link the self to the body and to promote an embodied, first-person, perspective. As noted earlier, interference with the temporo-parietal junction may evoke vestibular sensations, break down the sense of unity between the self and the body, and evoke an extracorporeal, third-person, perspective (Blanke et al., 2002). In support of this proposition are recent data from whole-body mental imagery showing that natural vestibular stimulation (evoked by a rotating chair) impairs mental simulation of disembodied self-location (Deroualle et al., 2014; Van Elk and Blanke, 2013). In a recent study, Ferrè and colleagues (2014) questioned the influence of vestibular signals on spatial perspective taking, using for the first time an implicit and non-visual measure of perspective taking (known as graphesthesia task; Natsoulas and Dubanoski, 1964). They applied galvanic vestibular stimulation to healthy participants while an experimenter drew ambiguous letters (b, d, p, q) on the participant’s forehead using a cotton bud. Ambiguous letters can be perceived either from the participant’s first-person viewpoint (e.g., when the experimenter draws the letter b, the participant perceives the letter d) or from a disembodied third-person viewpoint (e.g., when the experimenter draws the letter b, the participant perceives the letter b). The data showed that galvanic vestibular stimulation increased the likelihood that ambiguous letters were ‘read’ from a first-person perspective. The authors interpreted this finding as a consequence of the natural role of vestibular signals in anchoring the self to the participant’s body. In this experiment, galvanic vestibular stimulation was applied at low intensity, which may have increased the contribution of vestibular signals to embodied self-location and body ownership (Lopez et al., 2008). Further studies are needed to determine whether galvanic vestibular stimulation would need to be applied a higher intensity, or may be combined with additional visual and somatosensory mismatches (as

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for example in Blanke et al., 2014; Lenggenhager et al., 2007; Macauda et al., 2014; Pfeiffer et al., 2013), to disturb the mechanisms that produce the usual experience of an embodied self. 3. Perceiving Bodies ‘from the Outside’ In this second part, I describe reciprocal relations between the vestibular sense and visual perception of bodies. That is: (1) How vestibular signals influence the visual interpretation of other’s body posture and movements and, conversely, (2) how observing human bodies in motion influences vestibular self-motion perception. In particular, I will examine how observing one’s own body (from the outside) being passively rotated can change the experience that ‘I have been moved’. 3.1. Vestibular Signals Influence the Visual Perception of Other’s Body Posture and Movement The visual system is highly tuned to detect bodies in motion, as this is crucial for the survival of the species. For example, the observation of dots that have been placed at main body joints is enough to detect that a body is moving within a random pattern of dots and affords the perception of social features such as the gender and emotion of the moving body (Brooks et al., 2008; Johansson, 1973; Troje and Westhoff, 2006; Westhoff and Troje, 2007). This ability is supported by several brain areas selectively activated by the observation of whole bodies, faces and other body parts (reviews in Peelen and Downing, 2007; Puce and Perrett, 2003). Although visual detection of biological motion is very accurate, it also benefits from other sensory signals, including sounds related to the body movements (Brooks et al., 2007). Of importance for the present review article, human bodies located around us are exposed to the gravitational field and consequently their motion is strongly constrained by physical laws of gravity and the biomechanics inherent to human morphology (Bonnet et al., 2005). As the vestibular otolithic system encodes gravitational acceleration, it is reasonable to propose that vestibular signals influence the visual interpretation of human body postures and movements. Several behavioral studies have demonstrated that biological motion perception is slower and less accurate when the pattern of dots depicting a body in motion is presented upside down with respect to gravity (i.e., inversion effect; Chang et al., 2010; Troje, 2003; Troje and Westhoff, 2006), an effect already present at birth (Bardi et al., 2014; Vallortigara and Regolin, 2006). There is evidence that such inversion effect is partly due to a disruption of configural processing of the body structure and to the processing of the motion of the dots representing the feet (Troje and Westhoff, 2006). The pattern of vertical motion of the feet is strongly constrained by gravity and visual

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processing of this motion may be influenced by mostly preconscious internal models of gravity (Lacquaniti et al., 2013; Maffei et al., 2015). Interestingly, there is evidence to suggest that gravitational information is also used to interpret and perceive the structure of human bodies that are not in motion. Lopez and colleagues (2009) investigated the influence of gravity signals with respect to the observer’s body orientation on visual perception of bodies, using a paradigm requiring participants to judge the stability of human body postures. Instead of using the apparent motion of the body, as in previous biological motion perception studies, the authors presented static pictures with implied motion (Fig. 2A). In these pictures the movement of the body was not apparent, but suggested by the depiction of a body that was, or was not, in the process of falling. Participants observed the picture of a virtual body seen from the back, more or less tilted, and standing on a circular platform. They were asked to indicate as fast as possible whether the body would fall over onto this platform. Visual stimuli were presented in different orientations with respect to gravity and the participants were also tested while seated on a chair and lying right side down on a mattress (Fig. 2B). The task required that participants judge the stability of the human body postures with respect to the platform

Figure 2. Influence of gravity and the observer’s body position on the visual perception of human body postures. (A) Visual stimuli are pictures representing a human body seen from the back and tilted either to the right or to the left on a platform. (B) Observers were tested upright and lying right side down. For each orientation of the observer, all visual stimuli were presented in four orientations with respect to gravity: upright, upside down, and rotated by 90° clockwise (CW) and counterclockwise (CCW). (C) Mean percentage of postures perceived as unstable is shown as a function of the amplitude and direction of the human body roll: leftward roll (blue curves) vs. rightward roll (red curves); roll with respect to the platform. Histograms in the inserts represent the mean point of subjective instability (PSI). Data are presented for only two orientations of the platform (upright and 90° CCW). Detailed results can be found in Lopez et al. (2009).

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Figure 2. (Continued.)

and imagined the direction of gravity that was concordant with the orientation of the platform, rather than with true physical gravity. Results revealed that when participants were tested in the seated position judgments of stability were strongly modulated by the orientation of the images. While postures of avatars tilted to the right and left sides of the platform were judged similarly unstable when pictures were oriented vertically (Fig. 2C), this was not the case when pictures were tilted. For example, when pictures were tilted by 90° in the counterclockwise direction, human postures tilted rightward on the platform (i.e., opposite from the direction of gravity) were judged as more stable than the same postures tilted leftward (i.e., downward, in the direction of gravitational pull). Figure 2C shows the corresponding shift of the psychometric curve and increase in the point of subjective instability for the postures shown tilted rightward on the platform. When pictures were tilted by 90° the interpretation of the image changed with respect to both gravity and the observer’s body axis. As a result it was not possible to determine the relative contribution of gravitational and bodycentered references for the visual judgment of body postures. However, participants were also tested lying right side down. The results indicated that

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for pictures rotated by 90° counterclockwise, and thus presented in an upside down orientation with respect to the observer, body postures tilted downward (toward gravity) were perceived as more unstable than those tilted upward. Because the human body postures were oriented symmetrically with respect to the observer’s body, this result showed the gravitational influence on visual perception of human body postures. In addition, when pictures were aligned with the gravitational axis, thus tilted by 90° with respect to the observer’s body axis, there was a difference between judgment of stability for the bodies tilted leftward (perceived as more unstable) and rightward (perceived as more stable). This effect is likely mediated by the orientation of the pictures with respect to the participant’s body axis and indicates that the visual perception of human body postures is also body-centered. Altogether, the data summarized above suggests that internal representations of gravity and the observer’s body position influence the visual perception of static bodies with an implied motion. It is notable that while observers were instructed to perform stability judgments with respect to the platform, they were not able to ignore the influence of the gravitational pull. The results demonstrate how gravitational signals (likely mediated by otolithic vestibular receptors) strongly constrain the visual processing of static pictures with implied motion. Such an effect is also evident from research in experimental psychology showing that gravity influences visual processing of other types of static images, including letter recognition (Dyde et al., 2006), perception of shape from shading (Jenkin et al., 2004), geometrical illusions (Clément et al., 2012), and reversible figures (Yamamoto and Yamamoto, 2006). As we have evolved under the constant acceleration of gravity, we have likely internalized the ‘up’ and ‘down’ directions of gravity and the influence of the gravitational pull on objects located in our visual environment. Developmental data in humans also demonstrate a gravitational influence on visual perception of moving objects as early as five to seven months after birth (Kim and Spelke, 1992). The influence of gravity on visual perception can be interpreted in relation to the existence of internal models of gravity in the brain (review in Lacquaniti et al., 2013). Models of gravity have been revealed using tasks requiring to estimate the time of collision of a ball that is falling down or requiring to intercept a ball (Bosco et al., 2008; Indovina et al., 2005; Lacquaniti et al., 2013; McIntyre et al., 2001; Miller et al., 2008; Senot et al., 2005; Zago and Lacquaniti, 2005). Neuroimaging studies have revealed a network of brain regions that are likely involved in the internal models of gravity. Areas located in the depth of the lateral sulcus, such as the insula and retroinsular cortex, are activated by the movement of objects that are displaced according to the physical laws of gravity, but not by object motions that violate physical laws of gravity (Indovina et al., 2005). Importantly, these areas overlap with the

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human vestibular cortex (Lopez, 2015; Mazzola et al., 2014). A recent fMRI study showed that different brain regions may support the selective effect of gravitational cues on biological motion perception (Maffei et al., 2015). These authors found that gravitational cues (i.e., motion of a point-light display coherent with 1G or with microgravity) influenced biological motion perception mainly in the occipito-temporal cortex. 3.2. Vestibular Influence on Mental Body Imagery Many social situations require that we make judgments about another person’s body or body parts. For instance, it can be useful to determine quickly if another person is holding an object in her right or left hand. There is a large body of evidence showing that such laterality judgments require mental rotation of the observer’s body in space also known as imagined spatial transformations of the body (Parsons, 1987a, b; Zacks et al., 1999, 2002). Interestingly, mental rotation of one’s own body and body parts is a strongly embodied cognitive process that takes into account postural somatosensory signals from the observer’s body. Thus, the current spatial configuration of the observer’s body influences the performance of mental spatial transformation of the body (Ionta and Blanke, 2009; Ionta et al., 2007, 2012; Kessler and Thomson, 2010). For example, participants are usually faster to decide if a visually presented hand is a left or right hand when their own hands are in a congruent posture (e.g., palm down) rather than incongruent posture (e.g., palm up) (Ionta and Blanke, 2009; Ionta et al., 2007, 2012). Clinical investigations in patients with muscular proprioceptive deafferentation (Ter Horst et al., 2012) or premotor cortex lesion (Arzy et al., 2006) indicate that normal sensorimotor processing is required to perform efficient mental own body transformations. Other studies used brachial plexus anesthesia or imagined paralysis to demonstrate that somatosensory signals are used for mental rotations of body parts (Hartmann et al., 2011; Silva et al., 2011). On the basis of this large corpus of evidence showing that processing of somatosensory signals influences visual judgments about another person’s body, it is justified to determine whether vestibular signals also contribute to mental rotations of visual objects and own body mental transformations. A relation between vestibular processing and mental imagery of the body or other visual objects has been proposed by several authors (Grabherr and Mast, 2010; Lenggenhager et al., 2006; Lopez et al., 2011; Mast et al., 2007, 2014). Clinical studies in patients with vestibular disorders indicate that mental rotation of complex three-dimensional objects or bodies is less efficient than in control participants, a finding that seems to be a consequence of bilateral rather than unilateral vestibular deafferentation (Candidi et al., 2013; Grabherr et al., 2011; Péruch et al., 2011). More generally, motor imagery of the entire body is impaired in patients with bilateral vestibular loss (Demougeot

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Figure 3. Examples of visual stimuli used during mental imagery tasks combined with vestibular stimulation. For the first three visual stimuli, participants indicated as fast and accurately as possible whether the extended arm or colored hand (for the bodies) or leaf (for the plant) was a left or right one. For the fourth stimulus, participants indicated which direction was east on a view of a cockpit according to the position of the plane on a map. For the fifth stimulus, participants realized mental rotation of letters and decided whether a presented letter matched the result of the mental rotation. Arrows indicate increase or decrease in response time (RT) or error rate (ER) as a result of vestibular stimulation (CVS: caloric vestibular stimulation, GVS: galvanic vestibular stimulation).

et al., 2011). Several studies have used vestibular stimulation to manipulate mental imagery in healthy participants (Fig. 3). A recent study by Van Elk and Blanke (2013) used passive whole-body rotations produced by a rotating chair in participants performing a mental imagery task to decide whether a virtual avatar had a left or right hand colored. These authors found that the direction of the chair rotation interacted significantly with the direction of the whole-body mental rotation: participants tended to be slower when the two directions (physical body rotation and mental body rotation) were opposite, suggesting that vestibular signals are used to mentally rotate one’s own body in space. Several studies used artificial vestibular stimulations (caloric or galvanic vestibular stimulation) to evaluate the contribution of vestibular signals to mental imagery. Various results have been reported: Falconer and Mast (2012) found that caloric vestibular stimulation improved mental rotation of bodies (shorter response times), whereas others reported that caloric vestibular stimulation impaired mental rotation of letters (larger number of errors, Mast et al., 2006) and that galvanic vestibular stimulation impaired own-body mental transformation (longer response times, Lenggenhager et al., 2008). In

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a task requiring changes in the visuo-spatial perspective, Dilda et al. (2012) found that galvanic vestibular stimulation disturbed the participant’s ability to orient themselves according to the main cardinal axis of a map. The reasons for the discrepancies in the results summarized above are not yet clear and further investigations are needed to understand the neurophysiological mechanism through which vestibular stimulation influences mental imagery. It has been proposed that vestibular stimulation enhances updating of the egocentric references and the body schema, and thus facilitates the projection and mapping of bodily reference frames during own-body mental transformations (Falconer and Mast, 2012). This hypothesis is in line with neurological data showing that caloric vestibular stimulation may promote access to the internal body model (Le Chapelain et al., 2001) as well as with the fact that egocentric signals are used for mental own-body transformations (Ionta et al., 2012). Other authors (Lenggenhager et al., 2008) have proposed that artificial vestibular stimulation provides a self-motion signal to the brain that has no physiological equivalent, and that such sensory signal can disturb sensory processing in areas involved in mental rotations of bodies, such as the posterior parietal cortex and temporo-parietal junction (Blanke et al., 2005; David et al., 2006; Schwabe et al., 2009; Tadi et al., 2009; Zacks, 2008). Thus, vestibular signals would disrupt own-body mental imagery in the same way as transcranial magnetic stimulation applied over the temporo-parietal cortex disturbs full-body mental rotations (Blanke et al., 2005). A common feature of the studies reported above is that vestibular signals appear to be preferentially used to mentally align one’s own body reference with that of a distant avatar or human being, while used to a lesser extent in mentally rotating objects in space. Accordingly, we have shown that galvanic vestibular stimulation increases response time of laterality judgments only for participants who used an own-body mental transformation strategy (Lenggenhager et al., 2008). This was not the case for participants who used an object-based mental transformation strategy to solve the same task, i.e., for participants who did not mentally rotate their body in space. In conclusion, vestibular signals may be preferentially used to simulate geometric transformations necessary to rotate one’s own body in space and this could occur in the temporo-parietal regions involved in vestibular processing and mental imagery (Lopez and Blanke, 2011; Zu Eulenburg et al., 2013b). 3.3. Observation of Human Body Motion and Self-Motion Perception Sections 3.1 and 3.2 focused on how vestibular signals influence visual perception of human bodies, particularly for static images of humanoid figures. In this section, we will examine the reverse influence: how the observation of human bodies in motion influences vestibular perception. It should be noted that this question constitutes a very novel development in the research field

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of vestibular cognition. Until now, studies on self-motion perception measured vestibular thresholds under various motion parameters and situations (manipulating the frequency, acceleration and axis of the movement) or while participants were exposed to various static or moving visual patterns (Grabherr et al., 2008; Hartmann et al., 2013; Zupan and Merfeld, 2008). Visual environments presented in earlier studies never included representations of human beings, although the observation of human bodies moving in our extrapersonal space is a very common feature of modern societies — we walk in streets within crowds of people, practice team sports, etc. Vestibular cognition was until recently lacking connections with the field of social neuroscience, which could have dramatically hampered research on vestibular self-motion perception (for detailed descriptions, see Deroualle and Lopez, 2014; Lenggenhager and Lopez, 2015a, b). Cognitive neuroscience has recently accumulated a growing amount of evidence showing that sensorimotor processing at the level of one’s own body is influenced by the observation of others, an effect referred to as shared body representations between self and others or sensorimotor resonance (Decety and Chaminade, 2003; Iacoboni, 2009; Thomas et al., 2006). Contagious yawning and itching are prototypical examples of shared representations between others and the self. Research in this field repeatedly showed that observing a conspecific executing an action facilitates the execution of the same action by the observer (Fadiga et al., 1995). This facilitation has been related to a mirror neuron system in the human fronto-parietal cortex (Iacoboni et al., 2005; Rizzolatti and Craighero, 2004; Rizzolatti and Sinigaglia, 2008, 2010). In addition to the motor resonance between the self and others, the mirror neuron system has been implicated in sensory resonance between the self and others. For example, observing someone experiencing pain activates parts of the cortical pain network in the observer’s brain, including the insula and anterior cingulate cortex (Singer et al., 2004), and observing someone smelling disgusting odorants similarly activates parts of the observer’s insula involved in disgust (Wicker et al., 2003). The accuracy of detection of tactile stimuli applied to one’s own face is also modulated by the observation of bodies receiving a tactile stimulation. Serino and colleagues (2008) showed that the observation of one’s own face being touched, as well as observing someone else’s face being touched, facilitates tactile detection applied to the self, with a stronger effect found for the observation of the self than the other face. In the vein of studies on shared body representations mentioned above, we have recently investigated whether observing passive whole-body movements of another human influenced vestibular self-motion perception (Lopez et al., 2013). Participants were passively rotated around their vertical body axis (yaw rotations) while seated on a full-body motion platform (Fig. 4A). They were asked to detect as fast and accurately as possible whether they were rotated to

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Figure 4. Influence of the observation of self and other whole-body motion on vestibular perception. (A) Full-body motion platform used to measure self-motion perception. Participants were rotated to their right or left side for 5 s (at 0.1°/s, 0.6°/s, 1.1°/s, and 4°/s) and were asked to detect as fast as possible the direction of the rotation. (B) Participants were shown self and other videos in a head-mounted display. During congruent trials the participant and the object depicted in the video were rotated in the same direction (specular congruency). (C) The graph illustrates the magnitude of the congruency effect for each participant (depicted by a dot) for the observation of self and other videos. The congruency effect has been calculated as the difference in response time between the congruent trials (the participant is passively rotated on the full-body motion platform to one side and the body depicted in the video rotates in a congruent, specular, way) and the incongruent trials. Squares represent the average congruency effect for self and other videos. (D) The congruency effect was positively correlated with the subscale ‘emotional reactivity’ of the empathy quotient for the observation of other videos, but not for the observation of self-videos. Adapted from Lopez et al. (2013).

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their right or left side. At the same time, they were shown videos in a headmounted display depicting a front view of a body also rotated on the same motion platform and with the same motion parameters. The video was either a pre-recorded video of the participant’s body, another body, or a video of a white cylinder rotating in the yaw plane. The motion of the observer’s body and the body depicted in the video could be either congruent (a type of specular congruency) or incongruent, so as to create situations of visuo-vestibular conflicts (Fig. 4B). Figure 4C shows the visuo-vestibular congruency effects for self and other videos. While the visuo-vestibular congruency effect for self-motion perception was evident when observing self-videos, this effect was reduced when observing someone else’s body being rotated. Thus, observing one’s own body moving in a direction incongruent to the physical body rotation disrupts self-motion perception. Results also revealed important interindividual differences in the sensitivity to visuo-vestibular conflicts, so that participants were unequally affected by the observation of another body passively rotated. Interestingly, there was a positive correlation between the magnitude of the congruency effect for the other videos (but not the self-videos) and a score of ‘emotional reactivity’, a subscale of the empathy quotient (Baron-Cohen and Wheelwright, 2004; Lawrence et al., 2004) (Fig. 4D). Participants that were more empathic tended to be more disturbed by the observation of another body being moved in the direction opposite to their own body. Lopez and colleagues (2013) have proposed that observing a body being passively rotated may evoke implicit and automatic third-person perspective taking, thus resulting in slower and less efficient self-motion perception (in the same vein as automatic imitations of other’s actions: Brass et al., 2009). In addition, the correlation between empathy and congruency effects for the other videos established connections between vestibular self-motion perception and shared body representations between self and others. In line with this idea are data showing that empathy scores are correlated with participants’ ability to put themselves into someone else’s shoes (Mohr et al., 2010) and their degree of self-identification with someone else’s face (Sforza et al., 2010). In conclusion, results from this study hint at the presence of a vestibular mirror neuron system whose neural bases need to be addressed by neurophysiological and neuroimaging investigations. 4. Conclusions and Perspectives A better understanding of the vestibular contribution to bodily perceptions — in addition to the well-known vestibular control of posture, eye movements and spatial memory — is an important step to improve the neuroscientific models of body and self-representations. While several studies have shown that vestibular signals modulate tactile and pain perceptions (i.e., perception

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of the body ‘from within’), more work is now needed to improve our understanding of the neurophysiological mechanisms supporting the vestibular effects on the body’s metric properties, body ownership and the experience of the embodied self. For example, neurophysiological recordings in monkeys have described the rules of visuo-vestibular integration in area MST, showing that both sensory signals combine in a statistically optimal way, that is in accordance with Bayesian models (Fetsch et al., 2007, 2012; Gu et al., 2007) as suggested by behavioral studies in humans (Butler et al., 2010; MacNeilage et al., 2007; Prsa et al., 2012). The same approach should now be realized to describe the rules of vestibulo-somatosensory integration in brain areas where these signals converge, such as the parieto-insular vestibular cortex and intraparietal sulcus. The present review article also aimed at highlighting a novel aspect of vestibular research: the influence of vestibular signals on sensorimotor mechanisms important for human social cognition. As summarized above, this influence is bidirectional (Fig. 5). Because vestibular and visual signals are integrated in various brain structures along the vestibulo-thalamo-cortical pathways, vestibular signals can modulate visual signals about other bodies. Thus, internal models of gravity can modulate the way we interpret and anticipate

Figure 5. Reciprocal relations between vestibular perception and visual perception of human bodies. Integration of visual and vestibular signals throughout the vestibulo-thalamo-cortical pathways may underpin the reciprocal relations between vestibular and visual perception. This figure also illustrates the connections between vestibular processing and social cognition, a research area that needs to be developed.

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the motion of others and the posture of other bodies. Conversely, we have shown that visual information about bodies being passively rotated can modulate the interpretation of one’s own body motion coded by the vestibular organs (i.e., perception of the body ‘from the outside’). I have proposed the idea that sensorimotor resonance and shared body representations — already revealed for actions, touch, pain and smell — also exists for the vestibular system (Deroualle and Lopez, 2014; Lopez et al., 2013). I am optimistic that this proposition will open new avenues of research in the field of vestibular cognition and propose that future neuroscientific investigations should endeavor to investigate how social situations modulate the interpretation of vestibular signals and their role for the body and the self. Establishing connections between the so far distinct fields of vestibular physiology and social neuroscience should be mutually beneficial for both fields and will certainly unravel new functions of the human vestibular sense of balance. Acknowledgements The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement number 333607 (‘BODILYSELF, vestibular and multisensory investigations of bodily selfconsciousness’). I am grateful to Dr Caroline Falconer and Dr Patricia Romaiguère for helpful comments on the manuscript. References Angelaki, D. E. and Cullen, K. E. (2008). Vestibular system: the many facets of a multimodal sense, Annu. Rev. Neurosci. 31, 125–150. Arzy, S., Overney, L. S., Landis, T. and Blanke, O. (2006). Neural mechanisms of embodiment: asomatognosia due to premotor cortex damage, Arch. Neurol. 63, 1022–1025. Aspell, J. E., Heydrich, L., Marillier, G., Lavanchy, T., Herbelin, B. and Blanke, O. (2013). Turning body and self inside out: visualized heartbeats alter bodily self-consciousness and tactile perception, Psychol. Sci. 24, 2445–2453. Balaban, C. D. (1999). Vestibular autonomic regulation (including motion sickness and the mechanism of vomiting), Curr. Opin. Neurol. 12, 29–33. Balaban, C. D. (2004). Projections from the parabrachial nucleus to the vestibular nuclei: potential substrates for autonomic and limbic influences on vestibular responses, Brain Res. 996, 126–137. Bardi, L., Regolin, L. and Simion, F. (2014). The first time ever I saw your feet: inversion effect in newborns’ sensitivity to biological motion, Dev. Psychol. 50, 986–993. Baron-Cohen, S. and Wheelwright, S. (2004). The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences, J. Autism Dev. Disord. 34, 163–175.

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Vestibular–Somatosensory Interactions: A Mechanism in Search of a Function? Elisa Raffaella Ferrè ∗ and Patrick Haggard Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, UK

Abstract No unimodal vestibular cortex has been identified in the human brain. Rather, vestibular inputs are strongly integrated with signals from other sensory modalities, such as vision, touch and proprioception. This convergence could reflect an important mechanism for maintaining a perception of the body, including individual body parts, relative to the rest of the environment. Neuroimaging, electrophysiological and psychophysical studies showed evidence for multisensory interactions between vestibular and somatosensory signals. However, no convincing overall theoretical framework has been proposed for vestibular–somatosensory interactions, and it remains unclear whether such percepts are by-products of neural convergence, or a functional multimodal integration. Here we review the current literature on vestibular–multisensory interactions in order to develop a framework for understanding the functions of such multimodal interaction. We propose that the target of vestibular– somatosensory interactions is a form of self-representation. Keywords Vestibular system, multisensory integration, somatosensory perception

1. Bridging Phenomenology and Anatomy The vestibular system plays an essential role in everyday life, contributing to a surprising range of functions from reflexes to the highest levels of perception and consciousness. Three orthogonal semicircular canals detect rotational movements of the head in the three-dimensional space (i.e., pitch, yaw and roll), and two otolith organs (utricle and saccule) sense translational acceleration, including the gravitational vertical. The importance of these vestibular signals for behaviour is self-evident, since almost all coordinated interactions *

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with the external world involve some movements of the organism with respect to the environment. How the same signals contribute to our perceptual awareness of the environment is less clear. Indeed, in normal sensorimotor coordination, it is hard to identify a distinctive vestibular phenomenology. What the literature often discusses as ‘vestibular sensations’, such as vertigo, can, in fact, be seen as interoceptions of the systemic consequences of extreme, or unusual, or unexpected vestibular signals. Moreover, most of the events detected by the vestibular system are also detected by other sensory systems, notably visual and proprioceptive systems. The perceptual experience of head rotation and acceleration is normally a synthetic result of mixing multiple redundant cues (Angelaki and Cullen, 2008). Phenomenal access to ‘raw’ vestibular sensation is questionable. The acceleration due to gravity transduced by the otoliths is a case in point. The signal is always on, but it is difficult to point to a specific phenomenal experience of gravity driven by this signal. Vestibular inputs are strongly integrated with signals from other sensory modalities, such as vision, touch and proprioception (Faugier-Grimaud and Ventre, 1989). This convergence perhaps reflects the importance for survival, and the redundancy with other systems, described above. Multimodal convergence has been described in almost all vestibular relays, including the vestibular nuclei, the thalamus and several areas in the cerebral cortex (Lopez and Blanke, 2011; Lopez et al., 2012; Zu Eulenburg et al., 2012). The evidence for this convergence comes from two main sources. On the one hand, neuroimaging studies have revealed a functional anatomy of vestibular cortical projections. These studies, which we review in detail below, have identified brain areas activated or deactivated by vestibular stimulations using fMRI and PET. For instance, inhibitory vestibular–visual interactions fundamental in maintaining and controlling gaze evoked not only an activation of the parietal vestibular areas but also a decrease in rCBF of the visual cortex (Brandt et al., 1998; Deutschländer et al., 2002; Wenzel et al., 1996). On the other hand, electrophysiological studies have recorded single neurons responses to vestibular stimuli in areas such as the parieto-insular vestibular cortex (PIVC) (Grüsser et al., 1990), the somatosensory cortex (Schwarz and Fredrickson, 1971) and the ventral intraparietal area (Bremmer et al., 2002). The human homologue of the primate PIVC may not be a single area, so much as a distributed set of regions including the posterior and anterior insula, temporoparietal junction, superior temporal gyrus, inferior parietal lobule, and somatosensory cortices (Lopez and Blanke, 2011; Lopez et al., 2012; Zu Eulenberg et al., 2012). These studies identified neurons responding to combinations of tactile, visual and vestibular inputs, confirming the multisensory nature of the vestibular cortical network. The predominant theme in recent electrophysiological work has been the convergence between vestibular information and vision for perception of self-

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motion, spatial orientation and navigation in the environment. In particular, vestibular–visual interactions are often interpreted within the framework of optimal cue combination, for multisensory perception of a single underlying quantity, namely one’s own heading direction (Fetsch et al., 2009). However, there is growing evidence for multisensory interactions also between vestibular and somatosensory signals from both neuroimaging (Bottini et al., 1994, 1995, 2001; Fasold et al., 2002), and electrophysiological (Fredrickson et al., 1966) techniques. 2. What Are Multisensory Interactions for? Large bodies of recent neuroimaging and electrophysiological evidence are consistent with a general framework of vestibular–multisensory interactions. However, neither neuroimaging nor electrophysiology, in themselves, are conclusive regarding function of these interactions. Neuroimaging responses to artificial vestibular stimulation identify the existence of a projection, but do not clarify what it does. For example, the neuroimaging results showing somatosensory activations to vestibular stimulation are consistent with independent somatosensory and vestibular populations of neurons in the same cortical area, but not interacting (Bottini et al., 1994, 1995, 2001; Fasold et al., 2002). Electrophysiological studies confirm that a specific physical quantity, e.g., heading direction, is coded in the central nervous system (Grüsser et al., 1990). However, recordings from single neurons cannot, in themselves, show how that code contributes to behaviour. In recent years, the combination of extensive single-unit recording, and explicit computational theory has allowed strong and convincing functional accounts linking neural firing to behaviour. The successful integration of multiple sensory cues has been proven to be essential for precise and accurate perception and behavioural performance (Fetsch et al., 2012). For example, the interaction between vestibular and visual signals has been interpreted as optimal intermodal combination of cues for heading (Fetsch et al., 2009, 2012). 3. Self-Representation as a Target of Vestibular–Multisensory Interactions In contrast, no convincing overall theoretical framework has been proposed for vestibular–somatosensory interactions, even though neuroimaging data has repeatedly identified an anatomical substrate for the interaction between vestibular and somatosensory signals (Bottini et al., 1994, 1995, 2001; Fasold et al., 2002), and perceptual studies have repeatedly shown phenomenological and perceptual effects of vestibular inputs on somatosensory measures (Bottini et

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al., 1995; Ferrè et al., 2011a, b; Vallar et al., 1990, 1993). However, it remains unclear whether such percepts are by-products of neural convergence, or a functional multimodal integration. Why have functional accounts of vestibular–somatosensory interaction made less progress than functional accounts of vestibular–visual interaction? In our view, this is because we lack a candidate for the physical quantity that is the target representation for vestibular–somatosensory interactions, analogous to heading direction in vestibular–visual interactions. Because the end-product of vestibular–somatosensory interactions is unclear, functional theories and explicit computational models are lacking. In this paper, we review the current literature on vestibular–multisensory interactions in order to develop a framework, or a sketch for a future functional theory, for vestibular–somatosensory interactions. In a nutshell, we propose that the target representation of vestibular– somatosensory interactions is a form of self-representation. This representation has the role of linking the spatial description of one’s own body to the spatial description of the outside world. The heading direction emerging from vestibular–visual interactions would thus be one, specific instance of a linkage between the animal’s own body and the external environment, embedded in a general network of tactile, nociceptive and other mechanisms for coordination of simple sensorimotor interactions. Importantly, the vestibular–visual interaction is essentially cyclopean, serving to navigate a point organism through a spatially-extensive world. In contrast, the vestibular–somatosensory interaction involves the spatial geometry of the body itself as a volumetric object. 4. Which Forms of Multisensory Interaction Could Contribute to Self-Representation? Haggard et al. (2013) have recently distinguished three different forms of multisensory interaction. The first is feedforward multisensory convergence, in which afferents carrying information in two distinct modalities converge on a single higher-order neuron. The higher-order neuron responds to stimulation in either modality, and is thus ‘bimodal’. The second involves transformation of information from one modality into the spatial reference frame of another. Such transformations involve a change in spatial tuning, but may not produce any overall change in neural firing rate. The third form of multisensory interaction is modulation by one sensory signal of the gain in a second sensory pathway. Accordingly, information in one modality is used to change synaptic connections in the afferent pathway of another modality. Our concept of vestibular–multisensory self-representation could involve all three forms of multisensory interaction. We give simple illustrations here, with the aim of showing that self-representation is not a reflexive, or a tran-

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scendental cognitive function, but could be accommodated within current computational frameworks about multisensory processing. First, vestibular signals from the canals converge with visual information for optimal feedforward computation of gaze and heading. Second, gravity-dependent signals from the otolith organs, could provide an absolute reference frame for spatial representation, into which other internal and external information is transformed. Third, gain regulation within different sensory pathways could flexibly balance the self-environment interaction towards the proximal environment surround the organism’s own body (e.g., boosting cutaneous sensation), or towards the distal environment (e.g., boosting visual transmission). Here we review the recent literature with a view to bridging the phenomenology-anatomy gap for vestibular and somatosensory systems. We develop an overall position of vestibular–multisensory interactions as a key element of self-representation, and vestibular–somatosensory interactions as a specific contribution to bodily self-awareness. To reach this view, we group current knowledge about vestibular–somatosensory interactions into three broad classes: vestibular contributions to sensorimotor control, vestibular effects on spatial attention and cognition and vestibular modulation of somatosensory afference.

5. Vestibular–Somatosensory Interactions: Vestibular Contribution to Sensorimotor Control

The vestibular system does not fit the classical model of a modality-specific, dedicated sensory pathway, such as vision and touch. Instead, multisensory convergence between vestibular and somatosensory signals has been described at several levels in the central nervous system. These multisensory interactions occur for instance at the primary relay station of the vestibular signals, the vestibular nuclei, where more than 80% of neurons are influenced by kinaesthetic afferents (Fredrickson et al., 1966). However, the majority of neurons reported to respond to both vestibular and somatosensory signals have been found in the cerebral cortex. Fredrickson et al. (1966) recorded the cortical potentials evoked by direct electrical stimulation of the vestibular nerve in the rhesus monkey. The results showed a vestibular–responsive area in the posterior part of the postcentral gyrus, close to the intraparietal sulcus, and located between the primary and secondary somatosensory cortex (Brodmann’s

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area 2). More importantly, single-unit recording showed that neurons in this area responded not only to vestibular stimulation but also to stimulation of the somatosensory median nerve (Fredrickson et al., 1966). This evidence suggested an interaction between vestibular and somatosensory afferents within area 2. Later studies localised the site of the multisensory convergence in an area located posteriorly to area 2v (Fredrickson and Rubin, 1986; Schwarz and Fredrickson, 1971; Schwarz et al., 1973). These data are additionally supported by results showing cortical responses evoked by peripheral stimulation of the vestibular receptors in monkey (Büttner and Buettner, 1978) and cat somatosensory area 2v (Jijiwa et al., 1991). Guldin and Grüsser (1998) estimated that about 30–50% of neurons in the somatosensory area 3aV receive vestibular inputs. Vestibular projections reach the primary somatosensory representation of the forelimb (Ödkvist et al., 1973, 1974, 1975), the area coding for the neck and the trunk representations and extend anteriorly into the primary motor cortex (Akbarian et al., 1994; Guldin and Grüsser, 1998; Guldin et al., 1992). Most authors assume that vestibular–somatosensory neurons play some role in sensorimotor postural control. Schwarz and Fredrickson (1971) claimed that “central convergence of these two modalities [vestibular and somatosensory] is apparently essential not only for lower reflex mechanisms but also for the conscious perception of position and movement”, suggesting that the multisensory convergence between vestibular and somatosensory signals might be functional for balance responses and motor control. Successive electrophysiological studies supported this explanation describing the vestibular–somatosensory interaction as an adaptive bimodal response for maintaining postural reflexes and for controlling the position of body parts in external space (Fredrickson and Rubin, 1986; Schwarz et al., 1973). The link between vestibular–somatosensory interaction and postural responses has been described in many situations in humans. For instance, vestibular inputs are critical for initiation of postural responses to head and body displacements (Horstmann and Dietz, 1988). Critically, vestibular– somatosensory interactions vary with the context in which stimuli are presented and with the qualities of the stimuli. While vestibular inputs have little effect when surface somatosensory information predominates, vestibular signals greatly influence lower extremity motor outputs when somatosensory information is unavailable or unstable (Horak et al., 1994). This pattern of results suggests that vestibular and somatosensory systems provide alternative, complementary information relevant for postural control. Integrating these signals would thus potentially provide optimal postural control.

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6. Vestibular–Somatosensory Interactions: Vestibular Effects on Spatial Attention and Cognition .

The first description of the influence of vestibular stimulation on somatosensory processing in human was reported by Vallar and colleagues in 1990 (Table 1) (Vallar et al., 1990). In three right brain-damaged patients, the irrigation of the left ear canal with cold water (caloric vestibular stimulation) temporarily ameliorated left tactile imperception (hemianaesthesia) and many manifestations of the syndrome of left hemispatial neglect (Vallar et al., 1990). Critically, the mirror-reversed paradigm, i.e., right ear cold caloric vestibular stimulation in right hemianaesthesia has been unsuccessful so far (Bottini et al., 2005; Vallar et al., 1993). Such hemispheric differences suggest that left hemianaesthesia in right brain-damaged patients was a manifestation of inattention for the left side of space (Vallar et al., 1990, 1993). Accordingly, the temporary remission induced by vestibular stimulation was due to vestibular activation of an attentional orientation mechanism. Specifically, vestibular stimulation caused a shift of attention toward the neglected side of the space/body, partly restoring its normal representations (Vallar et al., 1990, 1993). It has been recently described that galvanic vestibular stimulation modulates tactile extinction (inability to process or attend to the contralesional stimulus when two stimuli are simultaneously presented) in right brain-damaged patients. The quality of remission of tactile extinction is polarity-specific (Kerkhoff et al., 2011; Schmidt et al., 2013) (Table 1). Interestingly, a repeated number of galvanic vestibular stimulation sessions can induce significant changes in tactile extinction that remain stable for several weeks. Although these studies provided some insights for rehabilitation, no clear functional explanation of such long lasting effects has been provided. Instead a range of different explanations can be hypothesised, including vestibular-induced changes in attentional mechanisms to recovery of altered or damaged body representations. The current consensus view regarding these clinical observations favours the idea that vestibular remission from apparently ‘primary’ sensory deficits, such as hemianaesthesia or tactile extinction, may in fact be an attentional phenomenon (Miller and Ngo, 2007; Utz et al., 2010, 2011). Effects of vestibular stimulation on attention have been extensively described. As early as 1941, Silberfenning (Silberfenning, 1941) suggested that the vestibular system plays a role in the spatial allocation of attentional resources. Rubens (1985) applied caloric vestibular stimulation to the auditory canal of the left ear in right brain-damaged patients with left hemispatial neglect, and observed a transient improvement. He interpreted this recovery as reflecting low-level visual–vestibular interactions arising because the vestibular-induced nystagmus leads to direction-specific changes in visual in-

Left ear cold CVS Left ear cold CVS Right ear cold CVS Left ear cold CVS Left ear cold CVS Right ear cold CVS Left ear cold CVS Passive whole body rotation LA/RC GVS RA/LC GVS Left ear cold CVS Left ear cold CVS Left ear cold CVS LA/RC GVS RA/LC GVS Left ear cold CVS LA/RC GVS RA/LC GVS Passive whole body rotation

Vallar et al., 1990 Vallar et al., 1993

Ferrè et al., 2014

Ferrè et al., 2013b Ferrè et al., 2013c

Ferrè et al., 2011a Ferrè et al., 2011b Ferrè et al., 2012 Schmidt et al., 2013

Kerkhoff et al., 2011

Figliozzi et al., 2005

Bottini et al., 1995 Bottini et al., 2005

Vestibular stimulation

Study

RBD RBD HP HP HP RBD RBD HP HP HP HP

RBD RBD LBD RBD RBD LBD LBD HP

Group

Tactile extinction Tactile extinction Tactile detection Tactile detection SEPs Tactile extinction Tactile extinction Touch/Pain threshold Tactile detection Tactile detection Tactile detection

Tactile detection Tactile detection Tactile detection Tactile detection Tactile detection Tactile detection Tactile detection TOJs

Task

Remission of left side tactile extinction (identical stimuli) Remission of left side tactile extinction (different stimuli) Increase in detection rate Increase in tactile sensitivity Modulation of N80 SEPs component Remission of tactile extinction (identical and different stimuli) Remission of tactile extinction (identical and different stimuli) Decrease in tactile threshold, increase in pain threshold Increase in tactile sensitivity No effects Increase in tactile sensitivity, no spatial congruency effects

Remission of left side hemianaesthesia Remission of left side hemianaesthesia and tactile extinction No effects Remission of left side hemianaesthesia Remission of left side hemianaesthesia No effects Remission of right side hemianaesthesia Spatial congruency effects on touch

Behavioural effects

Table 1. Vestibular modulation of touch: behavioural evidence. Summary of behavioural effects elicited by vestibular stimulation on somatosensory perception in brain-damaged patients and healthy participants. CVS: caloric vestibular stimulation; LA/RC GVS: left anodal and right cathodal galvanic vestibular stimulation; RA/LC GVS: right anodal and left cathodal galvanic vestibular stimulation; RBD: right brain-damaged patients; LBD: left brain-damaged patients; HP: healthy participants: TOJs: temporal order judgments; SEPs: somatosensory evoked potentials

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put (Rubens, 1985). However, this explanation has been challenged by several clinical reports. Rorsman and colleagues (1999) reported a reduction of the attentional bias in visuo-motor tasks during galvanic vestibular stimulation. Similarly, vestibular stimulation decreases attentional bias in the bisection task (Utz et al., 2011) and visuospatial constructive deficits in the Rey figure (Wilkinson et al., 2010). These findings suggest an effect far beyond a mere by-product of vestibular–oculomotor reflexes, and instead affecting cortical mechanisms of visuospatial cognition. In the specific case of visuospatial attention, vestibular stimulation causes both modulations of attentional bias in neurological patients (Bisiach et al., 1991, 2000; Cappa et al., 1987; Rode and Perenin, 1994; Vallar et al., 1990), and reports of contralateral cortical activation, suggesting a direct interaction with a cortical locus. More recently, similar modulations of spatial attention have been reported in healthy participants receiving galvanic vestibular stimulation (Ferrè et al., 2013a). However, vestibular stimulation may have direct effects on somatosensory processing, in addition to changes in spatial attention. First, vestibularinduced remission of somatosensory deficits in brain-damaged patients has been proven to be independent of visuo-spatial hemineglect (Vallar et al., 1993). Second, remission of tactile imperception has been described even in a patient affected by a lesion directly involving the primary somatosensory cortex (Bottini et al., 1995). In that patient, the neural correlates of the temporary remission of left hemianesthesia after caloric vestibular stimulation included activations in the right hemisphere (insula, right putamen, inferior frontal gyrus in the premotor cortex). These data have been interpreted as a modulation of somatosensory perception induced by vestibular stimulation and mediated by a right hemispheric neural network putatively involved in somatosensory processing and awareness (Bottini et al., 1995, 2005). In other words, an undamaged subset of “sensory body representations” (cf. Bottini et al., 1995) is able to mediate tactile perception when an appropriate physiological manipulation is introduced. However, this manipulation would need to have sufficient anatomical specificity to reduce the distorted sensory representation caused by the brain lesion. Bottini et al. (1995) suggested that shared anatomical projections between vestibular and somatosensory system might be responsible for these effects. 7. Vestibular–Somatosensory Interactions: Vestibular Modulation of Somatosensory Afference We recently hypothesised a different interpretation of vestibular–somatosensory interactions, based on intermodal gain modulation (Ferrè et al., 2011b, 2013b). Briefly, vestibular inputs would influence the gain of different stages along the somatosensory afferent pathway. This hypothesis can be distin-

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guished from multisensory convergence for sensorimotor control, because there is no transformation of vestibular or somatosensory information into another modality or an amodal format. The hypothesis can be distinguished from non-specific attentional or spatial effects because it proposes modality-specific changes in somatosensory processing (Table 1) (Ferrè et al., 2011a, b, 2013b). Caloric vestibular stimulation was administered in healthy volunteers to estimate vestibular effects on somatosensory perception (Ferrè et al., 2011b). The detection of faint somatosensory stimuli was estimated using signal detection analysis, to distinguish perceptual sensitivity from response bias. The most striking result was a clear enhancement of perceptual sensitivity by vestibular stimulation. This effect was found for detection of shocks on both left and right hands, i.e., both ipsilateral and contralateral to the side of caloric vestibular stimulation. A visual contrast sensitivity task was administered in the same group of participants during the same testing session to control for non-specific, supramodal effects such as arousal — no such effects were found. Since caloric vestibular stimulation does not allow precise control of vestibular activation, other studies investigated the vestibular modulation of somatosensory perception using galvanic vestibular stimulation. This involves a weak direct current passing between surface electrodes placed on the mastoid behind the ear (Fitzpatrick and Day, 2004). Although this method is quantitatively well controlled, it evokes rather unspecific pattern of activation in the whole vestibular nerve, mimicking a multidirectional head motion (Goldberg et al., 1984). Crucially, the polarity of stimulation can be reversed as part of the experimental procedure, producing opposite effects on firing rate in the two vestibular nerves, and thus reversing the direction of the virtual rotation vector (Fitzpatrick and Day, 2004). Moreover, placing the galvanic vestibular stimulation electrodes away from the mastoids allows a sham stimulation, producing the same skin sensations under the electrodes as real vestibular stimulation, but without stimulation of the vestibular nerve. Left anodal/right cathodal galvanic vestibular stimulation selectively improved the ability to detect faint tactile stimuli, confirming previous findings obtained with caloric vestibular stimulation (Ferrè et al., 2013c). This enhancement was found for shocks on both the left and right hand. Right anodal/left cathodal galvanic vestibular stimulation had no significant effects on somatosensory detection. Since left anodal/right cathodal galvanic vestibular stimulation mimics a decrease in the firing rate of the vestibular nerve on the left side and an increase on the right side (Goldberg et al., 1984), we suggested that polarity-specific influence on touch could reflect altered somatosensory processing in the right hemisphere. Effects of galvanic vestibular stimulation polarity on perception are well known and wide-ranging. Kerkhoff et al. (2011) reported that left anodal/right cathodal galvanic vestibular stimu-

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lation reduced tactile extinction in right brain-damaged patients (Table 1). Utz et al. (2011) reported that left anodal/right cathodal galvanic vestibular stimulation reduced rightward bias in line bisection in neglect patients, while right anodal/left cathodal had minimal effect. Lenggenhager et al. (2008) found that response times in a mental transformation task were increased during right but not left anodal galvanic vestibular stimulation for the larger angles of rotation. The disturbing effects of galvanic vestibular stimulation were selectively present in participants who performed egocentric mental transformation and not object-based mental transformation. This suggestion was consistent with the results of an electrophysiological study in which we recorded somatosensory evoked potentials elicited by left median nerve stimulation immediately before and immediately after left ear cold water caloric vestibular stimulation. The results showed a vestibular-induced modulation in the N80 component over both ipsilateral and contralateral somatosensory areas (Ferrè et al., 2012) (Table 1). The vestibular modulation was specific to this component, since neither earlier nor later somatosensory evoked components were affected. Moreover, the effect was also specific to somatosensory processing: visual evoked potentials to reversing checkerboard patterns were not influenced by caloric vestibular stimulation, ruling out explanations based on indirect vestibular effects mediated by general arousal or supramodal attention. Critically, the N80 component has been localised in the parietal operculum (area OP 1 — Eickhoff et al., 2010; Jung et al., 2009), which functionally corresponds to the secondary somatosensory cortex (Eickhoff et al., 2010). Our vestibular-induced modulation had similar amplitude contralaterally and ipsilaterally (Ferrè et al., 2012). This strongly supports the hypothesis of an origin for this somatosensory component in the secondary somatosensory cortex, given the bilateral organisation of this area (Iwamura et al., 1994). The secondary somatosensory cortex from which N80 is assumed to arise is immediately adjacent to the neuroanatomical site of vestibular–somatosensory convergence in the human homologue of the monkey PIVC, identified as OP 2 by Zu Eulenberg et al. (2012). OP 2 lies slightly deeper within the Sylvian fissure than OP 1, at the junction of the posterior parietal operculum with the insular and retroinsular region (Eickhoff et al., 2006a, b). Caloric and galvanic vestibular stimulation influence both low-level perceptual and higher-level attentional functions (Figliozzi et al., 2005). Indeed, neuroimaging studies show vestibular activations in anterior parietal areas traditionally linked to somatosensory perception, and more posterior parietal areas traditionally linked to multisensory spatial attention (Bottini et al., 1994, 1995). Therefore, disentangling perceptual from spatial-attentional components of vestibular–somatosensory interaction is problematic. However, natural vestibular stimulation from whole-body rotations offers one way of doing

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this, because of uncontestable physical directionality of the vestibular signals. For example, ceteris paribus, if the body is rotated towards the left, modulation of somatosensation on the left hand might be either perceptual or spatialattentional, whereas modulation of somatosensation on the right hand could only be perceptual (Ferrè et al., 2014; Figliozzi et al., 2005). Accordingly, we investigated whether natural vestibular activation induced by passive wholebody rotation would also influence somatosensory detection, by measuring somatosensory detection during whole body rotation (Ferrè et al., 2014). We found that passive whole-body rotations significantly enhanced sensitivity to faint shocks to both left and right hands, without affecting response bias (Table 1). Crucially, there was no significant spatial congruence effect between the direction of rotation and the hand stimulated, suggesting that the spatialattentional component may be relatively minor. Thus, our results support a multimodal interaction at the perceptual, rather than attentional level. This effect could arise because of convergence of vestibular and somatosensory signals on bimodal neurons. Other studies, however, did find spatial congruence effects in natural vestibular rotation, though using rather different tasks. Figliozzi et al. (2005) administered temporal order judgement tasks for bimanual tactile stimuli during chair rotation. They found a bias to perceive touch earlier on the hand corresponding to the direction of chair rotation, leading to a spatial congruence effect (Table 1). Taken together, these results suggest that vestibular–somatosensory links have important effects on perception. These effects may be related to, or caused by, the neuroanatomical overlap or co-location of brain activations seen in neuroimaging studies. However, we have shown that they are distinct from vestibular driving of a supramodal attentional system (Macaluso and Driver, 2005). What might be the functional meaning of these interactions? We have shown that they go beyond a mere multimodal convergence for motor control. We speculate that somatosensory gain modulation is a functional corollary of the vestibular signalling of a new orientation with respect to the environment. With each new orienting movement sensitive pickup of information from novel environments becomes important, and is therefore prioritised. Thus, vestibular signalling of head rotation during orienting movements could trigger increased ability to detect somatosensory stimuli, so as to regulate the relation between the organism and the external environment. 7.1. One Vestibular–Somatosensory Interaction or Two? Effects of Vestibular Stimulation on Touch and Pain Somatosensory perception refers to information about the body, rather than information about the external world (e.g., vision, hearing or olfaction). Importantly, the somatosensory system processes information about several submodalities of somatic sensation (touch, temperature, pain, etc). We therefore

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hypothesised that vestibular signals could have dissociable effects on the various different channels within the somatosensory system. A reduction of chronic pain by means of caloric vestibular stimulation has been demonstrated (McGeoch et al., 2008a, b; Ramachandran et al., 2007). At least two alternative mechanisms have been suggested to explain these effects (McGeoch et al., 2008a, b; Ramachandran et al., 2007). First, pain relief may be caused by activation of the thermosensory cortex in the dorsal posterior insula adjacent to PIVC stimulated by the vestibular stimulation. Alternatively, the PIVC itself may be part of the interoceptive system and have a direct role in pain control. We recently administered caloric vestibular stimulation paradigm in healthy participants and we estimated the psychophysical thresholds for tactile detection and for contact-heat pain, and revealed a vestibular-induced enhancement of touch, but reduction in levels of pain (Ferrè et al., 2013b) (Table 1). However, these results are consistent with either of two possible neural models of vestibular–somatosensory interaction. In the first model, a common vestibular input has effects on independent systems coding for touch and for pain. Crucially, on this model there is no direct interaction between touch and pain: they are simply driven by a single input. In a second model, vestibular input has a direct effect on touch, but only an indirect effect on pain. The indirect effect could be due to inhibitory links between cortical areas coding for touch and pain: increased activation of somatosensory areas due to vestibular input could, in turn, cause decreased afferent transmission in pain pathways, because of the known tactile ‘gating’ of pain (Melzack and Wall, 1965). To compare the first and second models, we assessed the effects of caloric vestibular stimulation on thresholds for detecting radiant heat pain, evoked by laser stimulation of Aδ afferents, without touching the skin (Ferrè et al., 2013b). Vestibular inputs increased the detection threshold of pure nociceptive thermal stimuli (i.e., Aδ nociceptors). This pattern of results supports the first model, and cannot simply reflect vestibular-induced response bias, or non-specific effects such as arousal, habituation, or perceptual learning. A striking feature of vestibular–somatosensory interactions, therefore, is the independent modulation of distinct somatosensory submodalities, such as touch and pain. Decreases in tactile threshold demonstrate an up-regulation of tactile processing, while increases in pain threshold demonstrate a downregulation of nociceptive processing. The vestibular system thus modulates connections with different somatosensory submodalities, regulating the activity in multiple sensory systems independently. Human neuroimaging studies support this model, showing that vestibular stimulation both increases somatosensory cortical activations (Bottini et al., 1994, 1995; Emri et al., 2003; Fasold et al., 2002), but deactivates visual cortex (Bense et al., 2001). The secondary somatosensory cortex seems a good candidate for such interactions.

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Interestingly, this area plays a major role in both touch and pain perception (Ploner et al., 1999). However, the effects of vestibular signals on pain processing are less well understood, and potentially involving effects at multiple different levels of nociceptive processing (cf. Ferrè et al., 2013b; McGeogh et al., 2008b). A systematic investigation of the basis of this modulation is necessary to clarify the neural and functional correlates of these interactions. 8. A Functional Model for Vestibular–Somatosensory Interactions The evidence reviewed above suggests pervasive interactions between the vestibular and somatosensory systems. In this section, we summarise these interactions in a functional model (see Fig. 1). Any organism moving through its environment, and interacting with it by whole body navigational movements and reaching movements, receives a constant stream of both vestibular and somatosensory inputs. These will interact at several levels of input. First, and perhaps trivially, they will interact through the physical environment. Movements of the body are physical events transduced by both vestibular and somatosensory systems, so strong vestibular–somatosensory correlations are expected. In addition, vestibular signals drive postural reflexes,

Figure 1. A functional model for vestibular–somatosensory interaction. See text for explanation.

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which trigger characteristic somatosensory inputs. For instance, vestibulardriven balance responses cause somatosensory afference from the feet. Moreover, the vestibular and somatosensory systems interact within the central nervous system, even in the absence of any physical movement of the body. We have presented evidence for direct effects of vestibular signals on somatosensory perception. These effects can be described as vestibular modulations of the gain in somatosensory processing pathways. These direct interactions appear to involve convergence of vestibular signals on somatosensory cortical areas, possibly through bimodal vestibular–somatosensory neurons. We speculate that this form of direct vestibular–somatosensory interaction within the brain could facilitate optimal sensing of the environment. For example, vestibular signalling of head rotation during movements enhances the ability to detect somatosensory stimuli, so as to regulate the relation between the organism and the external environment. Finally, vestibular–somatosensory interactions also occur because of indirect links via high-level cognitive processes, notably spatial attention. In this case vestibular signals do not directly influence somatosensory processing. Rather vestibular inputs trigger changes in amodal spatial attention, which in turn influences somatosensory system performance. What is the consequence of these interactions? We speculate that vestibular– somatosensory interactions make an important contribution to one form of self-representation, namely the sense of one’s body as a stable and coherent object. In particular, vestibular signals allow the barrage of sensory afferences to be parsed into those that are due to self-motion within the environment (i.e., correlate with vestibular signals), and residual afferences that are not. Residual afferences that are not related to vestibular-signalled self-motion represent the stable, consistent features of the body that remain the same as we move through the world. In Gestalt psychology, elements that move coherently are perceived as more related than elements that do not. As a result of this principle of common fate, the coherent visual motion of a number of dots in a random dot kinematogram can readily define a visual object that is invisible in any single static frame of the same kinematogram (Uttal et al., 2000). Similar mechanisms have been identified in other sensory modalities (Gallace and Spence, 2011). The vestibular–somatosensory interaction amounts to a common fate for self-representation. Imagine our organism exploring the environment by sliding down a hill, and receiving tactile inputs from contact between the skin and the bumpy hillside as it slides. The population of all sensory afferent signals is divided into two classes. One rapidly varying set of signals correlates with vestibular signals of head rotation and acceleration. This reflects the somatosensory signals elicited by the contact with the environment. The remaining set of signals is consistent and coherent with each other, but relatively independent of the vestibular motion. These

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residual signals are sensations reflecting the continuous state and presence of the body, independent of current action, movement, and interaction with the environment. The vestibular signal plays the key role in distinguishing the coherent, unified, persisting body from the contingencies of its momentary interactions with the world. Interestingly, cortical vestibular dysfunction leads to disintegration in the normal unity of the self. For example, in cases of autoscopic phenomena, patients with damage to vestibular brain areas may localise the self outside their own body and may experience seeing their body from this disembodied perspective (Blanke and Mohr, 2005). In depersonalisation/derealisation phenomena, the normal sense of familiarity with one’s own body is lost (Sang et al., 2006). 9. Conclusion The vestibular system provides fundamental signals about the position and motion of the body, relative to the external environment. Despite the highly specialized nature of the peripheral components of the vestibular system, no unimodal vestibular cortex has been identified in the human brain. Instead, several multimodal sensory areas integrate vestibular, visual and somatosensory signals. Here we have argued that vestibular signals are not only an input for motor control and postural responses, but also a distinct form of information about one’s own body. In particular, we have proposed that the target representation of vestibular–somatosensory interactions is a form of self-representation. This representation has the role of linking the spatial description of one’s own body to the spatial description of the outside world. Interaction between vestibular signals and somatosensory inputs might play the key role in distinguishing the coherent, unified body from the contingencies of its momentary interactions with the world. Acknowledgements PH and EF were supported by EU FP7 Project VERE WP1. PH was additionally supported by ERC Advanced Grant HUMVOL. Conflict of Interest The authors declare no competing financial interests. References Akbarian, S., Grüsser, O. J. and Guldin, W. O. (1994). Corticofugal connections between the cerebral cortex and brainstem vestibular nuclei in the macaque monkey, J. Comp. Neurol. 339, 421–437.

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Disrupting Vestibular Activity Disrupts Body Ownership Adria E. N. Hoover ∗ and Laurence R. Harris Centre for Vision Research and Department of Psychology, York University, Toronto, ON, Canada

Abstract People are more sensitive at detecting asynchrony between a self-generated movement and visual feedback concerning that movement when the movement is viewed from a first-person perspective. We call this the ‘self-advantage’ and interpret it as an objective measure of self. Here we ask if disruption of the vestibular system in healthy individuals affects the self-advantage. Participants performed finger movements while viewing their hand in a first-person (‘self’) or third-person (‘other’) perspective and indicated which of two periods (one with minimum delay and the other with an added delay of 33–264 ms) was delayed. Their sensitivity to the delay was calculated from the psychometric functions obtained. During the testing, disruptive galvanic vestibular stimulation (GVS) was applied in five-minute blocks interleaved with five minutes of no stimulation for a total of 40 min. We confirmed the self-advantage under no stimulation (31 ms). In the presence of disruptive GVS this advantage disappeared and there was no longer a difference in performance between perspectives. The threshold delay for the ‘other’ perspective was not affected by the GVS. These results suggest that an intact vestibular signal is required to distinguish ‘self’ from ‘other’ and to maintain a sense of body ownership. Keywords Cross-modal interactions, body ownership, visual perspective, body representation, vestibular cues, proprioception

1. Introduction The representation of body in the brain, sometimes referred to as the body schema, is created through convergence of proprioceptive, haptic, and visual signals (see Serino and Haggard, 2010 for a review). Recently the vestibular system has been implicated in a previously unsuspected role in the development of the body schema (Lopez et al., 2012). For example, individuals with *

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_011

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vestibular disorders, such as vestibular vertigo or vestibular deafferentation, tend to misrepresent the size, shape, and location of their body parts even though the vestibular system provides no information of direct relevance to making these judgments (Lopez and Blanke, 2007; Lopez et al., 2008; Sang et al., 2006; Schilder, 1935). Healthy individuals with no vestibular symptoms can also be made to show degraded performance on tasks that require knowledge about their body and self by adding temporary, disruptive galvanic vestibular stimulation (GVS). For example, Bresciani et al. (2002) found that unilateral GVS disrupted reaching movements toward the side being stimulated and created a less accurate estimate of where the hands were in space. More remarkably, caloric vestibular stimulation affects the ability to discern the size and shape of a participant’s own hands (Lopez et al., 2012) and increases susceptibility to self-attribution illusions such as the rubber-hand illusion (Lopez et al., 2010). Taken together, these observations suggest that intact vestibular background activity is integral for creating and maintaining a coherent representation of the self and that losing this signal undermines a person’s perception of self. However, reliable, quantitative assessments of how a person perceives themselves as themselves is lacking and studies have generally been restricted to using questionnaires or self report measures. Previous studies investigating self-recognition during active movement have found misattribution of hand movements to another agent when the participants’ movements and the other agents’ movements (superimposed over top of their movements) were similar and, in some instances, when there were discrepancies between the movements (Fourneret and Jeannerod, 1998; Nielsen, 1963; see Jeannerod, 2003 for a review). These results suggest the importance placed upon visual cues when making self/other judgements. Visual perspective, in particular, has been shown to modulate the ability to recognize our own body parts from others’ (Conson et al., 2010; Van den Bos and Jeannerod, 2002), discriminate between left and right hands (Dyde et al., 2011), and experience the rubber hand illusion (Holmes and Spence, 2007). We have previously shown that visual perspective also affects the threshold for detecting a temporal mismatch between a self-generated movement (e.g., of the finger) and visual feedback of the movement (Hoover and Harris, 2012, in press). We found that when body movements are seen from a first-person perspective (e.g., when looking down at your own hands) there is a signature self-advantage in detecting the delay: asynchrony is detected approximately 40 ms faster when viewed from this ‘self perspective’ than when movements are viewed from a perspective considered third-person or other (e.g., upside down) (Hoover and Harris, 2012, in press). Self-generated movements provided participants with efferent information as well as proprioceptive information, which are important factors in determining whether you are the agent of the action (Farrer et al., 2003; Gallagher, 2000; Tsakiris et al.,

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2005). In turn, the sense of agency is an important contributor to the sense of body ownership (Tsakiris et al., 2010). The advantage in asynchrony detection thresholds suggests an enhanced sense of body ownership when an action is viewed in a self perspective. This measure can therefore be taken as an objective measure of body ownership. Given that the vestibular system has been linked to registering spatial and temporal aspects of the self (Ferrè et al., 2013; Lopez et al., 2008) we examined whether disruption of vestibular activity using GVS in healthy individuals affected the self-advantage in temporal asynchrony detection. 2. Methods 2.1. Participants Nine right-handed adults, with a mean age of 29 (±12 SD) years, participated in this study. The experiment was approved by the York University office of research ethics and followed the guidelines of the Declaration of Helsinki. Handedness was determined by an adapted version of the Edinburgh Handedness Inventory (Oldfield, 1971). 2.2. Galvanic Vestibular Stimulation The vestibular stimulation consisted of a small current applied through electrodes positioned on the mastoid processes behind the ears. A reference electrode was placed in the centre of the forehead. The electrodes were 3.25 cm diameter round carbon-conductor electrodes (9000 series electrodes; Empi Recovery Sciences, St. Paul, MN, USA). The vestibular stimuli were generated by a GVS system (Good Vibrations Engineering Ltd., Nobleton, ON, Canada) controlled by a PC. Our vestibular stimulus was a sum-of-sines waveform with dominant frequencies at 0.16, 0.32, 0.43, and 0.61 Hz (maximum current limited to ±5 mA) which has shown to be disruptive to the vestibular system (MacDougall et al., 2006; Moore et al., 2006). Bilateral, bipolar stimulation was applied in 5-min blocks interleaved with 5-min blocks without stimulation so that data collected with and without GVS were interleaved over the total experimental time of 40 min. 2.3. Apparatus and Stimuli Participants sat on an adjustable chair at a table with their head on a chinrest 50 cm away from a LCD display (HP Fv583AA 20 widescreen monitor; 1600 × 900 pixels; 5 ms refresh response time) centred at eye level as shown in Fig. 1. They placed their hand on the table shielded from view by a black cloth. A PlayStation Eye camera (SCEI; resolution 640 × 480 @ 30 Hz) was mounted on the front of the chinrest and pointed down at their hand. The

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Figure 1. Participants sat on an adjustable chair at a table 50 cm from an LCD screen centred at eye level. The right hand was placed on the table shielded from direct view by a black cloth. A PlayStation Eye camera was mounted on the front of a chinrest and pointed down to capture the view as seen from a natural self perspective. Two stimulating electrodes were placed on the mastoid processes behind the ears and one reference electrode was placed on the center of the forehead. The electrodes were connected to a GVS generator. Foot pedals were used to make responses.

camera was angled to capture the view as seen from a ‘natural’ egocentric perspective as if participants were looking down at their own hands. The video signal from the camera was fed into a computer (iMAC11, 2, mid 2010), read by MATLAB (version R2009_b) and played through the LCD screen at either a minimal delay, or with an added delay of between 33 and 264 ms. To calibrate the system we had the camera view a flashing LED and compared the voltage across it with its appearance on the screen measured by a light sensitive diode. This revealed a minimum delay of 85 ms ± one-half camera refresh duration and confirmed the delay values we introduced with the software. We asked participants to perform a single flexion of the right index finger through approximately 2 cm. They made the movement as soon as they saw their hand on the screen in a given trial. Participants avoided touching the table or other fingers with their index finger during the movement so as to not introduce additional tactile cues. To reduce between-subject differences in the speed and type of movement, all participants went through a 15-trial practice phase during which the experimenter observed and corrected movement prior to testing. Video images were manipulated using the Psychophysics Toolbox extension of MATLAB subroutine PsychVideoDelayLoop (Brainard,

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Figure 2. (A) Thresholds for detecting an imposed visual delay in the visual feedback concerning a self-generated movement. The mean proportion correct is plotted as a function of the imposed visual delay. The curves are psychometric functions fitted through the data for the ‘self’ perspective (solid black line and black triangles), the ‘other’ perspective (dashed black line and inverted white triangles), GVS ‘self’ perspective (solid grey line and grey circles), and GVS ‘other’ perspective (dashed grey line and white circles). (B) The mean 75% thresholds averaged from the fits to the individual participant’s data in the control condition (black bars) and the GVS condition (grey bars) for the ‘self’ and ‘other’ perspectives. Error bars are SEMs. n.s. p > 0.05; ∗∗ p = 0.01; ∗∗∗ p = 0.001.

1997; Pelli, 1997). Participants were presented with two views of their movements: (1) a ‘self’ perspective (the expected first-person perspective), and (2) an ‘other’ perspective (the unexpected third-person perspective where the video images were flipped around the x and y axes so that they were upside down and back to front). Examples of these views are shown in insets in Fig. 2. 2.4. Procedure To assess the thresholds for detecting temporal synchrony, a two-interval forced choice (2IFC) discrimination paradigm was used. Each trial consisted

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of two 1 s periods separated by an inter-stimulus interval of 100 ms: in one period a minimal-delay presentation of the movement was shown and in the other, the presentation was delayed by a variable amount. Whether the minimal-delay presentation or the delayed presentation was displayed first was randomly chosen by MATLAB. There were nine possible differences in visual delays in any given trial: 0, 33, 66, 99, 132, 165, 198, 231, and 264 ms corresponding to a delay of an integral number of video frames. Participants indicated which presentation was delayed using foot pedals (Yamaha FC5): left for first and right for second. The experiment was run in a block design where GVS was applied in five-minute blocks interleaved with five minutes of no stimulation for a total of eight blocks taking 40 min in total. Five participants started with a control block and four participants started with a GVS block. In total, the nine differences in visual delay were presented eight times for the two visual perspectives in a random order with and without GVS resulting in a total of 288 trials. 2.5. Data Analysis To explore differences in performance across conditions we fitted a cumulative Gaussian curve to the proportion of times participants correctly chose the delayed period as a function of the delay using: y = 0.5 +

0.5

, (1) 1 + e−((x−x0 )/b) where x is the delay, x0 is the 75% threshold and b is the standard deviation. The statistical analysis comprised of repeated measures analysis of variances (ANOVAs) and paired t-tests. For all tests, alpha was set at p < 0.05. 3. Results Figure 2 shows the mean proportion of trials in which the participants correctly identified the presentation with the delay, plotted as a function of the total delay (system delay plus added delay), averaged across the nine participants for the two experimental conditions (with and without GVS) and the two perspectives of the movement (‘self’ and ‘other’). Illustrative psychometric functions are plotted through these average data for the four conditions. Threshold values for detecting the added visual delay were defined as the 75% point of this curve. Each participant’s performance was analysed separately for the statistical tests. The mean thresholds and standard errors are shown in Table 1. A 2 × 2 repeated measures ANOVA revealed a significant interaction between the perspective of the hand (‘self’ vs. ‘other’) and whether GVS was applied or not, F(1,8) = 12.54, p = 0.008, ηp2 = 0.61. In the absence of GVS,

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Disrupting Vestibular Activity Table 1. Mean detection thresholds averaged across all participants, with SEs

‘Self’ perspective ‘Other’ perspective

GVS

Control

165 ± 10 ms 165 ± 11 ms

133 ± 3 ms 162 ± 6 ms

The values were obtained by adding the system delay (85 ms) to the delay added to the video.

when participants saw their hand in the expected ‘self’ perspective they were better at detecting the delay, showing a self-advantage of 29 ms on average compared to when the hand was viewed in the ‘other’ perspective (t(8) = 5.70, p = 0.001, d = 4.03). The presence of disruptive GVS increased the threshold to detect asynchrony in the ‘self’ perspective by 32 ms compared to the no-GVS condition (t(8) = 3.17, p = 0.01, d = 2.24) thus eliminating the self advantage that was apparent in the control condition. Critically, GVS did not affect performance while participants viewed their movements in the ‘other’ perspective: the GVS ‘self’ perspective showed no significant difference in performance from either the control or the GVS ‘other’ perspective (GVS ‘self’ vs. GVS ‘other’ t(8) = 0.10, p = 0.92, d = 0.07; GVS ‘self’ vs. control ‘other’ t(8) = 0.46, p = 0.66, d = 0.35). Analysis of the slopes of the psychometric functions (b, see Methods) showed no significant effect (F (3, 316) = 2.40, p = 0.07), although there was a trend in which the ‘self’ perspective without GVS tended towards being lower (20.3 ± 3 ms) than the other three conditions (GVS ‘self’ = 35.9 ± 6 ms; GVS ‘other’ = 36.5 ± 5 ms; and control ‘other’ = 27.9 ± 5 ms). 4. Discussion Here we showed that disruptive vestibular stimulation affected the ability to detect temporal asynchrony between a self-generated movement and visual feedback about the movement but solely when self-generated movement was seen in the expected ‘self’ perspective. We replicated our previous finding of a self-advantage where one is more sensitive to a temporal mismatch when the hand is shown in the expected ‘self’ perspective and showed that this self-advantage is completely abolished by disruptive GVS. Since threshold for detecting a delay for movements seen from the ‘other’ perspective were unaffected by GVS, the GVS was clearly not exerting its effect by, for example, degrading the visual scene by eye movements or any other such indirect influence. Does this effect indicate a reduced sense of body ownership or a reduced sense of agency?

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The sense of agency — the sense of being in control of your intended actions (Gallagher, 2000) — contributes to the sense of body ownership (Van den Bos and Jeannerod, 2002) but can be dissociated from it. Patients with vestibular disorders have reported that they experience a lessened sense of agency (Sang et al., 2006) and sense of agency can be felt for objects that are not seen as part of the body (such as using a computer mouse to control a cursor on a screen; Balslev et al., 2007). The current study required participants to compare efferent and proprioceptive information concerning the self-generated finger movement with visual information. It may be that the noisy vestibular information from the artificial vestibular stimulation may have caused participants to be less aware of their movements — reducing the sense of agency. However, one would expect that if our effect disrupted the ability to compare visual with proprioceptive/efferent signals (i.e., the sense of agency), both the ‘self’ and ‘other’ perspectives would be equally affected. Since this was not the case and the ‘other’ judgments were unaffected, it seems improbable that the disruptive GVS affected the sense of agency but rather that our task is probing the sense of body ownership. The fact that disruptive vestibular stimulation only affected performance when the hand was seen from the first-person perspective suggests that the vestibular system plays a role in providing some kind of grounding information to the multisensory representation of the body in the brain. This is inline with other research investigating the contribution of the vestibular system to the ownership of a body part seen in a first-person perspective. Ferrè and colleagues (2014) found that in the presence of vestibular stimulation, participants were more apt to identify characters drawn on their forehead as being from the self-perspective rather than from the third-person perspective. This propensity for responding to the first-person perspective during a graphesthesia task also suggests, but in a more indirect way than the present study, that vestibular inputs are an integral component of the development of the body representation in the brain. When movements are seen in the ‘self’ perspective, the self-advantage we report here of 29 ms (comparable to the 40 ms we reported previously — Hoover and Harris, 2012), provides a quantitative example of how the sense of body ownership aids performance (Gallagher, 2000). This enhancement suggests that participants are better able to detect temporal asynchrony between making a movement and seeing the movement when the visual information matches their internal representation of their hand moving. When disruptive GVS is applied, it seems that the disruption of the vestibular signal creates a reduced sense of body ownership, thus eliminating the self advantage. Under this interpretation our observation provides a quantitative measure of the effect of vestibular input on body ownership which is consistent with other more qualitative reports of vestibular stimulation leading to a lessened sense

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of self (Ferrè et al., in press; Lopez, 2013; Lopez et al., 2008) and being more susceptible to the rubber hand illusion (Lopez et al., 2010). Acknowledgements This work was supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) to LRH. AENH held an Ontario graduate scholarship. References Balslev, D., Cole, J. and Miall, R. C. (2007). Proprioception contributes to the sense of agency during visual observation of hand movements: evidence from temporal judgments of action, J. Cogn. Neurosci. 19, 1535–1541. Brainard, D. H. (1997). The psychophysics toolbox, Spat. Vis. 10, 433–436. Bresciani, J. P., Blouin, J., Popov, K., Bourdin, C., Sarlegna, F., Vercher, J. L. and Gauthier, G. M. (2002). Galvanic vestibular stimulation in humans produces online arm movement deviations when reaching towards memorized visual targets, Neurosci. Lett. 318, 34–38. Conson, M., Aromino, A. R. and Trojano, L. (2010). Whose hand is this? Handedness and visual perspective modulate self/other discrimination, Exp. Brain Res. 206, 449–453. Dyde, R., MacKenzie, K. and Harris, L. R. (2011). How well do you know the back of your hand? Reaction time to identify a rotated hand silhouette depends on whether it is interpreted as a palm or back view, J. Vis. 11, 868–868. Farrer, C., Franck, N., Georgieff, N., Frith, C. D., Decety, J. and Jeannerod, M. (2003). Modulating the experience of agency: a positron emission tomography study, NeuroImage 18, 324–333. Ferrè, E. R., Vagnoni, E. and Haggard, P. (2013). Vestibular contributions to bodily awareness, Neuropsychologia 51, 1445–1452. Ferrè, E. R., Lopez, C. and Haggard, P. (in press). Anchoring the self to the body: vestibular contribution to the sense of self, Psychol. Sci. DOI:10.1177/0956797614547917. Fourneret, P. and Jeannerod, M. (1998). Limited conscious monitoring of motor performance in normal subjects, Neuropsychologia 36, 1133–1140. Gallagher, I. (2000). Philosophical conceptions of the self: implications for cognitive science, Trends Cogn. Sci. 4, 14–21. Holmes, N. P. and Spence, C. (2007). Dissociating body image and body schema with rubber hands, Behav. Brain Sci. 30, 211. Hoover, A. E. N. and Harris, L. R. (2012). Detecting delay in visual feedback of an action as a monitor of self recognition, Exp. Brain Res. 222, 389–397. Hoover, A. E. N. and Harris, L. R. (in press). The role of viewpoint on body ownership, Exp. Brain Res. DOI:10.1007/s00221-014-4181-9. Jeannerod, M. (2003). The mechanism of self-recognition in humans, Behav. Brain Res. 142, 1–15. Lopez, C. (2013). A neuroscientific account of how vestibular disorders impair bodily selfconsciousness, Front. Integr. Neurosci. 7, 1–8.

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Lopez, C. and Blanke, O. (2007). Neuropsychology and neurophysiology of self-consciousness. Multisensory and vestibular mechanisms, in: Hirnforschung und Menschenbild. Beiträge zur interdisziplinären Verständigung, A. Holderegger, B. Sitter-Liver and C. W. Hess (Eds), pp. 183–206. Academic Press, Fribourg, Germany/Schwabe, Basel, Switzerland. Lopez, C., Halje, P. and Blanke, O. (2008). Body ownership and embodiment: vestibular and multisensory mechanisms, Neurophysiol. Clin. 38, 149–161. Lopez, C., Lenggenhager, B. and Blanke, O. (2010). How vestibular stimulation interacts with illusory hand ownership, Consc. Cogn. 19, 33–47. Lopez, C., Schreyer, H.-M., Preuss, N. and Mast, F. W. (2012). Vestibular stimulation modifies the body schema, Neuropsychologia 50, 1830–1837. MacDougall, H. G., Moore, S. T., Curthoys, I. S. and Black, F. O. (2006). Modeling postural instability with galvanic vestibular stimulation, Exp. Brain Res. 172, 208–220. Moore, S. T., MacDougall, H. G., Peters, B. T., Bloomberg, J. J., Curthoys, I. S. and Cohen, H. S. (2006). Modeling locomotor dysfunction following spaceflight with galvanic vestibular stimulation, Exp. Brain Res. 174, 647–659. Nielsen, T. I. (1963). Volition: a new experimental approach, Scand. J. Psychol. 4, 225–230. Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh inventory, Neuropsychologia 9, 97–113. Pelli, D. G. (1997). The VideoToolbox software for visual psychophysics: transforming numbers into movies, Spat. Vis. 10, 437–442. Sang, F. Y. P., Jáuregui-Renaud, K., Green, D. A., Bronstein, A. M. and Gresty, M. A. (2006). Depersonalisation/derealisation symptoms in vestibular disease, J. Neurol. Neurosurg. Psychiatr. 77, 760–766. Schilder, P. (1935). The Image and Appearance of the Human Body: Studies in the Constructive Energies of the Psyche. International University Press, New York, NY, USA. Serino, A. and Haggard, P. (2010). Touch and the body, Neurosci. Biobehav. Rev. 34, 224–236. Tsakiris, M., Haggard, P., Franck, N., Mainy, N. and Sirigu, A. (2005). A specific role for efferent information in self-recognition, Cognition 96, 215–231. Tsakiris, M., Longo, M. R. and Haggard, P. (2010). Having a body versus moving your body: neural signatures of agency and body-ownership, Neuropsychologia 48, 2740–2749. Van den Bos, E. and Jeannerod, M. (2002). Sense of body and sense of action both contribute to self-recognition, Cognition 85, 177–187.

Beyond the Non-Specific Attentional Effect of Caloric Vestibular Stimulation: Evidence from Healthy Subjects and Patients Gabriella Bottini 1,2,3,∗ and Martina Gandola 1,3 1

Department of Brain and Behavioral Sciences, University of Pavia, Piazza Botta 11, 27100 Pavia, Italy 2 Cognitive Neuropsychology Centre, Niguarda Ca’ Granda Hospital, Milano, Italy 3 NeuroMi — Milan Center for Neuroscience, Milano, Italy

Abstract Caloric vestibular stimulation (CVS) is a simple physiological manipulation that has been used for a long time in different clinical fields due to its rapid and relevant effects on behaviour. One of the most debated issues in this research field concerns the degree of specificity of such stimulation, namely whether the effects of CVS can be, and to what extent are, independent of the mere influence of non-specific factors such as general arousal, ocular movements or attentional shift towards the stimulated side. The hypothesis that CVS might cause a shift of attention towards the side of the stimulation has been largely supported; moreover, a large amount of evidence is available nowadays to corroborate the specific effect of CVS, providing behavioural and neurophysiological data in both patients and normal subjects. These data converge in indicating that the effects of CVS can be independent of eye deviation and general arousal, can modulate different symptoms in different directions, and do not merely depend on a general shift of attention. The present article is divided into three main sections. In the first section, we describe classical studies that investigate the effects of CVS on neglect and related symptoms. In the second and third parts, we provide an overview of the modulatory effects of CVS on somatosensory processes and body representation in both braindamaged patients and healthy subjects. Finally, we conclude by discussing the relevance of these new findings for the understanding of the neural mechanisms underlying the modulatory effects of CVS. Keywords Caloric vestibular stimulation, neglect, hemiplegia, hemianesthesia, anosognosia, somatoparaphrenia

*

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_012

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1. Introduction Caloric vestibular stimulation (CVS) is a safe and non-invasive technique used in the clinical routine to stimulate the vestibular apparatus. It consists in a cold or warm water irrigation of the external auditory canal that induces a change of the temperature across the semicircular canals. The modification of the temperature in the inner ear generates movements (i.e., convection currents) of the endolymph (the fluid contained in the membranous labyrinth of the inner ear) in the semicircular canals that change the firing rate of the cells of the vestibular nerve. As a consequence the stimulation induces the turning of the head and oscillatory movements of the eyes (called nystagmus, i.e., a back-and-forth involuntary rhythmic oscillation of the eyes, with a fast and slow component; for a detailed description of the physiology of the vestibular system see Goldberg et al., 2012). Warm water irrigation and cold water irrigation have different effects. Indeed, warm water causes an excitation within the semicircular canal, inducing slow eye movements (slow phase nystagmus) away from the irrigated side and as a consequence a fast movement of the eyes in the opposite direction, i.e., towards the stimulated ear (fast phase nystagmus). Conversely, cold water induces an inhibition of the semicircular canal, causing slow eye movements towards the irrigated side (slow phase nystagmus) and a fast movement in the opposite direction, i.e., away from the irrigated ear (fast phase nystagmus; see Fig. 1).

Figure 1. Effects (improvement versus worsening) of CVS on neglect as a consequence of the side of stimulation (left or right ear) and the temperature of the water (cold or warm water). The damaged hemisphere is coloured black. Green and orange arrows indicate direction of the slow and fast phase nystagmus. Thin arrows indicate the stimulated ear and water temperature [top (blue) arrows: cold water; bottom (red) arrows: warm water]. L: left; R: right; SPN: slow phase nystagmus; FPN: fast phase nystagmus.

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Although CVS was originally introduced to test the integrity of the vestibular functions (Bárány, 1906, 1967; see also Lopez and Blanke, 2014) the potentiality of this sensory stimulation as a rehabilitative tool for neurological patients became evident at the beginning of the 1940s, when the positive effects of this method in reducing neglect symptoms were first described (Silberpfennig, 1941). Spatial neglect is characterized by the inability to attend to stimuli located in the contralesional space, mostly caused by a right hemispheric lesion (De Renzi et al., 1970; Gainotti et al., 1972; Hécaen, 1972; Oxbury et al., 1974; see review in Vallar, 2001). Two of the most relevant signs of spatial neglect, emerging from the clinical observation of the patients, are spontaneous gaze deviation and postural turning towards the ipsilesional side (Rubens, 1985). The observation that CVS induces eye deviation (nystagmus) prompted some authors to explore the possibility that CVS might ameliorate spatial neglect inducing a gaze deviation towards the neglect side, i.e., in the direction opposite to the ipsilesional bias caused by the brain lesion. This intuitive reasoning inspired the first CVS experiments in patients with neglect (Rubens, 1985; Silberpfennig, 1941). In 1941, Silberpfenning described two patients with frontal lobe tumours, both presenting a deviation of the eyes to the right side and signs of neglect. Unilateral CVS was performed using cold water. In the first patient Silberpfennig found (i) an amelioration of gaze movement to the left, (ii) a diminished rightwards head deviation and (iii) an improvement of reaching in the left side after cold water left CVS that induced a third degree nystagmus (see Note 1) to the right. The amelioration was observed also in the second patient after applying a cold water right CVS that induced a third degree nystagmus to the left. After this stimulation the patient’s performance in reading words ameliorated and she became able to read from left to right, reversing her pathological tendency to read words in the opposite direction. Notably, the improvement was observed only when a third degree nystagmus was elicited. On the basis of this observation Silberpfenning argued that the crucial aspect for the efficacy of the stimulation was the “quantitative factor” (i.e., the strength/intensity of the reaction evoked by CVS in the two labyrinths) rather than the direction of nystagmus. More than forty years later Rubens (Rubens, 1985) performed the first group study aimed at investigating more systematically the effect of CVS on neglect. He tested 18 right brain-damaged patients (RBD) using all possible combinations of water temperature and side of stimulation: (i) ice water left CVS, (ii) ice water right CVS, (iii) warm water left CVS and (iv) warm water right CVS. The efficacy of these stimulations was tested both on gaze and visual neglect using formal tests. The results were clear-cut in showing an improvement of both gazing to the left and of visual neglect after the irrigation of the left ear with cold water and the irrigation of the right ear with warm water. By contrast, right ice water CVS and left warm water CVS were inef-

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fective and even worsened the deficits. Rubens (1985) interpreted these data in terms of oculomotor deviation towards the neglect side, mediated by low level vestibulo-ocular mechanisms: indeed, as summarized in Fig. 1, the benefit of the procedure was not related to the side of the stimulation but instead to the direction of the slow phase nystagmus (i.e., CVS ameliorated neglect even when the right ear was stimulated with warm water). The stimulation was effective only when the slow phase nystagmus occurred to the left, i.e., in the direction opposite to the rightward gaze and postural deviation (e.g., deviation ipsilateral to the side of the brain lesion) observed in neglect patients (e.g. after both cold water left CVS and warm water right CVS, see Fig. 1). These findings, together with the observation that the stimulation with ice water per se, in the absence of nystagmus (Note 2), was not sufficient to produce an improvement of the symptoms (as observed in patient 9, described in Rubens, 1985), ruled out interpretations in term of mere non-specific arousal mechanisms (e.g., uncomfortable feeling due to water temperature). Even if the effects of CVS were mainly considered as a consequence of vestibulo-ocular and vestibulospinal mechanisms, Rubens (1985) also suggested the hypothesis of a higher-level attentional mediation of the caloric effects through the activation of cortico-limbic reticular circuits. The idea that the efficacy of CVS might be mediated by more central mechanisms (attentional or representational in their nature) was supported by subsequent studies that demonstrated that CVS is effective even on symptoms that did not require visual exploration. Cappa and co-workers (Cappa et al., 1987), for example, observed the remission of personal neglect and anosognosia for hemiplegia (Note 3) after both ice water left CVS and warm water right CVS (performed only in patient 3). The presence of personal neglect, i.e., the failure to explore the side of the body contralateral to a brain lesion (Zingerle, 1913), was assessed using the four-point scale proposed by Bisiach and co-workers (Bisiach et al., 1986). This simple test consists in asking the patient to touch his/her left hand with the right one. In three patients (cases 2, 3 and 4, see page 779 in Cappa et al., 1987) the presence of personal neglect was assessed with eyes both closed and open and notably CVS was effective even when the presence of personal neglect was assessed without visual control (condition with eyes closed). Moreover, in two patients out of four (patients 3 and 4) presenting with anosognosia for hemiplegia, CVS reduced the severity of the deficits. The fact that both deficits were tested with eyes closed ruled out the interpretation in terms of mere leftwards eye deviation. The authors speculated that the more probable mechanism to explain the effects of CVS was the “activation of the hemisphere opposite to the relatively hyperactive vestibular system” (Cappa et al., 1987, page 781), namely the left hemisphere. In RBD patients, the amelioration of anosognosia after cold water left CVS was confirmed by many studies (Geminiani and Bottini, 1992; Ramachan-

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dran, 1995; Rode et al., 1992, 1998a; Vallar et al., 1990) and recently an amelioration of anosognosia for right hemiplegia was also described in a left brain-damaged (LBD) patient (Ronchi et al., 2013). The stimulation was also effective on other symptoms such as representational neglect (i.e., a deficit in representing the contralesional side of the mental space, see Bisiach and Luzzatti, 1978; Geminiani and Bottini, 1992; Rode and Perenin, 1994), motor weakness (Rode et al., 1998a; Vallar et al., 2003) and postural asymmetry (Rode et al., 1998b). Different interpretations have been proposed to explain the effects of CVS and these range from accounts in terms of (1) ocular deviation towards the stimulated side or (2) general arousal (Rubens, 1985), to more cognitive hypotheses based on the role of vestibular inputs in (3) re-orienting attention towards the neglected side (attentional hypothesis, Gainotti, 1993, 1996) or (4) restoring the egocentric spatial representation (see for example Vallar et al., 1993). In the present paper we critically review classical and recent literature on the efficacy of CVS in modulating tactile perception, body representation and body ownership providing increasing evidence in favour of a specific effect of this manipulation beyond non-specific factors such as general arousal or spatial attention. We first review recent literature on the effects of vestibular stimulation on somatosensory processes that suggested a direct effect of CVS on tactile perception, grounded in the combined activation of brain regions that shared vestibular and somatosensory projection. By analogy with this literature we also present an overview of the studies that demonstrate a positive effect of CVS on body schema (in particular on body representation and body ownership), demonstrating the specificity of the effects of CVS even in this domain. 2. Effect of Vestibular Stimulation on Tactile Perception 2.1. Vestibular Modulation of Somatosensory Perception in Brain-Damaged Patients The first evidence that CVS can ameliorate contralesional tactile deficit (hemianesthesia) in patients with brain damage came from the study of Vallar and co-workers (Vallar et al., 1990). They described the transient remission of hemianesthesia in three right brain-damaged (RBD) patients during both left cold water CVS and right warm water CVS (only performed in case 2), although the effect of this last stimulation was quicker and less intense (see also Rubens, 1985 for a similiar observation on neglect; Vallar et al., 1990). The authors explained these findings assuming that hemianesthesia might be considered a manifestation of neglect and therefore caused by a central attentional

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deficit that transitorily ameliorates after CVS. This observation was replicated by the same authors in a group study three years later (Vallar et al., 1993) in which the investigation also included left brain-damaged patients (LBD). In both RBD and LBD patients the stimulation was performed by irrigating with cold water the contralesional ear (i.e., left ear in RBD patients and right ear in LBD patients). The authors observed a clear hemispheric asymmetry: indeed, the transient recovery of left haemianestesia and tactile extinction (Note 4) was observed only in RBD patients. By contrast, the stimulation was ineffective in LBD patients, with the only exception of two cases that also presented with right neglect. These findings called into question low level interpretations in terms of both (i) oculomotor deviation towards the contralesional side or (ii) non-specific general hemispheric activation. First, the observation of a benefit on tactile deficits, even when patients were tested with eyes closed, called into question explanations in terms of a mere ocular deviation towards the contralesional side of the space due to the nystagmus (Cappa et al., 1987). Second, if the effects of CVS were due to a simple non-specific hemispheric activation one should expect the presence of comparable effects on right and left tactile deficits rather than the hemispheric asymmetry found by Vallar and colleagues (1993). Finally, the worsening of neglect symptoms after both left warm water and right cold water CVS made the hypothesis that CVS effects might be explained by the mere activation of the right (hypo-aroused) hemisphere highly improbable (Vallar et al., 1993). Vallar and co-workers (1993) interpreted their results in the context of the theory posed by Ventre and colleagues that explained neglect as a disturbance of the egocentric frame of references (“egocentric reference” hypothesis; Jeannerod and Biguer, 1987; Ventre and Faugier-Grimaud, 1986; Ventre et al., 1984). Patients with neglect may present an ipsilesional shift of the egocentric references (see for example Heilman et al., 1983; Karnath, 1994), i.e., the internal representation of extrapersonal space and body based on the sagittal axis (body midline) that divides space and body in two symmetric halves (Jeannerod and Biguer, 1987; Ventre and Faugier-Grimaud, 1986; Ventre et al., 1984). Ventre and collaborators (1984) suggested that this egocentric reference is constructed by the symmetrical activities of bilateral associative neural structures (i.e., the posterior parietal cortex and the superior colliculus; Ventre et al., 1984) that integrate multisensory (visual, proprioceptive and vestibular) inputs coming from the right and left hemispaces into a unitary representation. Following this hypothesis, the unilateral lesion of these regions caused a “permanent asymmetrical activity” (Ventre et al., 1984, page 804) and as a consequence a displacement of the egocentric reference. Vallar and co-workers (1993), within this theoretical frame, hypothesized that CVS “modifies the pattern of sensory input” (Vallar et al., 1993, page 84) used by the brain to construct this egocentric representation and consequently restores the ipsile-

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sional shift of the egocentric (body-centred) spatial representation induced by the brain lesion. A further step forward in the comprehension of the brain mechanisms underlying the effects of CVS on hemianesthesia was made thanks to a positron emission tomographic (PET) study performed by Bottini and co-workers (1995). The authors studied four healthy subjects and one RBD patient (case R.F.) with hemianesthesia. Two normal subjects received tactile stimulation of the left hand during PET scans, the other two received cold water left CVS before the beginning of scanning. The authors found an overlap between tactile and vestibular projections in the hemisphere contralateral to the stimulated hand (i.e., the right hemisphere) that involved the right putamen, the insula, the premotor cortex, the secondary somatosensory cortex (SII) and the inferior parietal cortex (Fig. 2; Bottini et al., 1995). To examine in depth the physiology of this recovery, Bottini and co-workers (1995) also recorded PET activity during the improvement of conscious tactile perception (i.e., the ability to perceive light and short tactile stimuli delivered by the examiner with the tip of the index finger on the fourth metacarpal space of the subject’s hand) after CVS, in a patient with a right brain damage and left hemianesthesia (case R.F.). The amelioration of tactile performance was associated with increased brain activity mainly in the putamen and insular cortex to the right, in the same regions where the authors found shared vestibular and tactile projections in normal subjects. This result provided the first neurofunctional evidence supporting the idea that CVS produces tactile recovery through a direct and specific activation of brain regions involved in hand representation (Bottini et al., 1995). Moreover, the fact that patient R.F. did not present extrapersonal neglect offered the chance to study the specific effect of CVS on tactile perception, indepen-

Figure 2. Brain regions activated in healthy subjects by both tactile stimulation of the left hand and left cold CVS. The figure illustrates brain regions of relative regional cerebral blood flow (rCBF) increase shared by both tactile and vestibular stimulation, overlapped onto a MRI template (slice thickness 4 mm). The activations (t-maps, coloured areas) are localized in the right putamen, insula, somatosensory area II, premotor cortex and supramarginal gyrus. In the left hemisphere increased activations were found in the premotor cortex and the thalamus. Images are presented in neurological convection (left hemisphere is illustrated on the left and right hemisphere on the right). L = left hemisphere; R = right hemisphere; ac-pc: intercommissural plane. Adapted by permission from Macmillan Publishers Ltd: Nature, Bottini et al. (1995), © 1995.

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dently from the concomitant presence and recovery of spatial symptoms (see also Bottini et al., 1996). A recent finding gave an important contribution to the evidence that CVS acts through specific physiological mechanisms that are independent from a general attentional effect. In 2005, Bottini and co-workers (Bottini et al., 2005) demonstrated that contralesional hemianesthesia could be ameliorated with comparable effects in both RBD and LBD patients by stimulating the left ear with cold water. By contrast, cold water right CVS in LBD patients was ineffective, as previously demonstrated by Vallar and co-workers (Vallar et al., 1993). Furthermore, the physiological mechanisms underlying the benefit of cold water left CVS on right hemianesthesia were investigated in one of the LDB patients (Patient L6 in Bottini et al., 2005) using fMRI. Notably, the authors found that the amelioration of contralesional hemianesthesia was associated with increased activation in the right SII and in the supramarginal gyrus (Fig. 3; Bottini et al., 2005). In healthy subjects, the same part of SII

Figure 3. Brain regions activated in patient L6 during the recovery of conscious tactile perception. Increased activations (depicted in white) were found in the right temporoparietal junction, including SII and the supramarginal gyrus. In the left hemisphere the large left frontotemporal lesion involving SII, the postcentral gyrus, the posterior limb of the internal capsule and the thalamus is visible. In the bar plot, on the right, the y-axis illustrates the average fMRI blood oxygenation level-dependent signal change before (CVS−) after (CVS+) and post CVS (30 minute delay; CVS-2). The image is presented in neurological convention. R = right hemisphere. Reproduced by permission from Bottini et al. (2005), Left caloric vestibular stimulation ameliorates right hemianesthesia, Neurology 65, 1278–1283.†

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Figure 4. Positive and negative effects of CVS on tactile perception in (A) right and (B) left brain-damaged patients. The damaged hemisphere is coloured black. Thick arrows indicate the direction of the slow phase nystagmus. Thin arrows indicate the stimulated ear and water temperature (blue arrows: cold water; red arrow: warm water). L: left; R: right; SPN: slow phase nystagmus. Improvement of the tactile deficit is indicated by a green hand in (A) left and right, and (B) left; no effect on tactile perception by a red hand in (B) right.

was also more activated than the same regions in the left hemisphere when ipsilateral stimuli were delivered, suggesting that the right hemisphere contains a more complete representation for both the left and right side of the body surface. These results clearly showed that the efficacy of CVS was a consequence of the modulation of specific brain regions (such as SII) in the right hemisphere containing a more complete representation of the body, rather than depending on a mere attentional shift towards the affected side induced by CVS (see Fig. 4). Although the majority of the studies reviewed in our paper employed CVS to modulate tactile perception, even galvanic vestibular stimulation (GVS; see Lopez et al., 2010 for a discussion of the difference between the two techiques) has been used to modulate somatosensory processing (in particular tactile extinction) in neurological patients (Kerkhoff et al., 2011; Schmidt et al., 2013b). GVS is a non-invasive technique that consists of applying a weak direct percutaneous current via two small electrodes (an anode and a cathode) placed over the right and the left mastoids processes (i.e., behind the ears). When the bilateral bipolar configuration is used the anodal electrode is placed behind one ear and the cathodal electrode behind the other ear (Fitzpatrick and Day, 2004; Utz et al., 2010; Utz et al., 2011a). GVS modulates the firing rate of the vestibular nerve: cathodal currents induce an increase in firing rate (depolarization) while anodal stimulation a decrease (hyperpolarization; Fitzpatrick and Day, 2004; Goldberg et al., 1984). Neuroimaging studies demonstrated that GVS

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activates different cortical regions including the insula and retroinsular cortex, the superior and middle temporal gyrus, the parietal lobe, the basal ganglia, the thalamus, the anterior cingulate gyrus and finally the cerebellum (Bense et al., 2001; Bucher et al., 1998, see Lopez et al., 2012a for an illustration of commonalities and differences between CVS and GVS). This technique has been used to modulate different symptoms among which neglect (Rorsman et al., 1999; Utz et al., 2011b; Wilkinson et al., 2014; Zubko et al., 2013) or arm position sense in hemiparetic patients (Schmidt et al., 2013a). Recently, Kerkhoff and collaborators (Kerkhoff et al., 2011; Schmidt et al., 2013b) demonstrated a long lasting GVS-induced modulation of tactile extinction in RBD patients, in accordance with previous evidence that found a similar effect using CVS (Vallar et al., 1993). Interestingly, the efficacy of GVS was independent of the polarity of the stimulation (indeed, both L-GVS and R-GVS were effective). These results might be explained considering that, as demonstrated by Fink and collaborators (2003), while left-anodal/right-cathodal GVS (i.e., L-GVS; excitation of the right and inhibition of the left vestibular nerve) led to a unilateral activation of the right vestibular cortex (see Fig. 2a in Fink et al., 2003), left-cathodal/right-anodal GVS (R-GVS; excitation of the left and inhibition of the right vestibular nerve) produced a bilateral activation of the vestibular cortex (see Fig. 2b in Fink et al., 2003). It follows that while the left vestibular cortex is activated only by R-GVS, the right vestibular cortex is activated by both L-GVS and R-GVS, indicating a dominance of the right hemisphere for vestibular processes (see Fig. 2 in Fink et al., 2003). 2.2. Vestibular Modulation of Somatosensory Perception in Healthy Subjects The idea that the efficacy of CVS is due to a specific effect on somatosensory perception, by way of mechanisms of multisensory integration, has been elucidated by recent work on healthy subjects using both CVS and GVS. These data strengthen the idea that explanations in terms of general arousal or attentional shift are not sufficient to explain the effect of CVS on tactile perception. In healthy subjects, unilateral vestibular stimulation (i.e. left ear cold water CVS) improved the detection of faint tactile stimuli applied to both the ipsilateral (Ferrè et al., 2011a) and contralateral hand (Ferrè et al., 2011b, 2013a). This bilateral effect was replicated using ‘left anodal–right cathodal’ galvanic vestibular stimulation (L-GVS; Ferrè et al., 2013b), while ‘right anodal–left cathodal’ stimulation was ineffective (R-GVS). Notably, the effect of CVS was modality-specific: indeed, left cold CVS enhanced tactile perception (Ferrè et al., 2011a, b) but was ineffective on visual sensitivity (Ferrè et al., 2011b). Moreover, cold water left CVS modulated somatic processing in opposite directions (Ferrè et al., 2013a) as it facilitated tactile perception and increased pain threshold (inhibition of pain, i.e., analgesia). These results demonstrated

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the high specificity of the effects of CVS on independent sensory submodality (i.e., touch and pain perception) and were compatible with the idea that a common vestibular input differently affected tactile perception and pain inducing respectively an up-regulation or a down-regulation of sensory processes (see Fig. 3 in Ferrè et al., 2013a, page 754). The authors suggested that these effects might be grounded in the interaction between vestibular and somatosensory systems through physiological mechanisms that remain a matter of speculation. In particular, the vestibular inputs might modulate the sensitivity of bimodal neurons to somatosensory input inducing excitatory (EPSPs) or inhibitory (IPSPs) post-synaptic potentials or, alternatively, causing a long term potentiation (LTP) or a long term depression (LTD) of respectively tactile and pain pathways (Ferrè et al., 2013a). Multimodal neurons responding to visual, vestibular and tactile inputs were found in the parieto-insular vestibular cortex (Grusser et al., 1990), in the somatosensory cortex (Schwarz and Fredrickson, 1971) and also in the ventral intraparietal area in the macaque (Bremmer et al., 2002). The first direct electrophysiological demonstration of an interaction between vestibular and somatosensory processing derived from the study of Ferrè and collaborators (Ferrè et al., 2012) who observed, after left cold CVS, an enhancement of the N80 somatosensory evoked potentials (SEPs) component evoked by left median nerve stimulation, recorded over both the contralateral (C4) and ipsilateral (C3) somatosensory cortex. Even if the origin of this component is still debated, some authors hypothesised that long latency components (in the range of 70–150 ms) are predominantly generated in the secondary somatosensory cortex (SII; Garcia-Larrea et al., 1995; Hari et al., 1984). Notably, the authors did not find any modulation of those long latency components more linked to attentional processes (such as the N140 component) and of visual evoked potential (VEPs). This specificity (i.e., the observation that CVS modulates only the N80 SEPs component) strengthened the idea that the effectiveness of CVS might derive from the activation of brain regions that shared vestibular and somatosensory input, such as SII (Bottini et al., 1995, 2005). Further evidence that vestibular stimulation directly affects the somatosensory system through multimodal interaction, independently of attentional effects, came from a recent experiment in which the authors induced a natural activation of the vestibular system (Ferrè et al., 2014). The experimental task consisted of a whole-body passive rotation, obtained using a chair mounted on a beam platform fixed to an electrical engine and controlled by a system that allowed body rotation (for a detalied description of the experimental apparatus see Ferrè et al., 2014; van Elk and Blanke, 2012). The subjects’ task consisted in detecting tactile electrical stimuli delivered to the left or to the

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right hand during spatially congruent (for example left hand tactile stimulation/left body rotation) or incongruent (left hand tactile stimulus/right body rotation) passive body rotation. The authors found that passive whole-body rotation improved the detection of faint stimuli independently from the spatial coherence “between the direction of the rotation and the hand stimulated” (Ferrè et al., 2014). These data clearly demonstrated that the increase of tactile perception induced by vestibular stimulation is independent of the side in which attention is directed. In conclusion, these findings (see Fig. 5 for a summary of the studies exploring the effect of vestibular stimulation on somatosensory perception) suggest that the crucial factor underlying the effectiveness of CVS is the interaction between vestibular and somatosensory signals, predominantly within the right dominant hemisphere. Specific activations within somatosensory and vestibular regions to the right transiently ameliorated both right and left tactile deficits (Bottini et al., 2005), while in normal subjects left cold water CVS and L-GVS produced bilateral benefits (Ferrè et al., 2011b, 2013a). This suggests a hardwired asymmetry in hand representation in SII with a dominance of the right hemisphere for both ipsilateral and contralateral stimuli. One might speculate that CVS modulates neurons in SII with ipsilateral receptive fields (Bottini et al., 2005; Ferrè et al., 2013b) inducing an improvement of tactile deficits in patients and an enhancement of tactile perception in healthy subjects. A possible mechanism to explain this modulation might be the activation of bimodal neurons (i.e., neurons activated by both tactile and vestibular inputs) that are used by the brain to build up a complete representation of the body in the space (Bottini et al., 1995, 2005; Ferrè et al., 2013a). 3. Effects of CVS on Body Ownership and Body Representation 3.1. Vestibular Modulation of Personal Neglect, Body Ownership and Body Representation in Patients The hypothesis that vestibular stimulation has a specific effect due to a topdown modulation of body representation and body ownership (the feeling that a body part belongs to the subject’s body) has been strengthen by the observation that it is effective in modulating personal neglect (see also the Introduction; Cappa et al., 1987) and somatoparaphrenia (Bisiach et al., 1991; Rode et al., 1992). The first observation of an influence of CVS on deficits of body ownership comes from the seminal study of Bisiach and co-workers (Bisiach et al., 1991). The authors described the case of a patient (Patient AR) with a dense somatoparaphrenia (SP) who claimed that her left hemiplegic arm belonged to her mother. After cold water left CVS the authors described a transitory remission of the feeling of disownership. Interestingly, even if immediately after this stimulation the patient recognized her left arm as her own

Figure 5. Summary of the studies exploring the effects of caloric and galvanic vestibular stimulation on somatosensory perception in patients and healthy subjects. LC: left cold water; RW: right warm water; RC: right cold water; RBD: right brain-damaged; LBD: left brain-damaged; RH: right hemisphere; L-GVS: ‘left anodal and right cathodal’ galvanic vestibular stimulation; R-GVS: ‘right anodal and left cathodal’ galvanic vestibular stimulation; PBR: passive whole-body rotation. We only report selected studies that demonstrated a modulation of vestibular stimulation on the detection of unilateral somatosensory stimuli.

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without hesitation, remission was not complete: indeed, when questioned by the examiner about her mother’s arm (“where is your mother’s arm?”), she answered that it was “under the bedclothes” (Bisiach et al., 1991, page 1030). This preliminary observation was replicated by Rode and co-workers (Rode et al., 1992) in a single patient (case TS) with a large right cortico-subcortical lesion in the territory of the middle cerebral artery. The patient presented a complete left hemiplegia and when questioned she attributed her left hemiplegic arm to the examiner. After cold water left CVS (cold water in the left ear) the feeling of disownership disappeared. The strength of CVS on body ownership delusion was interpreted as the consequence of the restoring, through CVS, of the ipsilesional shift of the egocentric frames of references (Rode et al., 1992). Interestingly, in 1999 Schiff and Pulver (Schiff and Pulver, 1999) reported a case of remission of neglect and SP after cold water right ear stimulation in a left brain-damaged patient. More recently, Ronchi and co-workers (Ronchi et al., 2013) described a patient (case GB) with a lesion in the left temporo-parietal junction that presented severe personal and extrapersonal neglect, anosognosia and a delusional feeling about his right hemiplegic hand: in particular, the patient claimed he had only the left hand. Moreover, when both his hands were placed side to side he said that the right hand was only “apparently” his hand. After cold water right CVS the authors observed a remission of neglect, anosognosia and personal neglect. Interestingly, the feeling of having only one hand also disappeared. This evidence suggested an effect of CVS on body delusion also in patients with left brain damage. CVS can also affect body representation (body’s metric proprieties) in patients without brain lesions (such as in amputees and in spinal cord patients) and even in normal healthy subjects (see next paragraph: review in Lopez, 2013). In amputees cold water CVS, performed in the ear ipsilateral to the amputated limb, induced or modified phantom limb perception (André et al., 2001). In patients with a complete section of the spinal cord left cold CVS evoked normal or deformed phantoms in the paralyzed body parts. Furthermore, Rode and collaborators (Rode et al., 2012) have recently observed the remission of macrosomatognosia (Note 5) after left cold water CVS in a patient suffering from a left lateral medullar stroke. The patient (AG) spontaneously reported the somatosensory sensation that the left part of his face had become larger. Interestingly, this effect showed to be selective as the benefit was restricted to the illusion of face enlargement and not generalized to the associated neuropathic facial pain. By contrast, transcutaneous electrical stimulation (TENS) had opposite effects (e.g., it was ineffective on macrosomatognosia but reduced facial pain). The authors suggest that CVS affects brain regions, predominantly located in the right hemisphere, which are involved in the construction of the topographic representation of the body. The

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absence of a modulatory effect on pain after CVS (pain score unchanged after stimulation) is in contrast with the results of Ferrè and co-workers (2013a; see also Section 2.2) who demonstrated a reduction of the sensitivity (analgesia) to nociceptive stimulation (heat pain generated by a thermode) in healthy subjects and with previous studies that proved a reduction of central post-stroke pain (McGeoch et al., 2008, 2009; Ramachandran et al., 2007) after CVS. Further studies are needed to clarify the efficacy of CVS on different types of pain (for example nociceptive versus neuropathic pain) and pathologies, also considering the extension and localization of the patient’s brain lesions. 3.2. Vestibular Modulation of Body Ownership and Body Representation in Healthy Subjects An effect of vestibular stimulation on body ownership has also been described in healthy subjects, by using the rubber hand illusion paradigm. In 2010, Lopez and colleagues demonstrated, after left anodal GVS (L-GVS) an enhancement of (i) the illusory ownership of the rubber hand (Lopez et al., 2010) and of (ii) the illusory location of touch. Indeed after L-GVS the feeling of ownership of the rubber hand was stronger than before (as assessed by subjective reports) and the subjects had a stronger sensation that the touches felt on the left hand were caused by the stroking of the rubber hand. Notably, L-GVS polarity induces an excitation of the right ear and causes a slow phase nystagmus in the same direction induced by cold water left ear CVS and warm water right ear CVS (Lopez et al., 2012a). Recently, Lopez and co-workers (Lopez et al., 2012b) used binaural caloric stimulation (warm air in the right ear and simultaneously cold air in the left ear) to study the relationship between vestibular system and the body’s metric proprieties (size and shape) in healthy subjects. During stimulation, subjects experienced an increase in the perceived length and width of the left hand, indicating a modification of the internal representation of the hand size. The authors postulate a crucial role of the multisensory vestibular cortex in integrating different afferent signals (vestibular, visual, proprioceptive and tactile). The body representation generated by this integration might be (i) distorted after vestibular disorders as reported in the seminal papers of Bonnier and Schilder (Bonnier, 1905; Schilder, 1935), (ii) artificially altered by caloric stimulation in healthy subjects (Lopez et al., 2012b) or (iii) restored in patients with macrosomatognosia (Rode et al., 2012). The neural counterpart of these behavioural effects lies on the anatomical overlap between different sensory inputs necessary to build up and update our body representation. However, the effect of vestibular stimulation on the body’s metric proprieties remains controversial considering that Ferrè and colleagues (2013c) using a similar experimental task did not confirm such an effect.

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Overall, these data on patients and healthy subjects suggest that CVS could directly modulate the activity of multimodal networks involved in body representation. By analogy with the above-mentioned evidence emerging in the domain of tactile perception (Bottini et al., 1995, 2005), the overlap between brain regions involved in vestibular and multisensory integration with areas underpinning body ownership and body representation is considered the key neural mechanism underlying these behavioural effects (see review in Lopez, 2013; Pfeiffer et al., 2014). Moreover, this hypothesis needs to be supported by neuroimaging studies aimed at directly investigating the psychological bases of the recovery or modulation of body ownership through CVS. 4. Conclusion In conclusion, divergent hypotheses have been proposed to explain the modulatory effects of CVS. In particular, the role of attention as a possible explanation for the observed widespread effects is still a matter of debate (review in Chokron et al., 2007). However several findings both in patients with brain lesions and in healthy subjects have challenged interpretations based on pure attentional effects or other non-specific and supramodal factors. The first evidence derived from the behavioural observation that CVS ameliorates deficits, such as left motor anosognosia, personal neglect or tactile deficits, even when visual control was not required (eye closed condition). Secondly, left cold CVS significantly reduced severe tactile imperception in both right and left braindamaged patients: in other words, whatever the side of hemianesthesia, left stimulation appeared to be effective (Bottini et al., 2005). Furthermore, neurophysiological evidence in both normal subjects and patients demonstrated that the vestibular projections and somatosensory inputs largely overlap in the cortex, far from cerebral areas involved in the control of attention (Bottini et al., 1995, 1996, 2005). Moreover, at least three main additional crucial findings corroborate the hypothesis of a specific and direct effect of CVS: firstly, vestibular stimulation selectively improves perception of bilateral subliminal tactile stimuli, corroborating that its effect does not depend on a general elicitation of arousal or on mere attentional modulation (Ferrè et al., 2011b, 2013a, b). Secondly, neurophysiological data demonstrated that the vestibular system, when stimulated, induces effects on different somatosensory districts (pain and touch) in dissociable directions (Ferrè et al., 2013a). Finally, caloric stimulation activates specific brain networks (Bottini et al., 1994, 1996; see Lopez et al., 2012a for a review) involved in multisensory integration (Bense et al., 2001; Bottini et al., 2001; review in Lopez et al., 2012a). We believe that further behavioural and neuroimaging studies are needed to systematically explore vestibular stimulation effects in cohorts of acute and

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chronic patients and to directly investigate the neural mechanisms underlying the recovery in both normal subjects and in patients. Acknowledgements This work was partially supported by grant PRIN 2010–2011. Notes 1. Alexander (1912) described three degrees of nystagmus: (1) first degree nystagmus is present only when the subject gaze is in the direction of the fast phase nystagmus; (2) second degree nystagmus is present when the subject looks straight ahead (primary position) and when the subject gaze is in the direction of the fast phase nystagmus; (3) third degree nystagmus is present in all gaze positions, when the subject gazes in the direction of the fast phase, straight ahead and in the direction of the slow phase nystagmus (Alexander, 1912). 2. The presence of nystagmus represents the clinical sign that the caloric stimulation is effective. 3. Anosognosia for hemiplegia is a neuropsychological condition in which the patient is not aware of his motor deficit (Babinski, 1914). 4. Patients with tactile extinction (extinction to simultaneous stimulation) are able to correctly detect tactile stimuli delivered to the side of the body contralateral to the brain lesion. In contrast, when two tactile stimuli are simultaneously delivered to the left and right side of the body, the patients failed to report contralesional stimuli (Loeb, 1885). 5. Macrosomatognosia is a clinical condition in which patients perceive one or more parts of their body as disproportionately larger (Frederiks, 1963). References Alexander, G. (1912). Die Ohrenkrankheiten im Kindesalter, in: Handbuch der Kinderheilkunde, M. Pfaundler and A. Schlossmann (Eds), pp. 84–96. Verlag von F.C.W. Vogel, Leipzig, Germany. André, J. M., Martinet, N., Paysant, J., Beis, J. M. and Le Chapelain, L. (2001). Temporary phantom limbs evoked by vestibular caloric stimulation in amputees, Neuropsychiatry Neuropsychol. Behav. Neurol. 14, 190–196. Babinski, J. (1914). Contribution à l’étude des troubles mentaux dans l’hémiplégie organique cérébrale (anosognosie), Rev. Neurol. 27, 845–848. Bárány, R. (1906). Untersuchungen über den vom Vestibularapparat des Ohres reflektorisch ausgelösten rhythmischen Nystagmus und seine Begleiterscheinungen, Monatsschr. Ohrenheilkd. Laryngorhinol. 40, 193–297.

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Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration Mariia Kaliuzhna 1,2 , Dominique Vibert 3 , Petr Grivaz 1,2 and Olaf Blanke 1,2,4,∗ 1

2

Center for Neuroprosthetics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Laboratory of Cognitive Neuroscience, Brain Mind Institute, School of Life Science, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland 3 Department of Otorhinolaryngology Head and Neck Surgery, University Hospital (Inselspital) of Bern, Switzerland 4 Department of Neurology, University Hospital, Geneva, Switzerland

Abstract Out-of-body experiences (OBEs) are illusory perceptions of one’s body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient’s behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient’s symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs. Keywords Out-of-body experiences, multisensory integration, vestibular, temporo-parietal junction, lucid dreams

*

To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_013

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1. Introduction Vestibular information plays a considerable role not only for situating one’s body in space, but also for perceiving the external environment (Berthoz et al., 1975; Lackner and DiZio, 2005; Pfeiffer et al., 2013; Siegler et al., 2000; Van Elk and Blanke, 2012). This importance is reflected in the influence of vestibular signals on tactile, auditory, proprioceptive and visual processing as well as the overlap of vestibular cortical regions with somatosensory, visual, and motor cortical regions in humans and non-human primates (Avillac et al., 2007; Bremmer et al., 2002; Grüsser et al., 1990a; Lopez and Blanke, 2011; Mazzola et al., 2014). For example, under normal conditions, maintenance of postural stability is associated with the integration of multisensory signals conveying the position of the body via proprioceptive cues from the lower limbs, motion of the visual scene on the retina, and vestibular signals about head motion (Mergner and Rosemeier, 1998; Rogers et al., 2001). Combining visual and vestibular information has also been shown to improve perception of self-motion and the differentiation between self- and object motion (Murray et al., 2012; Prsa et al., 2012; Wexler et al., 2001). Faulty integration of vestibular signals with other perceptual cues (e.g., proprioception, touch, or vision) has been hypothesised to result in different illusory own body perceptions ranging from feelings of depersonalisation (as in patients with vestibular lesions reporting alienation sensations) (JáureguiRenaud et al., 2008; Sang et al., 2006) to sensations of vection, room-tilt illusions, and disembodiment (Blanke and Mohr, 2005; Blanke et al., 2004; Lopez, 2013; Lopez et al., 2010). More complex illusory own body perceptions, also including alterations of self-consciousness, are reported by patients with out-of-body experiences (OBEs) (Blanke et al., 2004; Brugger, 1997; Devinsky et al., 1989; sometimes also called astral projections, e.g., Muldoon and Carrington, 1951). OBEs are defined as illusory perceptions of the environment and of one’s own body from a disembodied and elevated first-person perspective and self-location, accompanied by vestibular illusions of floating, flying, rotating or translation. These illusions are thought to arise due, on the one hand, to faulty integration of own body-related visual, proprioceptive and tactile information, and on the other, to additional disintegration of vestibular bodily cues with respect to external space such as visual signals (visuo-vestibular disintegration) (Blanke, 2012; Bünning and Blanke, 2005). The close link of OBEs to the vestibular system and the importance of altered vestibular signal integration with visual, proprioceptive and tactile cues has been confirmed by the induction of OBEs through direct stimulation of the temporo-parietal cortex (Blanke et al., 2002). Moreover, lesion location in patients with OBEs of neurological origin also centres on the core region of the vestibular cortex and adjacent multisensory cortex: at the junction of the right

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posterior parietal operculum, posterior superior temporal gyrus, and posterior insula (Calvert et al., 2000; Ionta et al., 2011a; Maguire et al., 1998; Vogeley et al., 2004). However, OBEs have also been reported in neurological patients with generalized disease (Blanke and Mohr, 2005; Blanke et al., 2004), with left temporo-parietal damage (Ionta et al., 2011a), with damage to the cervical spinal cord (Overney et al., 2009), and during sleep paralysis (Cheyne et al., 1999; Nelson et al., 2007). Some authors assume that ∼6 to 12% of healthy subjects from the general population may experience one or two OBEs in their lifetime (Blackmore, 1987; Blanke and Mohr, 2005; Blanke et al., 2002), of which some are due to general anaesthesia (Muldoon and Carrington, 1951), hypnapompic and hypnagogic hallucinations, or drug intake (Tart, 1974). It is currently not known how OBEs due to generalized aetiologies, interference at the brain stem, spinal cord, or the peripheral nervous system relate to OBEs induced by damage to the temporo-parietal cortex; however, it has been proposed that deficient integration of multisensory own body-related signals, including vestibular signals, is also present in many of these latter conditions (Blanke and Arzy, 2005; Bünning and Blanke, 2005). Here, we report the case of a patient with unilateral peripheral vestibular damage leading to repeated OBEs that were additionally associated with intensive oneiric activity (in the form of lucid dreams (Blackmore, 1982)). In order to test the hypothesis of faulty multisensory integration in OBEs we investigated the patient’s performance in paradigms testing visuo-vestibular integration (Prsa et al., 2012) as well as bodily self-consciousness (Lenggenhager et al., 2007; Pfeiffer et al., 2013). First, we employed a paradigm that allows to test optimal integration of visual and vestibular cues signalling selfmotion during both rotational and translational stimuli (Butler et al., 2010; Fetsch et al., 2009; Prsa et al., 2012). Previous data have revealed that healthy participants are more accurate in judging the amount or the direction of motion when visual and vestibular cues are present jointly as compared to the same motion indicated by just one (visual or vestibular) source of information. Thus, we here expected the patient to show deficient integration of the two self-motion cues, meaning that no benefit is achieved by using the redundant information, as compared to each cue separately. Such a result would speak in favour of the disintegration between personal (vestibular) and extrapersonal (visual) space. We also tested the multisensory mechanisms underlying bodily self-consciousness, using the Full Body Illusion paradigm (FBI) (Lenggenhager et al., 2007; Pfeiffer et al., 2014). Based on multisensory conflicts, the FBI allows manipulating self-location, self-identification and the first person perspective in healthy participants in a way that mimics OBE (Ionta et al., 2011a, b). We expected the patient to be more sensitive to these experimental manipulations, showing disintegration in the personal space, as predicted. Finally, we combined the classical FBI with a visual cue indicating self-motion

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(optic flow), expecting a further increase in changes of self-location as a result of increased multisensory conflict involving the vestibular sense. Our experiments revealed a deficit in visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts. By describing the interrelation of the patient’s symptoms (sleep-related disorders, lucid dreaming, OBEs) and their link to behavioural vestibular and visuo-vestibular deficits, this clinical case allows us to gain insights into the relevance of these cues for OBEs and the origin of complex alterations of consciousness that have not yet been investigated experimentally. 2. Case Report 2.1. Vestibular Symptoms and Neurootological Examination A 36-year-old male patient complained of recurrent vertigo attacks with dizziness and nausea occurring three to four times yearly, for the last five years approximately. He also indicated that these symptoms were amplified upon turning the head to the left or to the right. The patient further reported the sensation of floating when walking as well as falling sensations when lying down in bed. These sensations lasted from a couple of seconds to sometimes several hours and were recurrent. Sometimes the patient woke up at night because of these symptoms. Neither auditory complaints nor tinnitus were reported. A complete neurootological examination was performed including puretone audiometry, brainstem evoked auditory potentials (BEAP), clinical vestibular examination with the measurement of the subjective visual vertical (SVV) as well as electronystagmography (ENG). ENG consisted of recording the spontaneous nystagmus with (light on) and without visual fixation (in darkness); the positional nystagmus with the head in hyperextension, then turned to the right and to the left (positions of Rose); the optokinetic nystagmus at speeds of 25, 45, 70°/s (rotation to the left and to the right) with whole retinal field stimulation. The vestibulo-ocular reflex was recorded during the rotatory pendular testing (undamped rotation of 360° in 20 s; sinusoidal frequency of 0.05 Hz with a peak velocity of 60°/s) with (light) and without (darkness) visual fixation suppression as well as during the bithermic caloric testing with water at 44 and 30°C. The ENG showed the normal absence of the spontaneous and positional nystagmus, and right hyporeflexia on both the rotatory pendular and the bithermal caloric tests (Fig. 1, Table 1). Auditory tests (BEAP, pure-tone audiometry) as well as the SVV measure were normal. Magnetic resonance imaging results (MRI) as well as the routine neurological examination were normal. No EEG or polysomnography recordings have been carried out. Based on the history and the neurootological findings a vestibulopathy on the right side, probably of viral origin, was diagnosed. The patient then com-

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Figure 1. Results of the bithermal water caloric testing. (A–D) Nystagmic responses for each ear irrigation: (A, B) Caloric testing of the right ear (A with 44°C; B with 30°C), (C, D) caloric testing of the left ear (C with 44°C; D with 30°C). (E) Freyss diagram (Freyss and Toupet, 1978) of horizontal (left and right) nystagmus showing the numerical values of the peak slow phase velocity of horizontal nystagmus (y-axes) for each irrigation. The x-axis indicates the percentage of weakness of one ear compared to the other. In case of symmetrical reflexivity, the intersection of both curves is located at 0% on the x-axis and 0°/s on the y-axis. In our patient, the caloric testing showed a decreased nystagmic response in terms of frequency and amplitude (A–D) as well as a paresis of 27% (the norm being 20%; Demanez, 1986) of the right horizontal canal (E) with a discrete direction preponderance of the left nystagmus.

pleted vestibular physiotherapeutical training including optokinetic stimulations with regression, after 18 sessions of treatment, of his symptoms. During the clinical neurootological control examinations and interviews after treatment, he also spontaneously reported that his out-of-body experiences as well as lucid dreams (that he had experienced for the last years; see below) had also disappeared after treatment onset.

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Table 1. Nystagmus responses to rotatory pendular testing and optokinetic testing. The results of the rotatory pendular testing indicate a left directional preponderance of the nystagmus. The results of the optokinetic testing are within the normal range. SPV = slow phase velocity; D.P. = directional preponderance of nystagmus; OFI = ocular fixation index [(SPV with fixation/SPV without fixation) × 100] ROTATORY

PENDULAR TESTING

Leftward rotations

Rightward rotations

14.8 33% 2%

4.4 14% 6%

SPV (°/s) Gain OFI

O PTOKINETIC

D.P. to left = 54%

TESTING

Rotation direction

SPV (°/s) Gain

25°L

25°R

45°L

45°R

70°L

70°R

27.1 112%

22.3 95%

27.8 64%

31.9 74%

21.7 32%

32.8 49%

2.2. Out-of-Body Experiences and Sleep-Related Experiences The patient reported that he had experienced a single episode of an OBE around the age of 11–12 years and that he had frequent nightmares in childhood. Thus, lying in bed he experienced feeling unexplainable strong fear and an inability to move followed by the experience of being at the ceiling of his room (disembodiment), looking down (elevated first-person perspective), and seeing his body (autoscopy) in bed. The experience was brief and lasted for several seconds, stopping as briskly as it had started. During the last five years, that is, after the onset of the above-mentioned symptoms of nausea, floating and falling the patient reported the following OBEs and dream activity that occurred frequently. First, the following sleep changes occurred. He described that during his dreams he had the sensation — in the middle of a regular dream — to suddenly become conscious that he is dreaming with the apparent experience to voluntarily control the content of the dream. In such lucid dreams he would try to interact with the environment (i.e., try to pass through walls, try to speak to people without any experienced success). He experienced lucid dreams several times per month and often OBEs were associated with lucid dreams (most often as a continuation of a lucid dream with the patient experiencing to be able to voluntarily induce OBEs during a lucid dream state). OBEs occurred rarely and were estimated at an average frequency of three to four times a year. Both

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lucid dreams and OBEs only occurred at night, mostly in the morning hours (4–6 A.M.). The patient added further details about his nocturnal experiences: he reported that the ‘lucidity’ in the dreams and his experience to be able to control his behaviour as well as the onset of OBEs increased progressively over the years. He noted that initially lucid dreams only lasted for very short periods, but that they gradually increased in duration (it was during these later periods that he ‘managed’ to attempt more complex behaviours in his dreams). The course of a typical OBE was as follows. He would wake up at night and glance at the clock, close his eyes again and fall back to sleep, when suddenly he would experience the sensation of “falling in complete darkness”. Then the falling would stop and he would feel as if he were floating in the air, still in complete darkness. Next, he experienced hearing a crackling sound inside his head. At this point he would open his eyes and slowly experience disembodiment associated with the sensation of leaving his body and the bed and be turned around by 180° seeing himself lying on the bed. During most such OBEs he experienced being disembodied at a self-location under the ceiling of his bedroom or next to his bed; however on rare occasions he also experienced disembodiment to more distant self-locations such as outside his house. Rarely on such latter occasions he even experienced ‘walking’ in his neighbourhood. He experienced these episodes to last for about 2–3 minutes. Upon awakening he would feel a generalized tingling sensation across his body (that the patient described as a sort of ‘energy’) that lasted for about two minutes. He then felt invigorated, “like a charged battery” for several days. The patient reported that after the otoneurological rehabilitation lucid dreams and OBEs became much less frequent. On the day of our experimental investigation these experiences were reported to be gradually coming back. 3. Experimental Investigation 3.1. Experiment 1: Visuo-Vestibular Integration 3.1.1. Experimental Setup and Procedure To test for the link between faulty integration of vestibular information with visual cues in OBEs we tested visuo-vestibular integration (two months after the end of otoneurological physiotherapy). For a detailed description of the experimental setup, procedure and data analysis see Prsa et al. (2012). The experiment was approved by the local ethics committee (protocol number 07-170 (NAC 07-069)). The patient was seated in a centrifuge cockpit-style chair, which delivered passive whole body rotational stimuli around the earth-vertical axis (yaw plane). He was comfortably restrained, and a head fixation and chinrest prevented head movements. The rotation profiles of the chair were preset and designated the immediate angular position of the chair at a rate of 100 Hz. Each rotation was a raised cosine

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Figure 2. (A) Schematic view of the experimental setup. The patient was seated in a rotating chair that delivered whole-body rotations in the yaw plane. A computer monitor was positioned in front of him, showing a 3D pattern of dots that simulated self-rotation in the yaw plane. (B) Timeline of one experimental trial. The patient experienced two consecutive rotations in the same direction and had to decide whether the second rotation was bigger or smaller than the first one.

mimicking natural head motion. In front of the patient a 22 inch computer display was mounted on the chair and delivered the visual stimulus (Fig. 2). The limited visual field covered ∼80° of horizontal and 56° of vertical visual angle. The visual stimulus was a stereoscopic pattern of randomly distributed moving dots of different size. The dots were two-dimensional symmetric greyscale Gaussian blobs with a minimum and maximum standard deviation of 0.5 and 3 pixels, respectively. The simulation of rotation was achieved by placing the patient’s view-point in the middle of the scene and rotating it around the yaw axis. A stationary central point (filled red circle with a radius of 3 pixels, 0.5 intensity level presented at zero binocular disparity) was displayed in all conditions during rotation and the patient was instructed to fixate it at all times. The stereoscopic visual stimulus was generated by the Nvidia Quadro FX 3800 graphics card using the OpenGL quad-buffer mechanism. The stimulus was

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programmed with the Python language and viewed with the Nvidia 3D Vision kit (active shutter glasses) paired with a Samsung Syncmaster 2233RZ display (120 Hz refresh rate) via an infrared transmitter. The velocity and onset of the optic flow was the same as of the rotating chair. The patient wore headphones over which we presented masking white noise. On each trial two consecutive rotations occurred in the same direction. After the two rotations were over he had to judge whether the second rotation was bigger or smaller than the first (as in Prsa et al., 2012). Three types of trials were presented: two rotations of the chair alone (unimodal vestibular condition), two rotations of the stereoscopic image on the screen (unimodal visual condition) and two simultaneous rotations of the chair and the visual image in opposite directions (bimodal condition). The experiment started out with a short practice session to make sure the patient had fully understood the task. He performed a total of 560 trials, of which 186 were unimodal visual, 187 unimodal vestibular and 187 bimodal. The experiment was divided into several blocks about 7 min long each. The three types of trials were randomised within each block. The whole experiment lasted approximately an hour and a half. After the experiment was over we extracted discrimination thresholds for each of the three conditions and compared the patient’s bimodal thresholds to the prediction of a Bayes optimal observer model to test for optimal integration (see Prsa et al., 2012). 3.1.2. Results Multisensory integration in healthy subjects results in improved performance in the bimodal versus unimodal condition with the bimodal threshold being lower than the best single cue threshold. Figure 3 shows that this is not the case for the present patient. For both rightward and leftward rotations the patient’s bimodal threshold was higher than his best unimodal cue (i.e., vestibular) (see Table 2 for the experimental values and bootstrap comparisons). One-tailed bootstrap tests confirmed the absence of the integration of visual and vestibular self-motion cues: there was no significant difference between the bimodal and the best unimodal thresholds for either rightward (ipsilesional) or leftward (contralesional) rotations. In accordance with previous literature (Lopez et al., 2005, 2007; Valko et al., 2012; Von Brevern et al., 1997) we also note that the patient performed somewhat worse in the unimodal vestibular condition when rotated in the ipsilesional direction (i.e., rightward, mean threshold value 3.1) versus the contralesional direction (i.e., leftward, mean threshold value 2.6), although this was not found to be significant (p = 0.13). Importantly, on the deficit side the patient’s bimodal threshold was significantly different from optimality (p = 0.04); no such difference was observed on the healthy side (p = 0.15).

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Figure 3. Results of the visuo-vestibular integration task. The patient fails to show integration, as his bimodal threshold (red line) is not better than the best single cue threshold (vestibular, black line) and significantly different from the predicted optimal threshold (dashed red line) on the deficit side. Error bars represent bootstrap standard error.

Table 2. Experimentally obtained unimodal and bimodal thresholds. The upper panel represents experimentally obtained threshold values for each condition. The lower panels show the p values of the bootstrap analysis comparing the bimodal threshold to unimodal conditions, and the unimodal thresholds to each other, as well as the results of comparing each threshold between the two rotation directions. Values in bold show statistical significance Condition

Rotation direction Left

Right

Vestibular Visual Bimodal

3.05 5.09 3.84

2.35 5.67 2.80

p value vestibular vs bimodal p value visual vs bimodal p value vestibular vs visual

0.17 0.17 0.03

0.25 0.01 0.00

p value vestibular left vs right p value visual left vs right p value bimodal left vs right

0.13 0.36 0.10

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3.2. Experiment 2: Visuo-Tactile Integration During the Full-Body Illusion (FBI) 3.2.1. Experimental Setup and Procedure We next employed the FBI and tested multisensory mechanisms underlying self-identification and self-location that have been linked to OBEs (Ionta et al., 2011b; Lenggenhager et al., 2007; Pfeiffer et al., 2013, 2014). Spatially and temporally conflicting visual and tactile information about the location of the participant’s body was delivered using a robotic device. The robotic procedure of inducing the full-body illusion is described elsewhere (Pfeiffer et al., 2014). In brief, the patient lay supine in a darkened room on a robotic device designed to gently stroke the participant’s back (tactile stimulus), while wearing a head-mounted display (HMD) in which an image of a male body (seen from the back — virtual body) was shown against a black background. Superimposed on this image were two dots representing the stroking locations that the patient felt on his back, delivered by the robotic device (visual stimulus simulating ‘stroking’). We first tested the classical FBI. Two conditions were tested. In the synchronous condition the felt and seen position of the stroking were congruent in spatial and temporal terms; in the asynchronous condition the two positions did not coincide. Both conditions were repeated twice. On each trial, the stimulation lasted for 120 s, after which the robot stopped and a black scene was shown in the HMD. In order to measure self-location the patient performed the Mental Ball Dropping task (Pfeiffer et al., 2013). We asked the patient to imagine dropping a ball from his hand down to the floor; when he imagined to release the ball he pressed a keyboard button and kept it pressed. When the imaginary ball hit the floor he had to release the button. The duration of the button press reflects the perceived distance of oneself to the floor (Pfeiffer et al., 2013). After each trial the patient was questioned about his experience (free report). After these manipulations we administered a formal questionnaire (Fig. 4), quantifying illusory touch and self-identification with the virtual body and the differences between the synchronous and asynchronous conditions. The patient answered the questionnaire twice, first recalling his experiences in the synchronous and then in the asynchronous conditions. We compared the patient’s answers with those of a control group (N = 15, seven females, average age 22.3 years, SD = 2.52 years). 3.2.2. Results Figure 4 summarises the responses of the patient and of a control group to the experimental questionnaire reflecting self-identification with the virtual body in the synchronous and asynchronous conditions. In summary, we replicate previous research, the patient and the control group showing that illusory and

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Figure 4. (A) Patient’s full body illusion questionnaire results for synchronous (black bars) and asynchronous (white bars) stroking conditions. The red lines represent the 95% confidence intervals for the control group (N = 15), in the synchronous (solid lines) and asynchronous (dotted lines) conditions. (B) The questions employed.

referred touch were experienced as stronger in the synchronous as compared to the asynchronous condition. More specifically, visual inspection suggested that the patient scored higher in the synchronous (black bars in Fig. 4) than in the asynchronous (white bars in Fig. 4) condition on illusory touch (question 2: How strong was the feeling that the touch you felt was located where you saw the stroking?; question 3: How strong was the feeling that the red dot you saw was directly touching you?), as well as question 5 (How strong was the feeling that you were looking at someone else?), question 8 (How strongly did you feel the touch simultaneously at two locations in space?), question 9 (How strong was the feeling to float in the air?) and question 10 [How strong was the feeling that you were dissociated from your body (as if your self and your body were in different locations)?]. The response to illusory floating may corroborate the patient’s spontaneous verbal response, and shows that this feeling was stronger during synchronous visuo-tactile stimulation. No changes were observed for illusory self-identification. For the control group two-tailed Bonferroni cor-

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rected t-tests revealed a significant difference between the synchronous and the asynchronous condition for questions 2 and 3, the ratings being higher in the synchronous condition. To compare the patient’s scores to that of the control group (main analysis), a single score was computed for each question by subtracting the asynchronous rating from the synchronous rating for the control group and the patient. We then applied the Crawford t-test (Crawford and Garthwaite, 2002), which revealed a significant difference between the controls and the patient for questions 4 (How strong was the feeling that you were located at some distance behind the visual image of the body that you saw?) and 9 (p = 0.037 and p = 0.026, respectively). Visual inspection shows that the patient scored higher in the asynchronous than in the synchronous condition for question 4 (no significant difference between conditions was found for the control group on this question) and higher in the synchronous than the asynchronous condition on question 9 (no significant difference between the two conditions for the control group on this question). The patient did not differ from the controls on illusory touch and self-identification (questions 1–3). A single score was also computed for the MBD analysis, which showed no significant difference between the controls and the patient (p = 0.66). There was no difference between the synchronous and the asynchronous conditions for the control participants (p = 0.37). We also collected the patient’s free reports during the experiment. During the synchronous condition the patient reported a tingling sensation in his legs and lower back. He also felt as though his legs were lighter and going upwards. The sensation began shortly after the beginning of the stroking and lasted for a short period. When the condition was repeated the same sensation was experienced and was reported again only in the synchronous condition, but this time with much lower intensity. With respect to the virtual body, the patient felt as though he was looking at a body above him, but during the period of the tingling sensation he felt as though he was slipping under the virtual body (his legs moving upwards and above the feet of the virtual body). He reported that this sensation resembled in some way (but at weaker intensity) the sensations he has during OBEs. The asynchronous condition did not yield any of these sensations. 3.3. Experiment 3: Combining FBI and Optic Flow. Pilot Experiment 3.3.1. Experimental Setup and Procedure In order to further study the role of vestibular cues and visuo-vestibular combination we conducted an exploratory experiment combining the classical FBI (as described above) with an optic flow stimulus (a flow of randomly distributed white dots simulating translation at a speed of approximately 30 cm/s). Again, synchronous and asynchronous conditions were administered in conjunction with optic flow moving either towards (i.e., the direction and

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acceleration of the optic flow stimulus was compatible with the direction of physical gravity) or away (i.e., the direction and acceleration of the optic flow stimulus was incompatible with the direction of physical gravity) from the patient. 3.3.2. Results. Free Report First, we tested the condition where the optic flow was moving towards the patient. During this manipulation the patient again felt a tingling sensation only during the synchronous condition but this time it was stronger and was felt in the whole body. The patient reported that this sensation of lightness (but not floating) and “diminution of physical sensation” resembled feelings he has after his OBEs. During the asynchronous condition he felt as though he was standing and looking straight ahead at a body in front of him. Upon repetition of the same conditions (but with the direction of the flow away from the patient) the same feelings was experienced but much weaker. 4. Discussion We report a patient with a right peripheral vestibular deficit (objectified by the rotatory pendular and the bithermal caloric tests) associated with OBEs and a deficit in integrating visuo-vestibular self-motion stimuli. In addition, the patient experienced illusory floating, especially when experimentally applied visuo-tactile mismatch was associated with optic flow, although illusory touch and self-identification were experienced in similar strength as control subjects. Here, we discuss the present case with respect to the importance of vestibular signals and especially abnormal integration of visual and vestibular information in OBEs and develop an extended model of bodily disintegration in OBEs including cortical, subcortical, and peripheral sensory mechanisms with respect to what has been proposed previously (Blanke, 2012; Blanke et al., 2004). During his OBE the patient experienced all three key elements of OBEs, namely, disembodiment, autoscopy, and elevated first-person perspective from the disembodied location (Alvarado, 2000; Blackmore, 1987; Blanke et al., 2004; Brugger et al., 1997; Terhune, 2009). Interestingly, the present patient also reported other sensations that have been described in patients with OBEs of cortical origin. Thus, he reported the sensation of free falling in darkness (i.e., Blanke et al., 2002) as well as vection and vertigo (Blanke et al., 2004; Devinsky et al., 1989) that were associated (during the OBE) with sensations of flying, elevation, and lightness (e.g., Green, 1968). The latter sensations are characteristic of many OBEs and are generally classified as illusory vestibular sensations (Blanke and Dieguez, 2009). Here, we extend these observations of abnormal vestibular-visual processing in OBEs by providing experimental

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evidence for altered visual-vestibular integration. By testing the patient in a paradigm of visuo-vestibular integration we investigated his capacity of multisensory visuo-vestibular integration for the estimation of self-motion. Previous research has shown that healthy subjects (Butler et al., 2010; Fetsch et al., 2009; Prsa et al., 2012) optimally integrate such visual and vestibular stimuli, which results in improved performance levels for combined visuo-vestibular self-motion cues. Such optimal combination of visuo-vestibular cues (reduction of noise and variability inherent to the stimulus by combining multiple information sources) occurs quickly and effortlessly in healthy individuals. However, we found no evidence for such integration in the present patient, although his unimodal vestibular and visual thresholds were within the previously reported range (Prsa et al., 2012). It should be noted that the control subjects were not age-matched. Although, previous research does not point to an age-related decrease in multisensory integration (Cyran et al., 2015; Mozolic et al., 2012) we can thus not exclude that this difference is caused by age-related differences. For rotations in the ipsi- and contralesional directions the patient’s bimodal thresholds were not improved (i.e., not lower) as compared to the best single cue threshold (and also significantly different form optimality for ipsilesional direction), showing that the patient does not benefit from the simultaneous presence of two self-motion cues. This is, to our knowledge, the first experimental evidence for disintegration between bodily space (as represented by vestibular body-related information) and extracorporeal space (as represented by vision) that has previously been hypothesised to lead to OBE (Bünning and Blanke, 2005) together with the disintegration of bodily related senses (vision, proprioception, tactile perception). We suggest that this latter disintegration is also present in our patient for the reasons presented below. Thus, the impairment of the right peripheral vestibular function could have impacted visual and somatosensory processing early on in the computation stream already at the level of the brainstem, because vestibular nuclei are multisensory in nature and contain cells responding to vestibular, visual and somatosensory stimuli (Lopez, 2013; Waespe and Henn, 1978); it has, for example, been shown that peripheral vestibular damage increases the number of neurons in the vestibular nuclei that respond to proprioceptive stimuli (Jamali et al., 2014). Although weak, there is also a possibility that the vestibular dysfunction in our patient is due to a selective lesion at the level of the vestibular nuclei (Dieterich and Brandt, 2015), thus strengthening the hypothesis of a disintegration process at the level of the brainstem. It is also known that peripheral vestibular loss adversely affects the vestibular–ocular reflex and the processing of visual motion (Smith and Curthoys, 1989). Faulty and conflicting vestibular signals at the level of the brainstem might thus alter the processing of the visual, proprioceptive and somatosensory signals. Alternatively, an integration deficit could also be caused by interference at the level

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of the cortex, as visual, vestibular and somatosensory areas overlap in the socalled parieto-insular vestibular cortex (PIVC) (Bremmer et al., 2002; Grüsser et al., 1990b; Guldin and Grüsser, 1998) or other somatosensory-vestibular cortical regions (Lopez and Blanke, 2011). In support of these changes in the processing of bodily multisensory signals the patient described generalised paraesthesias associated with his OBEs, also induced during our FBI manipulation. The visuo-tactile FBI paradigm creates a visuo-tactile conflict between the seen and felt position of one’s body, and illusory own body perceptions during the FBI occur by resolving this conflict through the attribution of the felt position to the seen position, i.e., the experience of one’s body in the position of the seen virtual body (mimicking, to a certain extent, an OBE) (Ionta et al., 2011a; Lenggenhager et al., 2007; Pfeiffer et al., 2013, 2014). We further note that only in the patient did the visuo-tactile stimulation during the FBI evoke sensations that closely resemble the sensations accompanying his OBEs: floating, tingling, lightness. Moreover, he experienced changes in selflocation [either as elevated self-location in a supine or standing (90° rotated) position]. Especially these latter changes are absent in healthy subjects or are only induced in rare subjects after prolonged stimulations and rest periods with completely fixed head position in FBI induced during fMRI data acquisitions (Ionta et al., 2011a). Although we did not provoke a full-blown OBE in the present patient, the experimentally induced experiences (not reported by control subjects) and the associated vestibular sensations as well as the spontaneously felt changes in self-location suggest that the current system may potentially induce OBEs in selected subjects by exposing them simultaneously to conflicting visuo-tactile and visuo–vestibulo-tactile conflicts. The amplification of such conflicts [as, for instance, during bodily paralysis during REM sleep (see below)] might further boost the possibility of an OBE. Several studies report a link between sleep-related phenomena and out-of-body experiences and both processes have been linked to the brainstem sleep centres. Previous reports have claimed that in healthy participants OBEs mostly occur during sleep (Greenhouse, 1975; Poynton, 1975) and, interestingly, during sleep paralysis [a generally short conscious state at sleep onset or offset during which the subject is awake but can neither move nor speak (Dahlitz and Parkes, 1993; Hishikawa and Shimizu, 1994)]. OBEs have also been reported in the phases of sleep transition (both hypnagogic and hypnopompic phases) and persons with such OBEs had significantly more paradoxical (rapid eye-movement, REM) sleep intrusions in these transition phases (Cheyne and Girard, 2009; Cheyne et al., 1999). Further pointing to the link between OBEs and sleep is the presence of OBEs in patients with narcolepsy (a disorder characterised by a disrupted sleep–wake cycle with frequent REM sleep intrusions during the day): the frequency of OBEs has been reported to decrease with efficient treatment of narcolepsy (Nelson et al.,

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2007). Muscle atonia for the entire body observed during REM sleep and sleep paralysis are thus associated with the absence of movement as well as tactile and proprioceptive afferent signals. Finally, we note the case of an OBE in a patient with a cervical spinal cord lesion having severe somatosensory loss of nearly the entire body (Overney et al., 2009). This case is also compatible with the notion that lack of somatosensory signals from the body facilitates the occurrence of OBEs. In conclusion, in the present patient the alteration of vestibular signals caused by the unilateral peripheral vestibular deficit may have further enhanced the disintegration of multisensory bodily signals during this phase of the sleep cycle. Unfortunately, no EEG or polysomnography recordings were collected in the present patient, which could have provided additional markers of the patient’s sleep cycles allowing to compare changes in neural activity before and after vestibular physiotherapeutical training. Next to these classical elements of OBEs (disembodiment, elevated firstperson perspective, autoscopy, and vestibular sensations), the patient also described more complex experiences during his OBEs. These were characterised by lucid dreaming as well as more distant states of disembodiment and selflocations, as well as the experiences of voluntary control to induce and to alter the content of the OBE. OBEs and vestibular experiences have also been linked in the past to lucid dreaming (Noreika et al., 2010). Dreams involving vestibular sensations (flying, falling) are associated with lucid dreaming, and a correlation has been reported between both dream types (Gackenbach, 1988; Hunt, 1989; Schönhammer, 2004). In addition, individuals with a higher sensitivity to caloric vestibular stimulation were reported to have a higher frequency of lucid dreams (Gackenbach et al., 1986); and sleeping while receiving vestibular stimulation (i.e., a rocking hammock) was reported to increase personality variables such as self-reflectiveness, lucidity mentation, vestibular sensation, and dream bizarreness in healthy subjects (Leslie and Ogilvie, 1996). Interestingly, next to brainstem mechanisms (involved in REM-phase and dreaming), lucid dreaming has also been associated with parieto-temprooccipital cortex (Dresler et al., 2012), hinting towards a common functional and neural mechanism, at least partly, for these two altered states of selfconsciousness (for discussion see also Windt and Metzinger, 2007; Windt and Noreika, 2011). Apart from lucid dreaming, the presence of other complex sensations during OBEs has also been previously highlighted (Cheyne and Girard, 2009). Thus, combined vestibular (e.g., flying, floating, falling) and illusory displacement sensations (e.g., walking, moving one’s limbs) can be part of OBEs and may rarely include feelings of controlled illusory self-locations to more distant places. Our patient reported not only the experience of illusory walking of the disembodied self in his room, but also mentioned that on some occasions such changes in self-location also involved farther locations such as his neighbourhood. Such experiences are mostly reported by healthy subjects

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that frequently have OBEs (Green, 1968). It is possible that such complex experiences are associated with repeated OBEs as subjects get used to their OBEs and experience some form of control over them. The combination of lucid dreams and OBEs as well as the curiosity of the patient towards these experiences and his desire to explore (the patient kept a dream diary and searched for related literature) might increase the richness and phenomenology of the oneiric activity. These observations might also explain the first early OBE in our patient. Indeed, the patient reports having frequent nightmares around the age when his first OBE occurred (∼11–12 years), possibly suggesting early disturbances of the sleep cycle and of related brainstem mechanisms. We propose that the vestibular dysfunction amplified these processes (possibly through interference at the level of the brainstem as described above) thus producing frequent and phenomenologically rich OBEs. We suggest that several factors have to converge in order to give rise to complex OBEs, that is, OBEs that are associated with complex phenomena beyond classical OBEs reported by the majority of subjects. We argue that changes in bodily processing (motor, somatosensory, and vestibular signals) at the level of the brainstem are important to induce such complex OBEs and that such changes may be due to spinal cord damage (Overney et al., 2009), sleep disorders (Nelson et al., 2007; Osis and Mitchell, 1977; Sheils, 1978) or a peripheral vestibular lesion, as in the present patient. These alterations would result in significant deficits of body-related input as during muscle atonia or tetraplegia, or a significant distortion of these signals, for instance, at the level of multisensory vestibular nuclei (or at higher similar multisensory centres in thalamus or cortex — Lopez and Blanke, 2011). We argue that next to these strong deficits in full-body related processing, brainstem interference with sleep and dream-related mechanisms may further enhance the intensity and complexity of the OBE. Further upstream this would result in incomplete/altered input to multisensory cortical regions that process body related information, i.e., regions in the parietal, frontal, and temporo-parietal cortex. In order to form a coherent representation about the position of one’s body in space the brain has to weigh the incoming sensory signals and either combine them or discard the ones that appear unreliable. Being the core area for integrating visual, tactile and proprioceptive information within one reference frame (Calvert et al., 2000) and for other aspects of own body processing, regions within the temporo-parietal junction [with regions such as the ventral intraparietal area (VIP), parietoinsular vestibular cortex (PIVC), medial superior temporal region (MST) — in humans, the posterior parietal and insular cortices] are key candidates for such altered processing and are also part of the ‘vestibular cortex’ (Fasold et al., 2002; Guldin and Grüsser, 1998; Lopez and Blanke, 2011; Lopez et al., 2012). Importantly, in patients with spinal cord

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damage (Overney et al., 2009), sleep disorders (Nelson et al., 2007; Osis and Mitchell, 1977; Sheils, 1978) or a peripheral vestibular lesion (as the present patient) alteration of integration at the cortical level is accompanied by additional disintegration and lacking bodily signals at the level of multisensory brainstem centres. In support of this proposal, the onset of vestibular symptoms in the present patient coincided with the time period when he began experiencing frequent lucid dreams and OBEs. In conclusion, the present case report provides experimental evidence for a double disintegration process at the basis of OBEs. It also shows that at least for some OBEs multisensory disintegration most probably occurs both at the level of the brainstem and the temporo-parietal junction, regions where visual, vestibular, somatosensory and proprioceptive information should combine in order to allow adequate self-motion and self-location perception. Acknowledgements MK and OB were supported by EU FP7 Project VERE WP1, and additionally supported by the Swiss National Science Foundation and the Bertarelli foundation. References Alvarado, C. S. (2000). Out-of-body experiences, in: Varieties of Anomalous Experience: Examining the Scientific Evidence, E. Cardeña, S. J. Lynn and S. Krippner (Eds). American Psychological Association, Washington, DC, USA. Avillac, M., Hamed, S. B. and Duhamel, J.-R. (2007). Multisensory integration in the ventral intraparietal area of the macaque monkey, J. Neurosci. 27, 1922–1932. Berthoz, A., Pavard, B. and Young, L. (1975). Perception of linear horizontal self-motion induced by peripheral vision (linearvection) basic characteristics and visual–vestibular interactions, Exp. Brain Res. 23, 471–489. Blackmore, S. J. (1982). Out-of-body experiences, lucid dreams, and imagery: two surveys, J. Am. Soc. Psych. Res. 76, 301–317. Blackmore, S. (1987). Where am I? Perspectives in imagery and the out-of-body experience, J. Ment. Imagery 11, 53–66. Blanke, O. (2012). Multisensory brain mechanisms of bodily self-consciousness, Nat. Rev. Neurosci. 13, 556–571. Blanke, O. and Arzy, S. (2005). The out-of-body experience: disturbed self-processing at the temporo-parietal junction, Neuroscientist 11, 16–24. Blanke, O. and Dieguez, S. (2009). Leaving body and life behind: out-of-body and near-death experience, in: The Neurology of Consciousness: Cognitive Neuroscience and Neuropathology, S. Laureys and G. Tononi (Eds), pp. 303–325. Academic Publishers, London, UK. Blanke, O. and Mohr, C. (2005). Out-of-body experience, heautoscopy, and autoscopic hallucination of neurological origin: implications for neurocognitive mechanisms of corporeal awareness and self-consciousness, Brain Res. Rev. 50, 184–199.

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Vestibular Function and Depersonalization/Derealization Symptoms Kathrine Jáuregui Renaud ∗ Unidad de Investigación Médica en Otoneurología, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Colonia Doctores, CP 06720, México D.F.

Abstract Patients with an acquired sensory dysfunction may experience symptoms of detachment from self or from the environment, which are related primarily to nonspecific symptoms of common mental disorders and secondarily, to the specific sensory dysfunction. This is consistent with the proposal that sensory dysfunction could provoke distress and a discrepancy between the multi-sensory frame given by experience and the actual perception. Both vestibular stimuli and vestibular dysfunction can underlie unreal experiences. Vestibular afferents provide a frame of reference (linear and angular head acceleration) within which spatial information from other senses is interpreted. This paper reviews evidence that symptoms of depersonalization/derealization associated with vestibular dysfunction are a consequence of a sensory mismatch between disordered vestibular input and other sensory signals of orientation. Keywords Vestibular, depersonalization, derealization

1. Introduction To produce a unified, coherent representation of the outside world, the integration of information from different sensory systems is essential. This paper reviews evidence on the perception of unreality as a consequence of sensory dysfunction, particularly dysfunction of the vestibular system. A summary on spatial orientation and body representation is provided, with concepts on the perception of unreality, to augment the literature available on the relationship between sensory deficits and symptoms of depersonalization/derealization. *

E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_014

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2. Spatial Orientation The vestibular system is the main sensory organ that transduces head orientation in space. Since graviceptors are primarily required for the perception of the upright, vestibular afferents provide a frame of reference within which spatial information from other senses may be interpreted. Accordingly, to facilitate locomotion, head acceleration and velocity signals are centrally represented in a network that is organized within space coordinates and provides a common reference for multisensory integration (Hess, 2001). Patients with vestibular disease may experience illusions of self-movement or movement of the environment and false perceptions of orientation (Bender, 1965; Clément et al., 2009; Page and Gresty, 1985). Similar experiences of ‘spatial disorientation’ are encountered in the aerospace environment (Adams et al., 2014; Poisson and Miller, 2014), particularly when unusual motion challenges the vestibular system’s ability to transduce orientation so that the pilot misperceives the motion of his aircraft (Benson, 1973). Disorientation in flight not only compromises the pilot’s control of his aircraft, but may also result in experiences of derealization, termed the ‘break-off phenomenon’ (Benson, 1973; Clark and Graybiel, 1957; Sours, 1965). Apart from disorders in the aviator’s perception of attitude and motion of the aircraft, derealization incidents may vary from altered perception of the orientation of the aviator’s body with respect to the aircraft or the surface of the earth, to feelings of detachment and isolation, usually when flying straight and level at an altitude of more than 30 000 ft (9150 m), in conditions where the horizon is ill defined and there is a relative constancy in the aviator’s sensory environment (Benson, 1973). During spaceflight, adaptive changes in how the brain integrates vestibular signals with other sensory information can lead to spatial disorientation, impaired movement coordination, vertigo, and perceptual illusions after return to earth (Clément and Wood, 2014). The disorientation phenomena may be explained by the existence of an internal estimation of the gravitational vertical. In microgravity it is still maintained, but incorrectly updated. The otolith organs signal both head translation and head tilt relative to gravity, the stimulus profile and concurrent afferents allow discrimination between the two types of movement (Angelaki and Dickman, 2003). During adaptation to weightlessness, the sensory feedback anticipated by each movement is not consistent with the information given by the otolith organs. The nervous system reinterprets these signals to represent fore–aft or left–right linear acceleration, rather than pitch or roll of the head with respect to the vertical plane (Young et al., 1984). This, in turn, leads to illusions, and probably also facilitates space motion sickness (Glasauer and Mittelstaedt, 1998). Although a fully adequate theory of motion sickness is not presently available, it is recognized that when-

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ever there are deviations or variations from a 1G background force of the earth, motion sickness may result because of the disruption of vestibulo-ocular, optokinetic, and colic reflexes (Lackner, 2014). 3. Body Representation The pursuit of behavioral goals requires an integrated neural representation of the body and of the space around the body (Popper and Eccles, 1977). Among the diverse conceptions of body representation, Head and Holmes (1911) provided the classic description of different ‘schemata’ representing the body, including the postural schemata containing a continuously updated representation of current body posture. In this context, body posture can be defined as the orientation of the body and its parts with respect to the earth-vertical (gravitational vertical), whereas position designates the orientation of the body parts to each other (Mittelstaedt, 1998). The brain generates a coherent spatial representation of the body as a whole, the body parts, and the body as related to the external world by integrating multisensory signals. Although representation of the body and, to some extent, the environment is constructed from visual information through inspection (Critchley, 1950), proprioceptive information is combined with visual, tactile and motor feedback signals to represent the body (Maravita et al., 2003). Primary and secondary somatosensory cortex activity can be modulated by spatial and tactile attention and by visual cues (Tamè et al., 2012; Taylor-Clarke et al., 2002). The orientation of the visual world and the head is mainly perceived through vision and the vestibular system, and the posture of the trunk is mainly perceived through sense organs in the trunk itself (Mittelstaedt, 1998). However, there is no single brain area responsible either for maintaining a representation of the body or of space. Rather they are the result of a network of interacting cortical and subcortical centers (Holmes and Spence, 2004). Abnormalities in the sensory cortex and areas responsible for an integrated body representation are consistent with the proposal that the inferior parietal cortex is concerned with spatial orientation, visuo-motor and vestibular function (Brandt and Dieterich, 1999; Simeon et al., 2000). The concept of bodily self-consciousness consists of several aspects, including self-location, first-person perspective, self-identification and sense of agency (for review, see Pfeiffer et al., 2014). Evidence suggests that unambiguous self-location and egocentric visuospatial perspective are related to neural activity at the temporo-parietal junction (Blanke et al., 2005). Changes in bodily self-consciousness depend on visual gravitational signals and the experienced direction of the first person perspective depends on the integration of visual, vestibular, and tactile signals, as well as on individual differences in idiosyncratic visuo-vestibular strategies (Pfeiffer et al., 2013). Vestibular pro-

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cessing may serve as a spatial reference for the spatial determinants of bodily self-consciousness (Lopez et al., 2012; Pfeiffer et al., 2013), coding for embodiment and body ownership (Lopez et al., 2008). It also has an influence on the registration of somatosensory input onto a map of the body, but no influence on the stored knowledge about the spatial organization of the body as a physical object (Ferrè et al., 2013). Seeing one’s body in extra-personal space (autoscopic phenomena) is an illusory own body perception that affects the entire body and leads to abnormalities in embodiment as well as body ownership. There are three main forms of autoscopic phenomena: autoscopic hallucinations (Maillard et al., 2004), out-of-body experiences (Blanke et al., 2004) and heautoscopy (Brugger et al., 1994). Autoscopic hallucinations may be due to a visuo-somatosensory deficit, not associated with major deficits in bodily self-consciousness. Outof-body experiences and heautoscopy are frequently associated with pathological sensations of position, movement and perceived completeness of one’s own body, including vestibular sensations, visual body-part illusions and the experience of seeing one’s body only partially (Blanke et al., 2004, 2005). Evidence suggests that disturbed vestibular processing may play a key role in triggering out-of-body experiences (Schwabe and Blanke, 2008), while the abnormal bodily self-consciousness during heautoscopy may be caused by a breakdown of self–other discrimination regarding affective somatosensory experience (Heydrich and Blanke, 2013). 4. The Perception of Unreality Altered perceptions of the self and the environment are termed ‘dissociation phenomena’. Dissociative experiences are common in the general population, they may decline with age, but they are not related to socio-economic status, sex, education, religion, or place of birth (Lambert et al., 2001a; Ross et al., 1991). Depersonalization refers to experiences of unreality, detachment, or being an outside observer with respect to one’s thoughts, feelings, sensations, body or actions, while derealization refers to experiences of unreality or detachment with respect to the surrounding (American Psychiatric Association, 2013). Depersonalization/derealization symptoms may occur on a continuum of circumstances, from healthy individuals under certain situational conditions to neurological and psychiatric disorders (Bancaud et al., 1994; Cassano et al., 1989; Coons, 1998; Lambert et al., 2002). Also, depersonalization/derealization experiences are common under life-threatening stress (Bernat et al., 1998). A community questionnaire survey study in the United States of America reported prevalence rates of 19.1% for depersonalization, 14.4% for derealization and 23.4% for either dissociative experience

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(Aderibigbe et al., 2001). However, when the symptoms become recurrent or persistent the diagnosis of depersonalization/derealization disorder has to be considered. Depersonalization/derealization disorder is a dissociative disorder during which the patient feels as though he or she is detached from the self or from the environment (American Psychiatric Association, 2013). In circa one third of the patients, the disorder is episodic, and each episode may last hours, days, weeks or even months (Baker et al., 2003; Simeon, 2004). The most common, immediate precipitants of the disorder are severe stress, depression, panic, marijuana and hallucinogen ingestion (Simeon, 2004). Mood, anxiety and personality disorders are often comorbid with depersonalization disorder. However, a functional magnetic resonance imaging (fMRI) study has shown evidence of separate brain systems for each trait while performing tasks of facial emotion processing, and its correlation with self-report scales of somatization, depression, dissociation and anxiety (Lemche et al., 2013). The main differences between patients with depersonalization disorder and control subjects were: • for somatization in the right temporal operculum and ventral striatum, • for symptoms of depression in the right pulvinar and left amygdala, • for dissociation in the left mesial inferior temporal gyrus and left supramarginal gyrus, • for state anxiety in the left inferior frontal gyrus and para-hippocampal gyrus, and • for trait anxiety, in the right caudate head and left superior temporal gyrus. Phenomenological overlaps with the unawareness of ownership of one’s body parts (asomatognosia) suggest that depersonalization might result from parietal mechanisms disrupting the experience of body ownership and agency (Sierra et al., 2002). Likewise, phenomenological similarities between the inability to become emotionally aroused by visual cues (visual hypoemotionality) and derealization suggest that a disruption of the process by means of which perception becomes emotionally colored may be an underlying mechanism in both conditions (Sierra et al., 2002). Using event related fMRI, compared to control subjects, patients with depersonalization disorder showed a decrease in subcortical limbic activity as well as an increase in dorsal prefrontal cortical activity to emotionally arousing stimuli (Lemche et al., 2007). Although both higher order association areas and presumptive unisensory areas of the cerebral cortex may be multisensory in nature, evidence suggests that the multisensory processes in the association cortex may primarily compute a veridical representation of the outside world (Ghazanfar and Schroeder,

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2006). In a Positron Emission Tomography study on depersonalization disorder (Simeon, 2000), comparing patients to sex-matched controls, patients showed lower activity in the right temporal region (Brodman areas 22 & 21), bilateral higher activity in the parietal region (Brodman areas 7B & 39) and higher activity in the left occipital region (Brodman area 19). The results indicate that depersonalization may be related to disruptions in functioning along hierarchical sensory association areas responsible for the processing of incoming perceptions against pre-existing brain templates (Simeon, 2004). In patients with Kleine–Levin syndrome, which is characterized by episodes of hypersomnia, cognitive impairment, apathy, derealization and behavioral disturbances, during symptomatic periods, depersonalization/derealization symptoms strongly correlate with hypoperfusion of the right and left parietotemporal junctions, which are involved in cross-modal association between somatosensory, auditory and visual information (Kas et al., 2014). 5. Sensory Dysfunction and Depersonalization/Derealization Symptoms Early studies conceived of depersonalization disorder as a disturbance of the primary senses (Sierra and Berrios, 1997). Sensory dysfunction may provoke a discrepancy between the multi-sensory frame given by experience and the actual perception. In patients with depersonalization, across modalities, visual unreality may be the most frequent, followed by auditory, tactile, gustatory, and olfactory unreality (Sierra and Berrios, 2001). Using self-report measures of imagery ability in relation to a range of symptoms, the assessment of patients with depersonalization disorder compared to age/sex matched control subjects, showed a correlation between an impaired ability to generate visual images, particularly images pertaining to the self and other people as opposed to objects, with symptoms of depersonalization, other dissociative symptoms and depressed mood (Lambert et al., 2001b). Inversely, patients with an acquired sensory dysfunction may experience symptoms of depersonalization/derealization (Jáuregui-Renaud, 2008a; Lipsanen et al., 1999). The evaluation of non-clinical volunteers has shown that subjects with visual distortions can have higher scores for derealization, identity alteration, and depersonalization (Lipsanen et al., 1999). It is plausible that people with visual impairment are more likely to experience problems with functioning, which in turn leads to depression. However, controlling for potential confounding factors, particularly activities of daily living, markedly attenuated the association between visual impairment and depression (Evans et al., 2007). Additionally, a history of corrected visual acuity for refraction errors in healthy subjects may have no influence on reporting symptoms of depersonalization/derealization, while in patients with hearing loss and those with vestibular disease, corrected visual acuity may be related to the report

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of depersonalization/derealization symptoms (Jáuregui-Renaud et al., 2008a). This finding could be explained by considering that subjects with no other sensory dysfunction, than the corrected visual acuity, would have a consistent perception through all other senses, while in patients who have a sensory dysfunction, this ‘corrected’ vision could represent a second source of distortion to perceive the environment (Jáuregui-Renaud et al., 2008a). Compared to control subjects, patients with acquired hearing-loss, peripheral vestibular disease or bilateral retinal disease may have a higher frequency of symptoms of depersonalization/derealization (Jáuregui-Renaud et al., 2008a). Patients with retinal disease and those with vestibular disease may show higher depersonalization/derealization scores than patients with hearing loss and control subjects. The type of sensory dysfunction as well as the evidence of symptoms of common mental disorders (GHQ12 by Goldberg and Williams, 1988) may have an influence on the frequency and severity of symptoms of depersonalization/derealization assessed by self-report (questionnaire by Cox and Swinson, 2002). This finding is consistent with the notion that sensory dysfunction could provoke both, distress and a discrepancy between the multi-sensory frame given by experience and the actual perception (JáureguiRenaud et al., 2008a; Sno and Draaisma, 1993). 6. Vestibular Dysfunction and Depersonalization/Derealization Symptoms Increasing evidence supports that vestibular information underlies not only reflex responses but higher level processes, including cognition, emotion and the sense of self through information regarding self-motion and self-location (for reviews, see Carmona et al., 2009 and Smith and Darlington, 2013). The coexistence of vestibular and psychiatric symptoms is supported by clinical evidence and the relationship between vestibular pathways and the regions implicated in cognitive and emotion processing in the central nervous system (for review see Gurvich et al., 2013). In a sample of 547 patients recruited from a specialized interdisciplinary treatment center with organic and non-organic vertigo/dizziness, half of those with an organic cause, particularly patients with vestibular paroxysmia or vestibular migraine, had a current psychiatric comorbidity, with more depressive, anxiety and somatization symptoms, and lower psychological quality of life compared with patients without psychiatric comorbidity (Lahmann et al., 2014). In the general population, a survey of 1287 persons using standardized selfrating questionnaires on dizziness, depersonalization and mental distress identified depersonalization as a significant, independent predictor for dizziness and impairment by dizziness (Tschan et al., 2013). Patients attending neurootology clinics may report psychological symptoms (Eagger et al., 1992;

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McKenna et al., 1991), including unspecific feelings of unreality (Grigsby and Johnston, 1989), as well as symptoms of depersonalization/derealization (Jáuregui-Renaud et al., 2008a; Kolev et al., 2014; Sang et al., 2006). At the turn of the 20th century, the relationship between vestibular symptoms and depersonalization was described by Schilder (1964) and, several decades ago, the tendency for vestibular stimulation to provoke feelings of unreality was described in normal, healthy subjects undergoing caloric stimulation (Cappon and Banks, 1961, 1965). In a more recent study (Sang et al., 2006), healthy subjects reported that caloric stimulation provoked symptoms of depersonalization/derealization that they had not previously experienced, and many of these symptoms were similar to the ones reported by vestibular patients. Reassuringly, in patients with bilateral vestibular loss, caloric stimulation induced almost no symptoms. Vestibular dysfunction may underlie unreal experiences, such as ‘Dizziness’ and ‘Feeling as if walking on shifting ground’; these symptoms are, by definition, unreal experiences since the body is not spinning and the ground is not moving. In patients with peripheral, vestibular disease, symptoms of depersonalization/derealization can be related to both spatial disorientation and symptoms of common mental disorders (Gómez-Alvarez and JáureguiRenaud, 2011; Jáuregui-Renaud et al., 2008a, b; Sang et al., 2006). The more erroneous the spatial reorientation estimates are, the more the patient experiences depersonalization/derealization symptoms (Jáuregui-Renaud et al., 2008b). Even more, patients with peripheral vestibular dysfunction and recent balance symptoms may report symptoms of detachment from reality more frequently and more severely than patients without recent balance symptoms (Jáuregui-Renaud et al., 2008a, b), and those with incomplete recovery may remain disoriented (Gómez-Alvarez and Jáuregui-Renaud, 2011). This finding is consistent with recent evidence showing that, after an acute unilateral vestibular lesion, vestibulo-ocular and vestibulo-perceptual thresholds essentially reflect the sensitivity of the fused peripheral receptors; while for supra-threshold stimuli, time constants and duration of the vestibulo-ocular and vestibuloperceptual responses are reduced, asymmetrically for the vestibulo-ocular and symmetrically for perception; at recovery, vestibulo-ocular responses remain shortened and asymmetric, while vestibulo-perceptual responses normalize (Cousins et al., 2013). A vestibular deficit may have an impact on the multisensory mechanisms involved with perceiving orientation in space. In order to interact with the environment, a frame of reference should be recovered. To assess the correlation between the results of simple tests of updating spatial orientation (JáureguiRenaud et al., 2008b) and the occurrence of common psychological symptoms (questionnaires by Goldberg and Williams, 1988; Hamilton, 1960; and Zung, 1971) with depersonalization/derealization symptoms (questionnaires by Carl-

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son et al., 1993a, and by Cox and Swinson, 2002), a three months follow-up study was performed in patients with acute vestibular neuritis. During the first days, patients were disoriented and reported depersonalization/derealization symptoms and depression symptoms, including attention/concentration difficulties. During the following weeks, updating spatial orientation improved, most of the symptoms of instability disappeared (questionnaire by JáureguiRenaud et al., 2003), disability declined (handicap inventory by Jacobson and Newman, 1990) and the frequency and severity of the depersonalization/derealization symptoms decreased (questionnaire by Cox and Swinson, 2002). The larger the decrease on the depersonalization/derealization score was, the larger the improvement on the reorientation estimate and on the symptoms of instability. In this study, symptoms of anxiety were infrequent and no evidence of an interaction between depersonalization/derealization symptoms and symptoms of anxiety were observed. However, since symptoms of anxiety, panic or agoraphobia frequently coexist with symptoms of depersonalization (Cassano et al., 1989; Putnam et al., 1996), the assessment of patients with vestibular disease with/without anxiety has shown that in patients with anxiety the frequency and severity of the symptoms of depersonalization/derealization may increase (Kolev et al., 2014). Interestingly, although a strong loading on derealization symptoms was found by the depersonalization/derealization questionnaire by Cox and Swinson (2002) and by the dissociative experiences scale by Carlson et al. (1993a), patients reported a low frequency of other type of dissociative experiences explored by the questionnaire by Carlson et al. (1993a). The depersonalization/derealization questionnaire by Cox and Swinson (2002) was developed for use with clinically anxious patients to self-report depersonalization/derealization symptoms. On the other hand, the dissociative experiences scale inquires about the frequency of a variety of dissociative experiences, including amnesia, depersonalization, derealization, absorption, and imaginative involvement, but the scale will reliably measure only the general dissociation factor (Carlson and Putnam, 1993b). The low frequency of general dissociative experiences in patients with acute, peripheral, vestibular disease suggests that their feelings of unreality may be related to more specific deficits on the perception of surrounding and self-consciousness, more than to the alterations in awareness and memory for events that are related to detachment on dissociation. However, among the symptoms of depersonalization/derealization observed during the acute phase of a vestibular deficit, the occurrence of symptoms related to attention/concentration and its decrease during follow-up (GómezAlvarez and Jáuregui-Renaud, 2011), are consistent with cross-sectional studies showing evidence of an association between vestibular function and difficulty concentrating (Yardley et al., 1998), as well as with reports on the

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adverse effect of vestibular dysfunction on attention processes (Redfern et al., 2004; Smith et al., 2005; Talkowski et al., 2005). These results are in agreement with the hypothesis that the requirement of cognitive resources involved in successful processing and integration of vestibular information would be increased in patients with vestibular dysfunction, and the integration of vestibular information could be associated to the cognitive resources required for adequate spatial orientation (Talkowski et al., 2005). In conclusion, interaction with the environment requires continuous updating of the relationship of the body and the body parts with the surrounding. The vestibular system has widespread connections with multisensory cortical networks, and may provide a frame of reference within which spatial information from other sources is interpreted. A false sense of orientation arising either from inappropriate vestibular signals or from disordered central interpretation of vestibular information may interfere with an accurate representation of body orientation (Saj et al., 2013) and with updating orientation during motion (Gómez-Alvarez and Jáuregui-Renaud, 2011; Jáuregui-Renaud et al., 2008b). This, in turn, can underlie the perception of unreality, which may decrease with recovery, but persist whenever the inappropriate signals interfere with the representation and continuous updating of self-orientation in the environment. References Adams, M. S., Curry, I. P. and Gaydos, S. J. (2014). British army air corps accidents, 1991– 2010: a review of contrasting decades, Aviat. Space Environ. Med. 858, 852–856. Aderibigbe, Y. A., Bloch, R. M. and Walker, W. R. (2001). Prevalence of depersonalization and derealization experiences in a rural population, Soc. Psychiatry Psychiatr. Epidemiol. 3, 63–69. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Publishing, Arlington, VA, USA. Angelaki, D. E. and Dickman, J. D. (2003). Gravity or translation: central processing of vestibular signals to detect motion or tilt, J. Vestib. Res. 13, 245–253. Baker, D., Hunter, E., Lawrence, E., Medford, N., Patel, M., Senior, C., Sierra, M., Lambert, M. V., Phillips, M. L. and David, A. S. (2003). Depersonalization disorder: clinical features of 204 cases, Br. J. Psychiatry 182, 428–433. Bancaud, J., Brunet-Bourgin, F., Chauvel, P. and Halgren, E. (1994). Anatomical origin of déjà vu and vivid ‘memories’ in human temporal lobe epilepsy, Brain 117, 71–90. Bender, M. B. (1965). Oscillopsia, Arch. Neurol. 13, 204–213. Benson, A. J. (1973). Spatial disorientation and the “break-off phenomenon”, Aerosp. Med. 44, 944–952. Bernat, J. A., Ronfeldt, H. M., Calhoun, K. S. and Arias, I. (1998). Prevalence of traumatic events and peritraumatic predictors of posttraumatic stress symptoms in a nonclinical sample of college students, J. Trauma Stress 11, 645–664. Blanke, O., Landis, T., Spinelli, L. and Seeck, M. (2004). Out-of-body experience and autoscopy of neurological origin, Brain 127, 243–258.

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The Moving History of Vestibular Stimulation as a Therapeutic Intervention Luzia Grabherr 1,∗ , Gianluca Macauda 2,∗ and Bigna Lenggenhager 2,3,∗,∗∗ 1

Sansom Institute for Health Research, University of South Australia, Adelaide, Australia 2 Neuropsychology Unit, Department of Neurology, University Hospital Zurich, Zurich, Switzerland 3 Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

Abstract Although the discovery and understanding of the function of the vestibular system date back only to the 19th century, strategies that involve vestibular stimulation were used long before to calm, soothe and even cure people. While such stimulation was classically achieved with various motion devices, like Cox’s chair or Hallaran’s swing, the development of caloric and galvanic vestibular stimulation has opened up new possibilities in the 20th century. With the increasing knowledge and recognition of vestibular contributions to various perceptual, motor, cognitive, and emotional processes, vestibular stimulation has been suggested as a powerful and non-invasive treatment for a range of psychiatric, neurological and neurodevelopmental conditions. Yet, the therapeutic interventions were, and still are, often not hypothesis-driven as broader theories remain scarce and underlying neurophysiological mechanisms are often vague. We aim to critically review the literature on vestibular stimulation as a form of therapy in various selected disorders and present its successes, expectations, and drawbacks from a historical perspective. Keywords Historical perspective, vestibular system, motion device, caloric vestibular stimulation, galvanic vestibular stimulation, treatment

“Nothing happens until something moves.” (Albert Einstein)

* **

All authors contributed equally. To whom correspondence should be addressed. E-mail: [email protected]

© Koninklijke Brill NV, Leiden, 2015

DOI:10.1163/9789004342248_015

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1. Introduction Artistotle’s famous description of the five senses (i.e., sight, audition, smell, touch and taste) has not only informed lay understanding but also “guided the [scientific] study of perception for two thousand years” (Wade, 2003, p. 151). Although phylogenetically very old (e.g., Goldberg and Fernández, 1984), the vestibular system and its functions were discovered and described only in the 19th century, most prominently by Flourens (1830), Purkinje (1820) and Ménière (1861). Marie Jean Pierre Flourens (1830), for example, observed that pigeons showed oscillatory eye movements and postural impairments after a labyrinthectomy. This finding was surprising and informative, because at that time the anatomy of the labyrinth was known, but its function was attributed to auditory perception. Thus, the labyrinth seemed clearly to be implicated in other ways than previously thought of. Today, the vestibular system, which includes sensors detecting threedimensional linear (otoliths) and angular (semicircular canals) acceleration, is — at least in the scientific community — accepted as a ‘sixth sense’. Its important roles in the control of posture, balance and eye movements have been intensively studied. Besides these more basic functions, the investigation of vestibular contributions extends to various fields of clinical and cognitive neuroscience (for reviews, see, e.g., Gurvich et al., 2013; Lenggenhager and Lopez, 2015; Mast et al., 2014; Palla and Lenggenhager, 2014; Pfeiffer et al., 2014; Smith and Zheng, 2013). Especially the study of the cognitive aspects of vestibular stimulation, though already highlighted by Griffith (1922), has recently gained importance. Despite this new trend, insights and knowledge, especially concerning vestibular cortical representations, are still rather limited compared to other senses (for a brief discussion see, e.g., Mast et al., 2014). Contrasting the late discovery and limited understanding of the neurophysiological mechanisms, vestibular stimulation has often been suggested as a cure for various clinical disorders, and provided some seemingly surprising data suggesting for example increased eye contact in autistic children (Slavik et al., 1984) and the report of an instant and complete cure of hysterical deafness (McKenzie, 1912). In the following, we will describe how vestibular stimulation has been developed and — with varying success — used in therapeutic contexts over more than 2000 years. The advantages of vestibular stimulation as a therapy and its resulting popularity are evident, given that it is usually non-invasive (even if some of the methods used in the early 19th century would nowadays be regarded as torture), rather cheap and easily applicable. Yet, it is often ignored that vestibular stimulation is highly complex because (a) its effects depend on the exact application parameters and (b) vestibular stimulation is never pure, requiring elaborate and well-controlled studies.

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The aim of this review is to outline and critically discuss the use of therapeutic vestibular stimulation in humans in a historical framework. We will first describe the discovery and development of the three main methods of passive vestibular stimulation, i.e., motion devices, caloric vestibular stimulation (CVS) and galvanic vestibular stimulation (GVS). Then, we will review the literature that investigates the effects of vestibular stimulation on various clinical conditions, including sleep difficulties, mood disorders, chronic pain, bodily disorders, schizophrenia, neurodevelopmental and neurodegenerative disorders. Finally, we will provide a short outlook on the potential of vestibular stimulation for cognitive enhancement. It is important to point out that it is by no means possible to cover all the relevant literature from the field within the scope of this review. It thus represents a selection of those topics and studies that seem most relevant and interesting to us. 2. The Discovery and Development of Vestibular Stimulation Techniques for Humans 2.1. Motion Devices Although cradles, which apply a basic form of passive vestibular stimulation, have existed for a very long time (Jütte, 2009), the first documented therapeutic motion devices were probably the so-called ‘lectos pensiles’ (hanging beds), built by ancient Greek physician Asclepiades of Bithynia (Vieth, 1795). Based on his observations, Roman physician Aulus Cornelius Celsus prescribed the ‘lecti suspensi motus’ (floating beds) for setting the body in motion to cure ‘phrenesis’, i.e., ‘madness’ (for a more exhaustive historical overview, see Jütte, 2009). The documentation of motion devices reappeared in the 18th century. Despite the fact that Erasmus Darwin (1801) is typically credited for reintroducing a sketch of a motion device (rotating couch) in his work ‘Zoonomia’ (e.g., Wade, 2005; Wade et al., 2005), it has been argued that it was in fact Christian Gottlieb Kratzenstein and his student Henrico Hövinghoff (see Note 1) who had described and built the ‘centrifuga’, a therapeutic motion device, in the mid-18th century (Jütte, 2009). While Kratzenstein’s work has rarely been cited, the English physician Joseph Mason Cox became famous with the socalled Cox’s chair (see Note 2) that he built according to Darwin’s idea (Wade, 2005; Wade et al., 2005). He used conventional swings, rotating chairs and rotating beds in the treatment of patients with various pathologies of the asylum where he practiced. A short time later, the Irish physician William Saunders Hallaran developed a chair and a bed (see Fig. 1A) that could be rotated up to 100 times per minute (Breathnach, 2010). The use of rotating chairs also fueled scientific theories about the vestibular system (Bárány, 1907). Around 1820, the Czech physiologist Jan Evangelista

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Figure 1. (A) A picture of Hallaran’s bed and chair used for therapeutic purposes in an asylum in the beginning of the 19th century (Hallaran, 1818), (B) the device used by Ernst Mach for experimental purposes (Mach, 1875) and (C) Bárány’s rotating chair that he used for clinical diagnostics (Bárány, 1907).

Purkinje (1820) observed systematic eye movements in psychiatric patients during and after their treatment on a rotating chair. He is therefore often identified as the ‘discoverer’ of the nystagmus (Bárány, 1907; Breathnach, 2010), although post-rotatory eye movements had already been described by Darwin and Wells (Wade, 2000; Wade et al., 2001). A more detailed description of the vestibular system, including the semicircular canals, was later provided by Ernst Mach and Alexander Crum Brown (Wade, 2000). To test the semicircular canals in more detail, Mach (1875) built a chair within a wooden rotatable frame, allowing horizontal and vertical rotations to investigate the effects of rotations as well as visual orientation in tilted positions (Wade, 2005) (see Fig. 1B). Crum Brown (1874), who was more interested in vestibular thresholds for detecting body rotation, developed a revolving stool, which was less elaborate than Mach’s device (Wade, 2005, p. 200). With Robert Bárány (1907, see Fig. 1C), the interest shifted towards the role of eye movements in vestibular disorders and the rotary chair started being used as a diagnostic tool, which it still is today (e.g., Valente, 2007). From the 1920s, Dodge’s experiments to investigate rotation thresholds and habituation to rotation stand out (Dodge, 1923a, b). To perform such experiments he needed very slow accelerating motion devices. With the beginning of aeronautic and manned space programs a few decades later, large-scale centrifuges were built to simulate an increase of gravitational force and to study its influence on human physiology and cognition (e.g., Graybiel and Brown, 1951; Kunkle et al., 1948). But other motion devices, such as a slow rotating room, were also developed for the space program (Graybiel et al., 1960). An extensive list of available motion devices is presented in Guedry and Graybiel (1961). Walsh (1961) used another notable device, which stimulated participants while they were immersed in water in a movable tank. This was done in an effort to reduce the co-involvement of the proprioceptive and somatic

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system as this is one of the important confounds and thus disadvantage of vestibular stimulation through motion devices. Another milestone in the development of modern motion devices was Stewart’s idea of a motion platform with six degrees of freedom, allowing the application of rotations and translations (Stewart, 1965). In contrast to early devices that usually allowed movements around one axis only, on this platform participants can be moved in different directions to stimulate the otoliths and semicircular canals separately or in combination. Nowadays, motion devices are increasingly used for vestibular research (for a review of different ways of stimulating the vestibular system see Palla and Lenggenhager, 2014). The advantage of such devices is that they provide access to precise information about and manipulation of acceleration, acceleration profile and duration of the applied movements. 2.2. Caloric Vestibular Stimulation (CVS) Robert Bárány is also credited for introducing CVS as a diagnostic clinical tool. He discovered that irrigating the external ear canals with warm or cold water elicits eye movements in a predictable fashion (Bárány, 1907; see Fig. 2A for a picture of his bedside setup). In fact, 100 years ago, Bárány (1914) was awarded the Nobel Prize of Medicine for his remarkable contributions (Breathnach, 2010; Lopez and Blanke, 2014; Wade, 2005). Thanks to otologists, who routinely prescribed syringing to remove cerumen, it was already known that syringing with warm or cold water could induce vertigo (Goltz, 1870) and provoke eye movements, while the use of body temperature water and syringing in an upright position does not lead to these symptoms. Bárány described how one day he irrigated the ear of a patient with cold water. As the patient complained about getting ‘giddy’, he used warmer (accidentally too hot) water and noticed that, curiously, the nystagmus changed direction

Figure 2. (A) Bárány’s (1907) bedside caloric test showing (a) rubber bag to collect the water, (b) nozzle for water irrigation, and (c) balloon filled with water (see also Baloh, 2002). (B) Early galvanic stimulation device; here used in order to cure tinnitus (Grapengiesser, 1801).

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(Baloh, 2002). This led him to propose the theory of endolymphatic flow, which is still largely accepted today. It is disputed however, how much his colleagues in Vienna contributed to these developments (see Baloh, 2002 for a detailed account on the controversy surrounding Bárány and the discovery of the caloric test). Importantly, Bárány recognized the value of CVS as a diagnostic tool for peripheral vestibular dysfunctions as it is still used in clinical settings. Bárány himself did not seem to have attributed a therapeutic value to CVS, but such stimulation was later also used in therapeutic settings. Less known is the fact that Bárány (1907) also described the application of galvanic vestibular stimulation (GVS), the history of which we will outline below. 2.3. Galvanic Vestibular Stimulation (GVS) The history of GVS (nicely reviewed in Fitzpatrick and Day, 2004) dates back to the beginning of the 19th century. In the context of Alessandro Volta’s discoveries, experiments with application of currents behind the ears have been described to evoke sensations of vertigo (Augustin, 1803), even if the underlying physiological mechanisms were still not known. This finding, as well as the fact that such stimulation induces disturbances of equilibrium, nystagmus, and the specific sensation of an illusory tilt towards the cathode, has later on been described by various authors (e.g., Hitzig, 1874) and was finally identified by Josef Breuer (1874) as a phenomenon of vestibular origin. GVS has been suggested early on as a therapeutic method, although initially as a treatment for deafness and tinnitus (see, e.g., Rubinstein and Tyler, 2004, for a discussion of the sudden rise and fall of GVS as a cure for auditory deficits, see Fig. 2B for a picture of the setup). While the devices of the first half of the 19th century all used direct current stimulation (thus galvanization), other stimulation methods, for example using alternating current, soon evolved (Rubinstein and Tyler, 2004). Nowadays, it is well-known that GVS, transmitted via two electrodes placed over the mastoid process, stimulates and/or inhibits all peripheral vestibular afferents of both the semicircular canals and the otoliths (Goldberg et al., 1984), and the type of stimulation depends on the current’s flow (e.g., Fitzpatrick and Day, 2004). The device itself has changed only marginally since its early application, and various relatively cheap, safe and simple stimulators are available, usually consisting of two electrodes and an electrical stimulation device that delivers currents in the range 0–3 mA. GVS is now increasingly used in cognitive and neuroscientific research to manipulate vestibular signaling in controlled ways, as — similar to motion devices but unlike CVS — it allows precise timing and coordination with other stimuli (see, e.g., Palla and Lenggenhager, 2014, for a review). Below we will review how GVS has been used as a therapeutic tool for various neurological and psychiatric disorders.

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2.4. Future Directions While becoming more high-tech and elaborate, the stimulation techniques have, in principle, not changed radically over the last decades (see, e.g., Palla and Lenggenhager, 2014, for an illustration of new applications). Nevertheless, for each method, certain trends might be foreseen. Motion devices can — due to technical advances — be controlled much more precisely in terms of type of motion, intensity, acceleration profile, and duration. New research trends point in two directions. On the one hand, laboratories have started to use top-notch motion devices like the MPI CyberMotion Simulator, which allows continuous motion in different axes and for which a big hall had to be constructed (e.g., Barnett-Cowan et al., 2012). Such large motions devices present great opportunities in basic research, but are less convenient for therapeutic purposes. On the other hand, there are trends to develop relatively small, affordable and easy to use therapeutic home devices (see, e.g., Dyk et al., 2008, for a model specifically designed for children), which are more relevant for therapeutic purposes. New methods for caloric vestibular stimulation strive to make its application safer. For instance, air caloric devices are gaining importance (for a discussion of air vs. water CVS, see, e.g., de Barros and Caovilla, 2012). In the same vein, other techniques such as CVS with near infrared radiation (Walther et al., 2011) or wet air (Gudziol et al., 2012) are being investigated. CVS activates the horizontal canal(s) because of the proximity to the external ear canal. It is still debated whether the vertical canals can also be stimulated by CVS (e.g., Ichijo, 2011, 2012; Shen et al., 2013), but if so, it would broaden the possibilities for applications. Particularly, this could (a) allow testing the integrity of the vertical canals and thus be interesting for diagnostic purposes and (b) allow to assess the implication of the vertical canals, for example, in an emotion or cognition paradigm and thus be interesting for basic research. Furthermore, increased safety could allow the use of home devices for prolonged and repetitive stimulation, which has shown to be important in some therapeutic setups (see below). A similar trend towards easier and safer application can be seen for galvanic vestibular stimulation. This technique also appeals to developers of virtual reality applications, who see in it a method to increase the feeling of presence in virtual reality (Maeda et al., 2005). This might also be important for the emerging field of VR-based therapeutic interventions and rehabilitation. In this context, GVS as a ‘remote-control’ has already been used to steer human walking (Fitzpatrick et al., 2006). Apart from such integrative methods, the main progress of GVS over the past might lie in the shift of application and stimulation parameters towards stochastic and sub-threshold galvanic stimulation (see, e.g., Oppenländer et al., in press, for the treatment of visual neglect).

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Such stimulation does not induce the side-effects typically associated with GVS, like pain on the skin (Lenggenhager et al., 2008), therefore allowing prolonged stimulation duration (e.g., Yamamoto et al., 2005) and allowing vestibular and sham stimulation to switch without the participants’ awareness. 3. The Use of Vestibular Stimulation as a Therapeutic Intervention The use of vestibular stimulation as a therapeutic instrument dates back to a time long before the physiology and function of the vestibular system were known. Yet, the interest in vestibular stimulation and its potential use in various therapeutic settings strongly increased in the 19th and 20th centuries. In the following chapters, we discuss a selection of interesting observations and studies in which vestibular stimulation has been used as a therapeutic method. We thereby try to judge its success and failure from today’s perspective and knowledge. 3.1. Vestibular Stimulation for General Soothing Effects and Improving Sleep Quality The use of cradles to induce sleepiness in children has already been described in ancient times (Jütte, 2009). Such knowledge of the hypnagogic effect of passive rocking seems culturally universal. There are, for example, reports about its early usage in the Himalaya (Burrows, 1828). However, empirical data on the topic are inconclusive. Some studies found prolonged quiet sleep during vestibular stimulation (Barnard and Bee, 1983; Johnston et al., 1997; Korner et al., 1990), while other studies found that it promoted wakefulness (Campos, 1994; Gregg et al., 1976), which is also in line with literature suggesting an influence of vestibular cues on arousal and sleep regulation (e.g., Horowitz et al., 2005). The velocity of rocking has been suggested to be crucial (Johnston et al., 1997): slower speed is thought to promote sleep (Gregg et al., 1976) while faster speed or a fall is thought to promote wake states (Campos, 1994) or even wake an organism from sleep (Horner et al., 1997). On a neurophysiological level, an animal model showed that the medial vestibular nucleus projects onto hypocretin neurons and thus regulates sleep and arousal (Horowitz et al., 2005). The first documented use of moving or rocking as a formal treatment probably dates back to the ancient Greek physician Asclepiades of Bithynia (Vieth, 1795). He invented hanging beds (‘lectos pensiles’) in which people could be rocked to reduce pain and induce sleep. Rocking was probably used as a sedative throughout the next centuries (Jütte, 2009), but only regained popularity with the construction of more sophisticated rotary chairs. In the beginning of the 19th century, Trommsdorf (1811) writes about the soothing effect of the rotary machines that were first recommended by Kratzenstein and, later, by

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Erasmus Darwin. Darwin thought that the rotatory movements would increase pressure on the patient’s brain and therefore induce sleep (Wade, 2005). Joseph Mason Cox (1806) was probably the first to implement those ideas more systematically in clinical settings. While curing patients in an English institution known as the Fishpond asylum, Cox observed and described the soothing effect of his swing in patients with various disorders. Apart from vertigo, the treatment on the swing was followed by ‘the most refreshing slumbers’ (Cox, 1806, p. 140), a characteristic which he considered highly valuable to cure his patients. Subjective drowsiness is nowadays listed as a cardinal symptom of motion sickness as well as the so-called ‘sopite syndrome’, a reaction in response to prolonged motion (Graybiel, 1969; Graybiel and Knepton, 1976; Guedry and Graybiel, 1961; Lawson and Mead, 1998), which matches Cox’s observations of patients’ becoming sleepy after having experienced his treatment. While investigating habituation to rotation, Dodge (1923a) reported that his participants described the experiment as having a ‘soothing and soporific character, both during and immediately after rotation’ (Dodge, 1923a, p. 21). In the past 60 years, sleep researchers have developed an increasing interest in the effects of vestibular stimulation on sleep physiology and quality. As an example, the first manned space flights fueled the interest in the effects of a lack of gravity on sleep and motion sickness (e.g., Graybiel, 1969; Graybiel et al., 1968, 1960; Oosterveld et al., 1973). A more recent study which focused on the intrinsic properties of sleep found that natural vestibular stimulation speeds up transition from wake to sleep and increases sleep stage N2 in daytime naps (Bayer et al., 2011). Vestibular stimulation was obtained using a bed that swung with a moderate to low frequency of 0.25 Hz and a peak horizontal acceleration of 0.1 m/s2 . Older studies have reported anecdotal but not statistical evidence for similar effects (Woodward et al., 1990). Bayer and colleagues (2011) argue that vestibular stimulation may enhance synchronicity in thalamo-cortical networks, caused by vestibular and somatosensory input to the thalamic nuclei, which could promote onset and maintenance of sleep. In a more therapeutic approach, Krystal and colleagues (2010) set out to investigate vestibular stimulation as a treatment of insomnia. They used GVS on normal sleepers with a model of transient insomnia, but found that it had an effect on sleep onset latency in only a specific subset of participants who had a sleep onset latency above the median (14 min). In an experiment on herself, Vose (1981), previously a poor sleeper, describes deeper and longer sleep days after vestibular stimulation. Vestibular stimulation seems to influence not only sleep characteristics but also properties of dreams (Leslie and Ogilvie, 1996). Indications about a connection arise from patients with vestibular disorders reporting strong vestibular imagery while dreaming (Doneshka and Kehaiyov, 1978). Additionally, in

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the aforementioned study by Woodward and colleagues (1990), participants claimed to have experienced intense dreams of a sexual nature after a night of vestibular stimulation. In this study, increased REM sleep density was measured. Longer and denser REM bursts after vestibular stimulation have also been found in children (Ornitz et al., 1973). On a side note, lucid dreaming is apparently more pronounced in young children (Voss et al., 2012). Interestingly, the frequency of lucid dreams seems to be related to the vestibular activity in sleep (Gackenbach et al., 1986). In a similar vein, Leslie and Ogilvie (1996) showed that vestibular stimulation leads to changes in dream mentation, including increased bizarreness and vestibular imagery. They hypothesized that activity of vestibular nuclei may contribute to lucid dreaming. Lucid dreaming is a promising treatment in various psychiatric conditions such as depression or post traumatic stress disorder, but induction of lucid dreaming is not always successful (Voss et al., 2014). Based on those findings, we speculate that vestibular stimulation during REM sleep could be an interesting way to induce lucid dreams (Noreika et al., 2010). 3.2. Vestibular Stimulation in Anxiety, Mania and Depression Next to calming effects, vestibular stimulation has been proposed to induce more specific mood changes. Early on, starting in ancient Greece, commonalities between vestibular related symptoms such as vertigo or dizziness and anxiety were noticed (see, e.g., Balaban and Jacob, 2001 for a historical perspective). Even Sigmund Freud (1962) listed ‘locomotor vertigo’, defined as illusory movement, as an important symptom in anxiety neurosis (‘Angstneurose’), a disorder described by him. During the 20th century, vestibular functions began to be objectively quantified by measuring the vestibulo-ocular reflex elicited by caloric, galvanic and natural stimulation (Balaban and Jacob, 2001). As a consequence, there was a first report about abnormal vestibular functioning in patients with anxiety neurosis (Hallpike et al., 1951). Curiously, the unusual vestibular situation experienced in space was reported to result in emotional disturbances amongst other alterations (Guedry and Graybiel, 1961). Moreover, it was found that patients with a vestibular disorder have a higher risk of suffering from depression, panic and anxiety disorders (e.g., Eagger et al., 1992; Godemann et al., 2004). Besides the long known relationship between affective disorders and vestibular disturbances, there are only few records of attempts to use vestibular stimulation as a therapeutic tool in anxiety or related disorders. From the analysis of Cox’s (1806) case reports it seems that he also treated patients with anxiety disorders on his swing, even if it is difficult to determine a clear psychopathological diagnosis based on his descriptions. He and also Hallaran further mention the cure of mania with motion devices (Breathnach, 2010), but again there is reasonable doubt as to whether their definition of mania would

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transfer to modern diagnostic criteria. Kelly (1989) describes a therapeutic approach in which rotation and spinning were applied in various body positions to provide complete vestibular stimulation of the semi-circular canals in order to treat agoraphobia. In one reported case, this treatment improved quality of life profoundly. Moreover, there is one study in which vestibular stimulation was used to test the integrity of the vestibular system in patients with major depression (Soza Ried and Aviles, 2007) and two case studies that used CVS in patients with mania (Dodson, 2004; Levine et al., 2012). Those showed that right hemispheric activation through left CVS alleviated manic symptom severity (Dodson, 2004; Levine et al., 2012) and increased (but nonsignificantly) bilateral frontal and central alpha EEG band activation (Levine et al., 2012). Inspired by the anecdotal knowledge of mood enhancing swinging and rocking, a study in patients with dementia found that the use of a glider swing improved mood and relaxation (Snyder et al., 2001). The mood altering effects of vestibular stimulation have also been described in healthy participants and seem to depend strongly on the type of motion applied. Using a motion device, passive yaw rotation elicited more comfortable feelings; pitch rotations elicited more alert and energetic feelings, and roll rotation elicited less comfortable feelings. Passive heave translation evoked more alert, less relaxed and less comfortable feelings, and surge translation more alerting feelings (Winter et al., 2012). Based on those findings and inspired by Cox’s chair (cf. Section 2.1), Winter and colleagues (2013) set out to look more closely at the effects of yaw rotation on mood. But in contrast to their previous findings, yaw rotation diminished positive mood. No study tried to use such knowledge yet for more specific, hypothesis-driven stimulation in patients with mood disorders. Next to inducing specific emotions, vestibular stimulation has been suggested to alter affect control. Preuss and colleagues (2014a) showed an improvement of affect control during right cold CVS when positive stimuli were presented and an increased positive mood rating, while positive mood decreased during left cold stimulation. In a similar vein, left cold CVS was shown to reduce the desirability of a product (Preuss et al., 2014b) and to attenuate unrealistic optimism (McKay et al., 2013). Overall, activation of the right hemisphere through left cold CVS lowers the mood and vice versa. In conclusion, lateralized vestibular stimulation has been found to modulate mood in healthy participants, but clinical studies are scarce. In a recent review, Coelho and Balaban (2014) hypothesize that visuovestibular conflicts are involved in a continuum of fear ranging from a lack of fear to panic attacks or exaggerated fear. Because in clinical practice fearevoking visuo-vestibular cues are often neglected, they propose the construction of new visuo-vestibular expectations as a possible treatment. With technical progress and thus affordable head-mounted displays, virtual reality has

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become a valid alternative to in vivo exposure therapy in acrophobia (fear of heights) (for a review see Coelho and Balaban, 2014). They also hypothesize that a visuo-vestibular reconfiguration might be involved in the effectiveness of virtual reality therapy. On a side note, we would like to point out that devices for vestibular stimulation are not only used in scientific and clinical settings but also for amusement. Hallaran noted, 200 years ago, that a few psychiatric patients used the motion device in the asylum for amusement (Breathnach, 2010). Today, they are an inherent part of playgrounds (swings, seesaw, rocking horses) and amusement parks (carousel, ferris wheel, roller coasters, graviton, tilt-a-whirl, drop tower). Furthermore, loud music with low frequencies, as played at rock concerts or in clubs, has shown to activate the vestibular system. Based on this finding, listening to such loud music is hypothesized to be partly just another form of vestibular-mediated amusement seeking (Todd and Cody, 2000). Since bone-conducted vibration results in vestibular-evoked myogenic potentials and thus acts in a similar way on the vestibular system (e.g., Curthoys et al., 2014), it would be interesting to investigate the effect of bone-conducted vibration on mood. 3.3. Analgesic Effects of Vestibular Stimulation One thing that is sometimes mentioned together with the soothing effect of vestibular stimulation is its analgesic impact. Despite the early use of hanging beds to reduce pain (see above), the ‘spin doctors’ of the 19th century did not seem to apply their rotating chairs and moving beds primarily to alleviate pain. To our knowledge, renewed interest in the use of vestibular stimulation to alleviate pain is fairly recent. Kolev (1990) reports that cold CVS reduced the symptoms of pain during a migraine attack in 11 out of 12 participants. The success of the stimulation varied. In some participants the symptoms completely disappeared while others only noticed a slight decrease, and the duration of the effect varied, lasting from only a few minutes to several days. Reduced pain after CVS has also been reported in amputees (André et al., 2001a) and paraplegics (Le Chapelain et al., 2001) with phantom limb pain — possibly mediated by a modification and normalization of the body schema by vestibular stimulation (see Section 3.4 below). Further analgesic effects of CVS, which were still reported during follow-up several weeks later, were also found in two patients with central post-stroke pain (Ramachandran et al., 2007a, b). These findings were replicated shortly thereafter; seven out of nine patients with central post-stroke pain reported decreased pain after CVS. The duration varied from only transient relief to several weeks (McGeoch et al., 2008). The analgesic effects were noticed mostly in the face and arms and less in the legs. The authors propose that this reflects the topographical map for pain in the posterior insula (Ramachandran et al., 2007a, b). Alternatively, we

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speculate that it could reflect more generally the enlarged somatotopic representation of the face and arms on which CVS can act upon. Finally, these authors also successfully applied a similar CVS treatment in one patient with central post-stroke pain and tactile allodynia (McGeoch et al., 2009), as well as in a patient with unilateral central pain of spinal cord origin (McGeoch and Ramachandran, 2008). Next to the effects of vestibular stimulation on chronic pain in patients, a recent experimental study in healthy participants found increased pain thresholds shortly after left cold CVS (Ferrè et al., 2013). It is not known, however, how long this effect lasts. Moreover, a study that investigated the effect of ‘simulated rocking’ on the pain response to the so-called heelstick procedure in infants, found inconclusive results (Johnston et al., 1997), which could suggest that artificial stimulation is more likely to alleviate pain than natural vestibular stimulation due to its hemisphere specific (lateralized activation) nature. While these analgesic effects of vestibular stimulation are potentially very important, more well controlled studies with adequate sample sizes are needed, and imaging or electrophysiological studies should be done in order to reveal the underlying mechanisms. An interaction between vestibular and nociceptive stimuli seems neurophysiologically plausible due to shared information processing (Balaban, 2011) particularly in the insula (zu Eulenburg et al., 2013) and/or the anterior cingulate cortex (McGeoch et al., 2009; Miller and Ngo, 2007); see Lenggenhager and Lopez (2015) and Mast and colleagues (2014) for a more thorough discussion of underlying physiological mechanisms. Furthermore, Ramachandran and colleagues (2007a) provide an interesting evolutionary and functional speculation on the link between pain and the vestibular system, in which they propose that activating the vestibular system is often a useful strategy to escape pain, which makes an interaction between the two systems plausible. Moreover, an interaction between pain and the vestibular system could generally be mediated by changes in the awareness of the bodily self, as hypothesized in a recent review (Lenggenhager and Lopez, 2015; see also next section). 3.4. Vestibular Stimulation in Neurological Body Disorders of the Bodily Self and Space Since the beginning of the 20th century, especially with the early work of Bonnier (1893, 1905) and later with the one of Lhermitte (1939) and Schilder (1935), a strong link between the vestibular system and the experience of the space, the body and the self has been suggested. For example, Bonnier (1905) described various body perception alterations in patients with vertigo. Such a link between the vestibular system and the sense of an embodied self was later confirmed and strengthened by various findings showing, for example, body

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misperception in patients with peripheral vestibular disturbances as well as in healthy participants during artificial vestibular stimulation (Jauregui-Renaud et al., 2008; Sang et al., 2006; see also Lopez, 2013 for a review). These patients describe feelings like being separated from the body, not being in control of their own body and changes in the size of body parts. Such symptoms overlap with the experiences of patients with psychiatric or neurologicallycaused disorders of the perception of the body, the self and space (see, e.g., de Vignemont, 2010, for a comprehensive list of clinical syndromes). These disorders are traditionally related to right parietal dysfunctions (e.g., Critchley, 1950, 1953), although similar experiences have been described with lesions in other brain areas (e.g., Lopez et al., 2010a). With the relatively early recognition of the importance of vestibular signaling in the representation of body and space, the use of vestibular stimulation to treat various disorders of the bodily self has increased slowly but steadily during the 20th century. In fact, Bonnier noticed already in 1893 that the bodily illusions he observed in vestibular patients transiently decreased during vestibular stimulation (i.e., head shaking) (Bonnier, 1893). In 1941, Silberpfennig describes two patients with ‘pseudohemianopic’ disorder, i.e., a problem of drawing attention to the contralesional space, which was clearly attenuated during CVS (Silberpfennig, 1941). Since then the use of vestibular stimulation to increase spatial functioning in hemineglect has gained importance, and while early studies report short-term effects during single applications (e.g., Cappa et al., 1987; Rubens, 1985), more recent studies suggest that long-term effects can be induced using multiple sessions of artificial vestibular stimulation (Wilkinson et al., 2014). Alongside successful application of vestibular stimulation to normalize space awareness (see, e.g., Chokron et al., 2007 for a review and a list of relevant studies), artificial vestibular stimulation has been used and suggested to be used as a therapeutic measure for patients with various bodily disorders. It has successfully been used to alleviate somatosensory hemi-inattention (Bottini et al., 2005; Schmidt et al., 2013), motor neglect (Vallar et al., 2003), anosognosia and personal neglect (Cappa et al., 1987), somatoparaphrenia (Rode et al., 1992), macrosomatognosia (Rode et al., 2012) as well as phantom limb sensation and pain (André et al., 2001b; Le Chapelain et al., 2001). Next to these positive (albeit not well-controlled) findings, vestibular techniques have been enthusiastically propagated to treat a variety of other bodily disorders of both, neurological or psychiatric origin (Ramachandran and McGeoch, 2007; Ramachandran et al., 2007a, b). While most of these studies lack an explicit functional hypothesis, the effects are commonly ascribed to an activation of a higher-level, multisensory body representation by vestibular stimulation, which presumably restores the body representations and triggers a more accurate body perception through unification of multisensory input. Vestibular stimulation has been shown to

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activate predominantly retroinsular and temporo-parietal areas (e.g., Lopez et al., 2010b), areas that have generally shown to be important in multisensory and higher-level body and space representation (Blanke, 2012; Pfeiffer et al., 2014 for reviews). Importantly, almost all of these studies are single case studies, many do not include any sham stimulation (see, e.g., Schmidt et al., 2013 for an exception) and have other methodological flaws. Furthermore, the effectiveness of the method might be overestimated due to publication bias (see Mast et al., 2014 for a brief discussion). For example, recent empirical evidence in a group of patients with a complex body disorder did not show any normalization during or after artificial vestibular stimulation (Lenggenhager et al., 2014). It remains to be seen whether other stimulation paradigms and types such as prolonged noisy GVS, used quite successfully in neurodegenerative patients so far (see Section 3.8), could increase effectiveness compared to traditional stimulations in certain psychiatric or neurological disorders such as body integrity identity disorder. 3.5. The Use of Vestibular Stimulation to Treat Conversion Disorders Conversion disorders cover a range of symptoms such as blindness or deafness, paralysis, numbness, motor deficits, and other neurological symptoms that cannot be fully explained by physiological findings. Historically, the term ‘hysteria’ was used until Freud progressively introduced the term ‘conversion’, which refers to his theory that psychological symptoms are converted into physical symptoms (Bogousslavsky, 2011). Ernst Horn (1818; see also Harsch, 2006) described the use of his rotating bed (and chair) to treat hysteria with considerable success. However, Horn’s apparatus was particularly unpleasant as it applied substantial g-force and the fear of repeated spinning was considered as therapeutically valuable (Harsch, 2006). Hundred years later, just shortly after Bárány published his book on caloric stimulation (1907), Abercrombie and McKenzie (1910) suggested that CVS might be a useful diagnostic tool to differentiate between hysterical and organic deafness. McKenzie (1912) reports that he therefore applied CVS in a woman who had been deaf in her right ear since childhood and recently started to show signs of hysterical deafness in her left ear. Curiously, after the procedure, the woman was able to hear well again on her left side, while the impairment on the right remained unchanged. McKenzie (1912, p. 19) states the following reasoning regarding the positive effect: “The patient then volunteered the information that she had several times lost her voice, and had had it restored ‘by the battery’. And there can be no doubt that it was the memory of this previous successful treatment, coupled with the profound mental shock of the violent vestibular stimulation, which cured her deafness on this occasion”. Another hundred years later, NollHussong and colleagues (2014) reported a case study of a young man with conversion disorder showing involuntary movements of the upper body. Left

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cold CVS of varying duration was applied three times. According to the patient’s report, the stimulation helped to attenuate the involuntary movements. Remarkably, after the third stimulation, these beneficial effects were still noticed three days later. Those authors assume that CVS — due to its cortical hemispheric lateralization — activates (and deactivates) critical brain areas (especially temporo-parietal areas, the anterior cingulate cortex, and insula) that drive the effects (compare also Lopez and Blanke, 2011). 3.6. Vestibular Stimulation in Schizophrenia Surprisingly, schizophrenia emerged as a specific disorder relatively late in psychiatric history. Only in the late 19th century did Emil Kraepelin define ‘dementia praecox’ more closely, and shortly thereafter, in the early 20th century, Eugen Bleuler introduced the term ‘schizophrenia’. Before this introduction, schizophrenic symptoms may have been classed under more general concepts like ‘madness’ or even just ‘insanity’ (Bürgy, 2008; Heinrichs, 2003). This makes it difficult to trace the use of therapeutic vestibular stimulation in patients with schizophrenia through time. However, a few case reports and mental states have been described that possibly allude to schizophrenia as we know it today. Cox (1806), for example, describes some case studies (e.g., cases XVI, XVII and XX) that might be diagnosed as schizophrenia today. Another physician during Cox’s era, Horn (1818; see also Harsch, 2006), reports using the rotating bed during acute episodes of ‘raving madness’. But again, given the changing understanding of terms and definitions, interpretations are difficult. Since the 1920s, vestibular dysfunctions have been repeatedly observed in children and adults with schizophrenia, especially abnormal eye movement responses; yet, some studies also failed to find significant differences compared to a control group (for an overview see, e.g., Hixson and Mathews, 1984; Kelly, 1989; Levy et al., 1983). With the onset of Anna Jean Ayres’s postulation of the sensory integration theory (e.g., Ayres and Heskett, 1972), which she started developing in the 1950s, sensory stimulation became the focus of different therapy interventions. Vestibular stimulation was typically an integral part in sensory integration therapies. Since the work of Schilder (1933), the vestibular system had been considered to help organize other sensory information and to have direct influences on both emotion, through the limbic system, and the experience of a coherent unified self. Furthermore, together with tactile and proprioceptive input, these ontogenetically earlier sensory systems were the focus because sensory integration aimed at promoting sequential development. However, because sensory integration therapy — as the name suggests — applies other sensory stimulation (typically tactile and proprioceptive) and also the vestibular stimulation often involves passive (e.g., swinging in a hammock) as well as active (e.g., riding a scooterboard) com-

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ponents (Ayres and Heskett, 1972), further elaboration is beyond the scope of this review [see instead Hixson and Mathews (1984) and Kelly (1989) for a review on the use of vestibular stimulation in this context]. Only recently, CVS was applied in two patients with schizophrenia (Levine et al., 2012). The results show transiently decreased delusions and decreased lack of insight-judgment as measured with the Positive and Negative Symptoms Scale after left cold CVS but not after right cold CVS (see also Section 3.2). Moreover, vestibular stimulation has been suggested to help improving the motor symptoms of catatonia (Miller and Ngo, 2007, see also Section 3.8) and it may also help to improve cognitive functions (see Section 3.9). It should, however, be noted that administering vestibular stimulation may be counter-indicative, at least during an acute phase, among other concerns, because visual hallucinations have been reported after CVS in healthy participants (Kolev, 1995) and overstimulation could exacerbate the symptoms. Generally, again, the underlying mechanisms by which vestibular stimulation should improve symptoms of schizophrenia is not well understood and vestibular and even multisensory stimulation remain negligible in the treatment of schizophrenia. 3.7. Vestibular Stimulation in Neurodevelopmental Disorders Following Alexander Crum Brown’s suggestion (1878), William James (1881) conducted early experiments with deaf children who ‘were whirled in a rotary swing’ (p. 412). He observed that they were often less prone to motion sickness compared to hearing children. Despite these early (and questionable) scientific investigations in children and the fact that children often seek the pleasure of movement (e.g., playgrounds are full of vestibular stimulation devices, see also Section 3.2) vestibular treatment of children seemed (luckily) less ‘fashionable’ than for adults in the first half of the 19th century. This changed in the second half of the 20th century, during which vestibular processes have increasingly been suggested to play an important role in a broad variety of developmental disorders (see, e.g., Kelly, 1989 for an impressive list of disorders with presumable vestibular deficits) including dyslexia (Frank and Levinson, 1973), attention deficit hyperactivity disorder (ADHD) (Bhatara et al., 1978), autism (Ritvo et al., 1969), as well as more general learning deficits (Ayres and Heskett, 1972). Interestingly, some of their core symptoms have shown to be present in patients with vertigo (e.g., dyscalculia; Risey and Briner, 1990; see Smith, 2012 for a discussion), suggesting a mutual interaction between these symptoms and vestibular signaling. As a consequence, vestibular stimulation — at the time mostly delivered by motion devices — was increasingly used to treat children. While such approaches are interesting in the context of this paper and will therefore be reviewed briefly

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below, it is important to note that within the huge research field on neurodevelopmental disorders, they play a rather minor role. In dyslexia, parallels have been drawn between various symptoms associated with developmental dyslexia (e.g., problems with postural stability, spatial orientation and eye movements) and the vestibular system, leading to the so-called cerebellar–vestibular dysfunction hypothesis of dyslexia (e.g., Levinson, 1988). Early therapies included treatment with anti-motion sickness medication (Levinson, 1991) as well as specific motion stimulation (e.g., Silver, 1986) and combined multisensory integration therapies (Ayres, 1978). Yet, these findings were already at that time heavily debated and even considered wrong (see Pope and Whiteley, 2003; Silver, 1986 for reviews), and have largely lost their influence on current models of dyslexia. Similarly, ADHD is often associated with poor balance control and postural coordination, suggesting a vestibular and cerebellar contribution (e.g., Sergeant et al., 2006). Such interaction might be mediated by vestibular contributions to the parasympathetic and sympathetic systems (see Clark et al., 2008 for a extensive explanation). Corroboratively, several studies found a positive effect on attention disorder during vestibular stimulation treatment using motion devices (e.g., Arnold et al., 1985; Bhatara et al., 1978, 1981). However, a recent well-controlled study with a relatively large sample of patients concluded that these results were probably due to nonspecific effects, such as experimenter expectancy or attention given to the child, as they found improvement both in the experimental (rotation on a chair) and the control condition (sitting on the chair watching a video and hearing the same noise) (Clark et al., 2008). About at the same time, a vestibular dysfunction theory was also proposed for autism, after data showed altered nystagmus response (Ornitz, 1970; Ritvo et al., 1969) as well as altered REM sleep in people with autism, and after vestibular stimulation was found to affect REM (Ornitz et al., 1973; see also Section 3.1). Most important in the context of this review, repeated rotatory stimulation has shown to improve motor skills of young autistic infants (Kantner et al., 1976). 3.8. Vestibular Stimulation in Neurodegenerative Disorders A relatively early, uncontrolled study reported that rotatory vestibular stimulation improved initiation of movement and a better posture in patients with Parkinson’s disease (McNiven, 1986). However, Kelly (1989) also mentions unpublished work of Young (1987) that provides empirical support for the therapeutic success of vestibular stimulation in Parkinson’s measured by an increase in step length. Recent attempts have used GVS, since it includes activation of the vestibular nerve, which innervates autonomic and limbic-to-motor functions, and the

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regulation of dopamine and noradrenaline in those areas (Albert et al., 1985; Anderson et al., 2002). GVS was therefore hypothesized as possible treatment in neurodegenerative diseases targeting those areas like Parkinson’s disease and multiple system atrophy (Yamamoto et al., 2005). However, because constant GVS causes unilateral oculomotor and postural responses (Fitzpatrick and Day, 2004) and would therefore limit the benefit of such a stimulation, stochastic/noisy GVS was used in all studies on neurodegenerative disorders that we know of (Pal et al., 2009; Pan et al., 2008; Yamamoto et al., 2005). In their pioneering study, Yamoto and colleagues (2005) found that noisy GVS alleviated autonomic and motoric disturbances in Parkinson’s disease and multi system atrophy, and that it decreased reaction time in an attention and response control task but did not modulate cognitive performance. Moreover, stochastic GVS was found to stabilize small sway in Parkinson’s disease (Pal et al., 2009). In conclusion, the underlying mechanisms are still largely unknown (Kim et al., 2013). 3.9. Cognitive Enhancement through Vestibular Stimulation? There is now accumulating evidence that impaired or absent vestibular input (e.g., vestibular deficits, during weightlessness, or complete vestibular loss) can negatively affect cognitive functioning and has even found to result in hippocampus atrophy (for a review see, e.g., Smith and Zheng, 2013). The question might therefore be if, conversely, additional vestibular stimulation can improve such functions. Here we briefly discuss studies that suggest that vestibular stimulation, beyond its therapeutic effects, might serve as a sensory and cognitive enhancer in healthy participants (Wilkinson et al., 2008). Besides the above reviewed positive effects of vestibular stimulation on various disorders, vestibular stimulation has shown to enhance both sensory (e.g., Ferrè et al., 2013) and cognitive (e.g., Falconer and Mast, 2012) functions. Especially, memory — visual memory recall (Wilkinson et al., 2008), and depending on stimulation side, verbal or spatial recall (Bachtold et al., 2001) — was found to be improved (for a review see Smith et al., 2010). Similarly, a recent EEG study suggested improved memory as well as altered frontal beta power after GVS (Lee et al., 2014). Given the positive effect of arousal on memory retention (e.g., Sharot and Phelps, 2004), one could speculate that such results might be explained by arousal caused by vestibular stimulation (Horowitz et al., 2005, see also Section 3.1). To further investigate this interesting question on the influence of vestibular-induced arousal, one could use different strengths of vestibular stimulation to see whether the positive effect on memory depends on stimulation parameters. Furthermore stochastic galvanic stimulation has been shown to alter modulation of synchrony patterns in the EEG across a broad range of oscillations (i.e., frequency bands), possibly due to stochastic facilitation/resonance (Kim et al., 2013). Such biologically

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relevant noise may enhance neural information processing and computational goals (McDonnell and Ward, 2011). Besides these positive effects on perceptual and cognitive processes, vestibular stimulation has been shown to decrease pain (Ferrè et al., 2013, see Section 3.3) and — depending on the side of stimulation — improve affect control (Preuss et al., 2014a), alter mood (Winter et al., 2012) and decrease unrealistic optimism (McKay et al., 2013, see Section 3.2). Moreover, there are some hints that vestibular stimulation has positive effects on sleep characteristics (see Section 3.1). All these outcomes are also linked to cognitive functioning, and cognitive enhancement after vestibular stimulation could be mediated by these positive effects on various states. Yet, it will probably play a minor role in the future compared to other neurocognitive enhancers, such as tDCS, that directly modulate cortical activation. Furthermore, most studies have not looked at long-term effects, and long-lasting improvements are unexplored. 4. Discussion The aim of this review was to recapitulate the therapeutic use of vestibular stimulation. We introduced the origins and developments of the three main methods to passively stimulate the vestibular system (i.e., motion devices, CVS and GVS) and presented a selection of topics from psychiatric and neurological research, in which it is suggested that vestibular stimulation may be beneficial. We critically reassessed history, success and effectiveness of vestibular stimulation. Although this literature review covers a broad range of applications, it is by far not complete. Disorders that we have not discussed, but which we would like to mention here in order to provide a better appreciation of how widely vestibular stimulation has been applied, include also: pusher behavior (Krewer et al., 2013; Nakamura et al., 2014), aphasic syndrome (Wilkinson et al., 2013), prosopagnosia (Wilkinson et al., 2005) and figure-copying deficit after right hemispheric stroke (Wilkinson et al., 2010), intellectual disability (Dave, 1992) and Down’s syndrome (e.g., BrocklehurstWoods, 1990). Moreover, we only briefly mention the effects of vestibular stimulation on hemispatial neglect, albeit this is probably one of the most promising and thus already most discussed (Schmidt et al., 2013; Utz et al., 2010; Wilkinson et al., 2014) research branch of this field. 4.1. Methodological and Ethical Considerations of Vestibular Stimulation The advantages and the resulting popularity of vestibular stimulation as a therapy are evident: it is usually non-invasive, rather cheap and easily applicable. Yet, while most of the studies reviewed here report a positive effect of vestibular stimulation (which might partly be due to publication bias), many of them

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need to be regarded with caution as they are often associated with methodological problems and their results might be heavily confounded by other effects. Furthermore, even if generally non-invasive, there are still counter indications of therapeutic vestibular stimulation. Already in the early 19th century it was for example not recommended to use vestibular stimulation in fragile, fearful, paranoid or hypochondriac patients nor in patients with organic disease (e.g., Horn, 1818). It was further only recommended in hopeless cases (Cox, 1806) or if no other less stressful methods could be used (Harsch, 2006), which has to be seen in the context of other medical treatments of that time. A contemporary view is important, as some of the former procedures would nowadays be regarded as torture. Such procedures were typically performed without the participant’s consent and in the case of vestibular stimulation purposefully intense and nauseating. In fact, during the first half of the 19th century, the peak period of therapeutically applied motion devices, it was deliberately intended to induce motion sickness, vertigo, nausea and vomiting. The latter was a desired method for treatment during this time, along with others, such as, purging, bleeding, bathing, blistering, and the use of sedatives and stimulants (Cox, 1806; Harsch, 2006; Wade, 2005). Therefore, what is now viewed as the undesired side effects of vestibular stimulation was at the time actually intended. With the change of perspective on psychiatric patients and the call for more ethical treatments introduced by Philippe Pinel at the end of the 18th century and the resulting growth of his followers in the 19th century, the use of such methods decreased, including the use of motion devices (Jütte, 2009). Today, measures are taken to minimize those undesired effects. For example, the proposed intensity of real motion stimulation is now usually a calming rocking instead of vertiginous swinging and efforts are made to investigate and apply GVS at a sub-sensory threshold with remarkable results (Wilkinson et al., 2010). But even above threshold, if GVS is applied with caution, there are mild side effects and these are of transient nature (Utz et al., 2011). Moreover, repeated treatment sessions may be needed for a satisfying outcome and the safety seems to be warranted when using ‘low-intensity’ (1 mA) GVS (Wilkinson et al., 2009). Yet, even if vestibular treatments today are much more humane, it should be noted that depending on stimulation parameters vestibular stimulation (especially artificial) might still induce considerable side effects (e.g., Lenggenhager et al., 2008). Independent of the side effects, it is important that the methods are carefully evaluated before suggesting vestibular stimulation as a therapy ‘for everything’ (e.g., see Section 3.7). Placebo effects as well as co-stimulation of other sensory systems (e.g., touch, pain) need to be considered as explanatory models and protocols should be hypothesis-driven rather than based on trial and error (Kelly, 1989). In addition, there are non-specific effects like stress (e.g., stress-induced analgesia, see Ossenkopp et al., 1988) which might influence the results. Importantly,

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such effects might not occur in a linear way. Low to modest intensity stimulation might for example lead to decreased stress-immune responses while high intensity may lead to increased stress-immune responses compared to no stimulation. Moreover, the duration and repetition of the stimulation needs to be taken into account. In fact, talking about ‘vestibular stimulation’ as it is often done in the present review is an oversimplification, because the vestibular system is complex and its responsivity can change depending on the stimulation parameters and the targeted organs (otoliths and/or semicircular canals). Importantly, GVS can be applied by varying intensity, pulse profile and duration, and modern motion devices allow to deliver vestibular stimulation in a similarly precise fashion while CVS does not have these characteristics (Palla and Lenggenhager, 2014). A clear, detailed and ideally a priori defined and hypothesis-driven protocol and selection of the method to stimulate the vestibular organ is thus indispensable. In this context it is interesting to note that historically there seems to have been a tendency to use ‘natural’ vestibular stimulation through the use of motion devices to treat psychiatric disorders and artificial vestibular stimulation (CVS, GVS) to treat neurological disorders — a distinction which seems not justified by any functional or physiological hypothesis. Furthermore, studies need to show that the effect of ‘vestibular stimulation’ is indeed due to the vestibular activation and not due to any co-activation of other sensory systems (e.g., touch, proprioception) or other unspecific effects. This is among the reasons why this review article focuses on passive vestibular stimulation as opposed to active vestibular stimulation (e.g., slacklining or rocking in a rocking chair), which may be beneficial due to other and difficult-to-control effects, especially motor activation. We also did not mention optokinetic stimulation, which has often proven useful in similar therapeutic approaches (e.g., Kerkhoff et al., 2006), but is not a genuine vestibular stimulation. 4.2. What Neurophysiological Mechanisms Can Explain the Effect of Vestibular Stimulation? While this review contains a list of beneficial effects of vestibular stimulation on various conditions and disturbances, the reasons for such effects are still far from understood. Explicit explanation of underlying mechanisms of the positive effect is often lacking, and if present, the mechanism might just target a very specific effect of the vestibular stimulation. In fact, different core mechanisms have been proposed to explain potential therapeutic effects of vestibular stimulation, most prominently probably (a) relocation of attention, (b) multisensory integration, (c) hemisphere specific activation, (d) neurotransmitter release.

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Relocation of attention, could be induced both by the directional nystagmus (for a discussion see Figliozzi et al., 2005) or by activation of attentional networks overlapping with brain areas targeted by vestibular stimulation (Oppenländer et al., in press). This mechanism has particularly been put forward to help explain the positive effects on neglect and similar symptoms (see, e.g., Karnath and Dieterich, 2006; Wilkinson et al., 2014). Such an attention shift could be caused by an unspecific activation of parieto-temporal cortical areas contralateral to the stimulated ear. However, an attention shift due to CVS does not seem to always occur in healthy participants (e.g., Rorden et al., 2001). Recently, Ferrè and colleagues (2014) showed that the effect of vestibular stimulation on somatosensory detection was modulated by multimodal interaction rather than spatial attention. The integration and activation of multisensory processing areas (e.g., insula, parietal operculum, anterior cingulate cortex) by vestibular stimulation has been proposed to be the underlying factor in disorders of the bodily self (e.g., Bottini et al., 2013). The vestibular system is intrinsically multisensory because of its neuroanatomical connections and a vestibular percept is thus rarely experienced purely (Angelaki et al., 2009; Blanke, 2012; Ferrè et al., 2012). Moreover, it has been hypothesized that the vestibular system and emotional circuits overlap (Preuss et al., 2014a) or that CVS would target the inferior frontal gyrus, a region involved in unrealistic optimism (McKay et al., 2013). On an lower level, the medial vestibular nucleus located in the medulla oblongata is connected to different brain areas associated with nociception, sleep and arousal, homeostasis and eye movements (Horowitz et al., 2005). It remains to be seen how those structural connections translate to a more functional level. The hemispheric specific activation/deactivation pattern has been suggested to enhance or hinder specific lateralized brain processes (McKay et al., 2013; Noll-Hussong et al., 2014; Preuss et al., 2014b). On a smaller scale, vestibular stimulation influences neurotransmitter release (for a discussion see Gurvich et al., 2013; Mast et al., 2014). The alteration of specific neurotransmitters such as dopamine, serotonin and GABA are thus crucial for understanding the influence of vestibular stimulation on cognition. For example GVS increases GABA release in rats (Samoudi et al., 2012). But also the sleep-wake system is influenced by vestibular input as projections of the medial vestibular nucleus to hypocretin neurons and vice versa have been found (Horowitz et al., 2005). Of course, such explanatory models act on differently scaled levels and are not mutually exclusive but may represent different aspects of a shared underlying mechanism. Finally, as already pointed out, non-specific effects like stress, general arousal, or placebo effects need also to be considered. The question remains whether there is a more general/common mechanism underlying all these effects and if so, which would be the most promising.

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Yet, given the broad spectrum of disorders targeted with different underlying dysfunctions, pursuing a ‘one-size-fits-all’ approach might be too ambitious. 4.3. Outlook This literature review shows that vestibular stimulation has been, and still is, a popular method and certainly contributed to the understanding and treatment of certain disorders. However, since most studies discussed in this review are case or small-scale studies, and often never replicated, an overestimation of its efficiency due to publication bias needs to be considered. This is especially important, because publication bias mostly affects exactly such studies, while sufficiently powered studies are usually published disregarding the actual outcome (Egger et al., 1997; Thornton and Lee, 2000). Therefore, large-scale studies including clinical trials and/or randomized control trials are needed. Such studies are feasible since vestibular stimulation is readily available, inexpensive and many of the discussed disorders, like sleep disorders, chronic pain, depression and anxiety, are unfortunately very prevalent. Acknowledgements We are grateful to Nicholas J. Wade and the other (anonymous) reviewer, as well as Victoria J. Madden, Leslie Russek and Peter Brugger for proofreading and their helpful suggestions on the manuscript. The authors are supported by the Swiss National Science Foundation (B.L. and G.M. grant 142601; L.G. grant 144848). Notes 1. His medical dissertation “Novum medicinae genus nimirum vim centrifugam ad morbos sanandos adplicatam more geometrarum proponit” from 1765 can be found online (http://www.ub.uni-kiel.de/digiport/ bis1800/Kd3153.html). 2. Pictures from Darwin’s drawings of his rotating couch and a photograph of Cox’s chair can be found in Wade et al., 2005. References Abercrombie, P. H. and McKenzie, D. (1910). Hysterical deafness with active vestibular reactions, Proc. R. Soc. Med. 3, 74–76. Albert, T. J., Dempesy, C. W. and Sorenson, C. A. (1985). Anterior cerebellar vermal stimulation: effect on behavior and basal forebrain neurochemistry in rat, Biol. Psychiatry 20, 1267–1276.

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Index

A Arm movements 5–19 Arm movements, cognitive processes in 13 Aschématie 137 Asomatognosia 137, 249 Attention deficit hyperactivity disorder (ADHD) 277 Aubert effect (A-effect) 45, 91 Autism 262, 277–278 Autoscopic phenomena see Outof-body experiences B Ballet dancers 35 Bárány, Robert 201, 265, 275 Bayesian model 47, 50, 63, 93, 96, 153 Biological motion 48, 59, 143, 147 Bodily awareness 3, 138 Bodily perception 3, 134, 152 Body identity integrity disorder (BIID) 141 Body ownership 3, 138–141, 210– 214 Body representation 137, 173, 196, 203, 209–214, 247, 274 Body representation, shared 150– 154 Body rotation 10, 16, 148, 151, 177, 178, 210, 227, 264 Body schema 137, 149, 189, 203, 272

C Caloric vestibular stimulation see Vestibular stimulation, caloric Cognitive enhancement 279 Consciousness 134, 137, 168, 222, 224, 227, 247, 253 Conversion disorders 275 Coriolis forces 6, 16, 17 D Darwin, Eramus 263, 264, 269 Depersonalization 3, 141, 245–254 Derealization 3, 245–254 Diffusor tensor imaging 36–37 Disembodiment see Out-of-body experiences Drift diffusion models (DDM) 102 Dyslexia 277–278 E Einstein, Albert 261 Einstein’s equivalence principle 95 Embodiment 141–142, 248 F Face recognition 73–86 First-person perspective 134, 141, 142, 190, 196, 222, 226, 247 Forward internal model 44, 98 Free fall 50, 54, 57, 234 (see also Weightlessness) Full body illusion 223, 231

298

G Galvanic vestibular stimulation see Vestibular stimulation, galvanic Gibson JJ 45, 62 Gravito-inertial force (GIF) 95, 102 Gravity 1, 43–64, 74–85, 95, 144, 154, 168 Gravity, internal representation of 146 H Head motion 8, 33, 176, 222, 228 Hemianesthesia, vestibular effects on 137, 175, 203–206 Hippocampus 3, 107–128, 279 I Idiotropic vector 47, 92, 93, 96 Internal models 90, 98 M Macrosomatognosia 212, 215, 274 Meniere’s disease 108 Mental imagery 90, 96–100, 147 Microgravity 147, 246 (see also Weightlessness) Mood 249, 270 N Navigation see Spatial navigation Neck proprioception 7 Neglect 141, 173, 200–205, 212, 274 Newton’s laws 63 O Object recognition 74 Oriented character recognition test (OCHART) 47, 48, 74, 76, 77 Out-of-body experiences 3, 141, 221–239, 248

Index

P Pain, vestibular effects on 136, 179–180, 208–214, 268, 272, 280 Perceptual upright 74 Perceptuo-reflex uncoupling 36 Place cells 108, 119, 120, 127 Principle of common fate 181 R Rubber hand illusion 139–140, 190, 213 S Schizophrenia 276 Self-motion 10, 27, 37, 57, 149 Self-perception 133, 134 Self-representation 3 Self-rotation test (SRT) 28 Sensorimotor control 2 Sensorimotor resonance 150 Sensorimotor transformation 10 Somatoparaphrenia 139–141, 210, 274 Somatoperception 138 Spatial cognition 2. 175, 274 Spatial disorientation 246 Spatial memory 3, 107–128 Spatial navigation 3, 28, 39, 108, 169, 180, Spatial orientation 2, 44 Spatial perception 27 Spatial updating 11, 12, 149, 252, Subjective visual horizontal (SVH) 92 Subjective visual vertical (SVV) 45, 91–92, 95, 97, 101, 224 T Tactile extinction 173, 177, 204, 207, 208, 215 Tactile perception, vestibular effects on 203 (see also

299

Index

Vestibular–somatosensory interactions) Temporo-parietal junction 119, 138, 142, 149, 212, 222, 238, 247, 275 Tilt-translation ambiguity 95–96, 98, 101 Time perception 43–64 Time to contact (TTC) 49 Transcranial magnetic stimulation (TMS) 30, 38 Trunk movements 7, 16–18, 247 V Velocity storage 33 Vertigo 33, 37, 38, 64, 137, 168, 190, 224, 234, 246, 251, 265, 270, 273 Vestibular cerebellum 35, 96, 208 Vestibular cortex (parieto-insular) 119, 135, 153, 168, 209, 236 Vestibular deafferentation 107– 128 Vestibular memory 30

Vestibular neuritis 108, 122, 253 Vestibular rehabilitation 3, 104, 173, 267 Vestibular sensations 168 Vestibular stimulation, caloric 1, 26, 37, 190, 199–215, 224, 234, 237, 252, 263, 265–266, 270, 275 Vestibular stimulation, galvanic 1, 8, 123, 136–139, 148, 173– 177, 190–191, 196, 207, 263, 266–267, 270 Vestibular thresholds 31, 264 Vestibular–somatosensory interactions 167–182 Vestibulo-motor adaptation 11 Vestibulo–ocular reflex (VOR) 7, 26, 31–37, 90, 91, 108 Vestibulo–spinal reflexes 27, 108, 202 W Weightlessness 246, 279