Multidimensional restitution of the vestibular function with a vestibular implant

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Thesis

Reference

Multidimensional restitution of the vestibular function with a vestibular implant

GUINAND, Nils

Abstract

Bilateral loss of the vestibular (BV) function leads to chronic imbalance and oscillopsia. This condition has a significant negative impact on quality of life, indicating a need to remedy the lack of effective treatment. The concept of the vestibular implant (VI) has emerged, it consists of a modified cochlear implant stimulator with one up to three additional electrodes positioned in contact with the vestibular nerve. An external processor, fed with motion information captured by a head-fixed motion sensor, is connected to the implanted stimulator. Finally motion modulated electrical stimulation is delivered to the vestibular nerve. Up to now, 13 patients with a BV loss have been implanted. We demonstrated that it is possible to significantly improve or in certain cases to normalize the vestibulo-ocular reflex (VOR) gains.

We further showed that the vestibulo-collic reflex could be elicited and that controlled postural responses could be obtained. Finally, the dynamic visual acuity (DVA) while walking has been significantly improved, or even normalized, in 6 subjects. This was the first demonstration of a functional [...]

GUINAND, Nils. Multidimensional restitution of the vestibular function with a vestibular implant. Thèse de privat-docent : Univ. Genève, 2019

DOI : 10.13097/archive-ouverte/unige:134022

Available at:

http://archive-ouverte.unige.ch/unige:134022

Disclaimer: layout of this document may differ from the published version.

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Clinical Medicine Section Department of Clinical Neurosciences

Division of Otorhinolaryngology and Head and Neck Surgery

" Multidimensional restitution of the

vestibular function with a vestibular implant "

Thesis submitted to the Faculty of Medicine of the University of Geneva

for the degree of Privat-Docent by

--- Nils GUINAND

Geneva, Switzerland 2019

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Summary

The vestibular system, located in the inner ear can be compared to a motion sensor.

It senses head movements and gravity. Together with the visual and somatosensory systems, it is an essential part of the multidimensional balance system. The

vestibular system generates among the fastest reflexes in the human body allowing for the efficient gaze stabilization and postural control. It is however far from being limited to those reflex functions. It is involved in a large spectrum of functions, such as motion perception, spatial orientation, blood pressure regulation, memory, sleep, bone metabolism and many others. Therefore, the bilateral loss of the vestibular function leads to a myriad of subtle symptoms accompanying the chronic imbalance and oscillopsia which are most frequently reported by affected patients. It has been now clearly demonstrated that this condition has a significant negative impact on quality of life and imposes an economic burden on society and affected patients, indicating a clear need to remedy the lack of effective treatment in the long term.

Inspired from the success of the cochlear implant in hearing rehabilitation and based on milestone’s experiments in animal and human research, the concept of a

vestibular implant has emerged. Our vestibular implant prototype consists of a modified cochlear implant stimulator with one up to three electrodes removed from the main cochlear array which are positioned in contact with terminal branches of the vestibular nerve using intra- or extralabyrinthine surgical approaches. Postoperatively a regular cochlear implant processor, fed with motion information captured by a head-fixed motion sensor, is connected to the implanted stimulator. Finally motion modulated electrical stimulation is delivered to the ampullary branches of the

vestibular nerve. The first prototype was implanted in Geneva in 2007. Confirmation that controlled vestibular responses could be elicited led to further development and refinement of the device. Up to now, 13 patients with a bilateral vestibular loss have been implanted with different vestibular implant prototypes. For all the experiments presented in this thesis, patients were selected among this pool of 13 patients. By using harmonic motion stimuli delivered by a rotatory chair and by performing the video head impulse test (vHIT), we successfully demonstrated that it is possible to significantly improve or in certain cases to normalize the vestibulo-ocular reflex (VOR) gains at various frequencies and for various angular velocities. In a next step, the recording of electrically elicited cervical vestibular evoked myogenic potentials

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(ecVEMPs) indicated the restoration of the vestibulo-collic reflex. Additionally, we that rapid changes in the “baseline” electrical activity delivered by the demonstrated

vestibular implant could elicit controlled postural responses while the patient was performing a stepping test. We hypothesized that it was the result of an activation of the vestibulo-spinal pathways. Finally, the dynamic visual acuity (DVA) while walking has been significantly improved, or even normalized, in 6 implanted subjects. This was the first demonstration of a functional rehabilitation with a vestibular implant prototype. Altogether, the presented results reflect the potential of the vestibular implant towards a clinically useful multidimensional restoration of the vestibular function. Moreover, by providing the unique opportunity for selective stimulations of the vestibular system, the vestibular implant opens doors to push the vestibular research beyond the traditional boundaries.

The timeline of the milestones of the Geneva-Maastricht vestibular implant (VI) project at a glance:

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1-Introduction

The vestibular system is essential for gaze stabilization and postural control.

Therefore, the bilateral loss of the vestibular function leads to a very handicapping condition, predominantly characterized by chronic imbalance and oscillopsia (blurred vision in dynamic conditions, such as walking). (Sun et al. 2014a; Guinand, Boselie, et al. 2012; Lucieer et al. 2018) However, the vestibular system also contributes to a wide range of other functions, such as spatial navigation, motion perception and many others.(Grabherr et al. 2011; Stackman, Clark, and Taube 2002; Gotoh et al.

2004; Tanaka et al. 2009; Aoki et al. 2012; Levasseur et al. 2004; Fuller et al. 2004;

Smith and Zheng 2013; Smith and Darlington 2013) Consequently, a large spectrum of subtle symptoms is often also present. The management of this pathology remains an unsolved challenge for clinicians. Indeed there is no high level of evidence of an effective treatment in the long term for this condition.(Krebs et al. 2003; Herdman et al. 2007; Gimmon et al. 2019; Zingler et al. 2008)

In the sixties, with their pioneer work, Cohen and Suzuki (Cohen, Suzuki, and Bender 1964; Suzuki and Cohen 1964, 1966; Suzuki, Cohen, and Bender 1964; Suzuki et al.

1969) showed that it was possible to elicit eye movements and postural responses by selective electrical stimulation of the ampullary branches of the vestibular nerve in monkeys and in cats. Based on those findings and most likely inspired by the growing success of the cochlear implant in auditory rehabilitation, the idea of an implant to restore vestibular function emerged. In 2000, the first proof of the concept was made by the team of Merfeld in Boston, USA. They demonstrated in guinea pigs that their vestibular implant prototype, could provide a rotational cue to the central nervous system using electrical currents to stimulate the vestibular nerve.(Gong and Merfeld 2000) During the following 2 decades, several teams studied the effects of the electrical stimulation on the vestibular system extensively using different vestibular implant prototypes in animals.(Della Santina, Migliaccio, and Patel 2007; Fridman et al. 2010; Davidovics et al. 2011; Migliaccio, Meierhofer, and Della Santina 2011; Dai, Fridman, Chiang, et al. 2011; Dai, Fridman, Davidovics, et al. 2011; Dai et al. 2013;

Boutros et al. 2019; Nie et al. 2011; Phillips et al. 2011; Nie et al. 2013; Phillips et al.

2012; Lewis et al. 2002; Merfeld et al. 2006; Merfeld et al. 2007; Lewis et al. 2010;

Lewis et al. 2012; Thompson et al. 2012; Lewis, Nicoucar, et al. 2013; Lewis, Haburcakova, et al. 2013; Phillips, Ling, Oxford, et al. 2015; Phillips et al. 2016) In

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parallel, early promising results obtained in animal studies led to the first vestibular implantation in a patient with a bilateral vestibular loss in 2007 in Geneva. The first results were published in 2011.(Guyot, Sigrist, Pelizzone, and Kos 2011) This pioneer work in humans set the foundations to the systematic evaluations of the effects of electrical stimulation on the multidimensional vestibular function that will be presented in this thesis. To date, three other teams performed vestibular

implantations on human patients, however only one team has published results.(Phillips et al. 2013; Golub et al. 2014; Phillips, Ling, Nie, et al. 2015) Altogether, the successful work on animals and humans raised the interest of the cochlear implant companies and, as an important side-effect, has progressively increased the awareness about the bilateral vestibular loss throughout the medical community.

I’ve been involved in the project of the development of the vestibular implant since 2009. Initially, my contribution to the project has been focused on demonstrating the impact on the bilateral vestibular loss on Quality of Life (Guinand, Boselie, et al.

2012) and on the development of an adequate functional test to assess the benefit of the vestibular implant. (Guinand, Pijnenburg, et al. 2012) In parallel, I participated to the development of the intralabyrinthine surgical approach (van de Berg, Guinand, et al. 2012) and I performed several successful vestibular implantations in patients.

(Guinand, van de Berg, et al. 2015). The four studies presented in this thesis represent the logical continuation of this previous work. The aim is to demonstrate the therapeutical potential of the vestibular implant and the unique role it can play in the vestibular research field.

1.1 The vestibular system

The peripheral vestibular organ and the cochlea form the inner ear which is located in the temporal bone. The peripheral vestibular organ consists of five subunits

containing sensory structures, the vestibular hair cells, specialized in sensing head accelerations (i.e. angular, linear, including gravity). In each ear, three orthogonally oriented semicircular canals sense angular accelerations, providing the central nervous system with tridimensional cues about head rotations. The two otolithic

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organs (saccule and utricule) are predominantly specialized to sense linear

accelerations, providing tridimensional cues about 3D head translations, including head position relative to gravity.

Integration of the sensory output of the semicircular canals and of the otolithic organs enables the central nervous system to be informed in real time about head

movements and about head position. In contrast to other sensory systems, like the visual or the auditory systems, the afferent vestibular signal is already subject to significant multimodal (i.e. multisensory) integration already at the level of the second neuron in several subcortical regions. While visual or auditory percepts can normally be described without ambiguity, there is no clear conscious or distinct sensation coming from the vestibular system. Yet, it has been clearly demonstrated that

multifocal brain activity can be elicited with a variety of vestibular stimuli, pointing out to the significant involvement of the vestibular system in multiple subcortical and cortical functions.(Lopez and Blanke 2011)

Vestibular sensory information is essential for several functions. The vestibulo-ocular reflex (VOR) is the fastest reflex of the human body. Within less than 10ms it

generates adequate compensatory eye movements upon head motion, enabling efficient gaze stabilization in dynamic conditions, such as walking. By activating motor neurons of the neck, the trunk and the limbs, the vestibulo-spinal (VCR) and vestibulo-collic reflexes (VCR) generate rapid complex body movements participating significantly in the control of posture. An additional function that relies on complex integration of vestibular input is motion perception. For example, to distinguish between a tilt and a forward translation, the integration of the canal and otolithic sensory output in an internal model is essential.(Merfeld, Zupan, and Peterka 1999) Moreover, vestibular information has a significant impact on the functionality of place cells which are located in the hippocampus and are important for spatial

navigation.(Chen et al. 2013; Kandel 2014) Another system influenced by the vestibular input is the autonomic system for the regulation of arterial blood pressure during gravity changes (Gotoh et al. 2004), or during head-up tilt (Tanaka et al.

2009). The vestibular system could also play a role in orthostatic hypotension.(Aoki et al. 2012) Others have shown interactions with the respiratory system(Woodring and Yates 1997) and with sleep patterns(Cordero, Clark, and Schott 1986). Finally, the multiple vestibular projections are known to influence emotions, memory,

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cognition(Smith and Zheng 2013; Fuller et al. 2004) and even personality.(Smith and Darlington 2013)

1.2 Bilateral vestibulopathy

Bilateral vestibulopathy has been recently defined in a consensus document of the classification committee of the Barany Society (Strupp et al. 2017). It is a chronic vestibular syndrome which is characterized by unsteadiness when walking or standing, which worsens in darkness and/or on uneven ground, or during head motion. Additionally, patients may describe head or body movement-induced blurred vision or oscillopsia. There are typically no symptoms while sitting or lying down under static conditions. The angular VOR gain is reduced or absent (calorics or/and vHIT or/and rotatory chair) and it is not better accounted for by another disease. The group of patients defined by those criteria is still quite heterogeneous, as the degree of residual canal function can vary significantly and the otolithic function is not

considered. Moreover there is no evident correlation between the level of residual vestibular function and the symptoms. In a systematic review on symptoms reported by patients with a bilateral vestibulopathy, it could be shown that imbalance, chronic dizziness and oscillopsia were the most frequent symptoms, present in 50-91% of patients.(Lucieer et al. 2018) Most of the studies focused mainly on those classical symptoms, several additional symptoms, such as tiredness, concentration difficulties, memory impairment, spatial disorientation, etc… were also reported. This indicates that the history taking is subtle and must be extended to cover the full spectrum of symptoms in this group of patients.(Lucieer et al. 2018) More recently a new entity was defined: the presbyvestibulopathy. It encompasses patients with at least two of the following symptoms: postural imbalance or unsteadiness, gait disturbances, chronic dizziness, recurrent falls. Additionally a bilateral abnormal residual vestibular function, but lying above the threshold for a bilateral vestibulopathy, must be

documented.(Agrawal et al. 2019) With the ongoing ageing of the population in the developed countries, a significant increase of patients presenting a progressive

bilateral loss of the vestibular function is expected. It will actually be a matter of public health, as it has been shown that bilateral vestibulopathy imposes an economic and social burden on affected patients and society(Sun et al. 2014a), and deteriorates significantly the quality of life of affected patients.(Guinand, Boselie, et al. 2012)

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Bilateral vestibulopathy can also affect children and newborn, leading to delayed motor development (Wiener-Vacher, Obeid, and Abou-Elew 2012; Rine et al. 2000) and learning difficulties.(Franco and Panhoca 2008) It could also impair various aspects of cognitive performances, such as spatial representation. It is hypothesized that deprivation of adequate vestibular information affects the development of critical regions of the hippocampus.(Wiener-Vacher, Hamilton, and Wiener 2013)

Within the frame of the vestibular implant project, our targeted population consisted of patients with a severe bilateral loss of the vestibular function. The inclusion criteria were stricter than those proposed latter by the classification committee of the Barany Society.(Strupp et al. 2017) All tests of the canal function showed minimal residual vestibular function. Although the otolithic function was systematically assessed it was not included in the inclusion criteria. In a group of 39 patients diagnosed with a

bilateral vestibular loss defined according our criteria, in almost half of the cases the etiology remained unknown. The ototoxic etiology was found in 7 patients, due to gentamicin in six cases and cisplatin in one case. Genetic, infectious, autoimmune and traumatic etiologies were also reported. Finally one patient had a bilateral Menière Disease.(Guinand, Boselie, et al. 2012) Other studies using the Barany criteria or other criteria have also found heterogeneous etiologies and variable

percentage of idiopathic cases (16-50%).(Zingler et al. 2007; Kattah 2018; Lucieer et al. 2016)

To date, the evidence for an effective treatment for patients with a bilateral vestibular loss is scarce (Zingler et al. 2008; Guinand, Boselie, et al. 2012; Sun et al. 2014b). It has been shown that some vestibular rehabilitation protocols can improve the

vestibular function in this patients’ group. However, the dynamic symptoms mainly remain. Moreover, there is no evidence of long term benefit.(Krebs et al. 2003;

Herdman et al. 2007; Gimmon et al. 2019) Other treatment options such as sensory substitution with auditory or vibrotactile feedback has shown contrasting results and is still under clinical investigation.(Janssen et al. 2010; Honegger et al. 2013; Ma et al. 2015; Kingma et al. 2019) Two teams reported a positive impact on stance and gait when noisy galvanic stimulation was applied on the mastoids. Stochastic resonance is thought to be the underlying mechanism. Although it opens very interesting perspectives, the level of evidence of this strategy is still low and its

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clinical application remains unclear.(Wuehr et al. 2016; Iwasaki et al. 2014) The vestibular implant is another promising concept towards the rehabilitation of the vestibular function (Guyot and Perez Fornos 2018). We believe this strategy has the highest potential to alleviate the chronic dynamic symptoms due to the bilateral vestibular loss. Indeed none of the other sensory systems involved in balance are fast enough.

1.3 Assessment of the vestibular system

Testing of the vestibular system is a challenging task. Indeed, angular or linear accelerations represent the adequate stimuli to activate the vestibular system. It is therefore virtually impossible to test the vestibular system independently, in particular without simultaneous activation of other sensory modalities (i.e., the somatosensory system). Although significant development has been made in the field of vestibular testing in the last decades, due the involvement of the vestibular system in a

multidimensional system, its holistic assessment remains challenging. The majority of tests still rely on the measurements of reflexes. Tests of the canal function are mainly based on the assessment of the vestibulo-ocular reflex (VOR) (i.e. calorics, rotatory chair, video Head Impulse Test…). The assessment of the otolithic function is mainly based on the recording of vestibular evoked myogenic potentials (VEMPs). All those tests only partly reflect the whole vestibular function. Moreover correlation with the patients’ symptoms quality and severity limited.

Several other tests corresponding to functionally relevant tasks have been

developed. Visual acuity in various dynamic conditions, such as while walking on a treadmill or during unpredictable passive head movements, has been shown to be a sensitive test of the integration of vestibular input into the balance system (Vital et al.

2010; Guinand, Pijnenburg, et al. 2012; Lambert et al. 2010; Herdman et al. 1998;

Schubert, Migliaccio, and Della Santina 2006). More recently, the functional head impulse test (fHIT) has been proposed. It consists in testing gaze ability during passive head impulses with high accelerations of 3000-6000°/s².(Bohler, Mandala, and Ramat 2010; Colagiorgio et al. 2013; Ramat et al. 2012) In patients with a bilateral vestibular loss, the fHIT results showed a better correlation with oscillopsia

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severity than the loss of visual acuity measured while walking on a treadmill. (van Dooren et al. 2019)

Assessment of motion perception thresholds allows exploring a different vestibular pathway to cortical regions. Although there is still a debate about the topographic delimitation of the cortex receiving the outputs from the peripheral vestibular system, significant progress and convincing results have been achieved with laborious motion perception thresholds protocols (Priesol et al. 2014). A group of experts of the

vestibular system foresees such tests to become part of the routine vestibular testing battery in the future. However this method has several important drawbacks. Indeed, heavy and expensive equipment is necessary, the test is time consuming (several hours) and it is barely impossible to rule out an effect of the somatosensory system.

Promisingly, it has been recently demonstrated that by using a modified protocol it is possible to obtain similar pattern of motion perception thresholds in a significantly reduced testing duration (<60 min). (Dupuits et al. 2019).

Posturography is another strategy to assess the vestibular function. It aims to evaluate postural control in different conditions (i.e. eyes open/eyes closed, hard floor/foam etc…). Although it is used by many clinicians, a group of experts in the field concluded that posturography doesn’t provide reasonable sensitivity and specificity for the diagnosis of vestibular disorders. (Kingma et al. 2011) They

suggested that perturbation techniques are most likely necessary in order to enhance the diagnostic yield. Finally, the impact of the vestibular function on gait is being under investigation. The challenge is to find the relevant parameters among a myriad of variables. The step width could be a promising parameter (unpublished data).

This points out that although the already available tests represents a good starting point to assess the performance of the vestibular implant, there is a clear need to further design tests that are more specific and with a better correlation to the symptoms. This is a challenge that has still to be overcome.

1.4 The vestibular implant: a neuroprosthesis to restore vestibular function The theoretical aim of the vestibular implant is to substitute the natural peripheral vestibular function, in all its multiple dimensions. Further in the text, we will expose

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the first steps undertaken towards this ambitious goal and report the most significant achievements.

The concept of the vestibular implant is based on another neuroprosthesis of the inner ear, the cochlear implant. The cochlear implant has been successful for now several decades in restoring functional hearing in case of severe to profound deafness. While the cochlear implant is made to capture sound and includes a microphone, the vestibular implant must capture head motion, therefore it includes head-fixed motion sensors. The captured motion information feeds a special processor (Pelizzone et al. 2013) where it is transformed into a neural pattern of electrical pulses. This information is then conveyed to the implanted stimulator via telemetry. The implanted stimulator is a modified cochlear implant stimulator with 1 up to 3 “vestibular” electrodes removed from the cochlear electrode array and put into separate branches designed to be positioned in the vicinity of the ampullary branches of the vestibular nerve. The electrodes have been specially designed; they are made of a mixture of Platinium and Iridium. Their shaft is stiff and coated, of variable length.

The ball tip of the electrode has a diameter in the range of 10² µm (Figure 1).

Figure 1 -- The implanted part of the vestibular implant consists in a modified cochlear implant stimulator (MED-EL, Innsbruck, Austria). In this example, 3 electrodes were removed from the cochlear array. Each of those vestibular electrodes will be implanted in the vicinity of the lateral, superior or posterior ampullary nerve. (Guinand, van de Berg, et al. 2015)

It is important to mention that, as could be expected from psychophysical studies that determined the minimum number of stimulation channels needed to achieve

language comprehension, reducing the number of “cochlear” electrodes down to 9 has no significant impact on the auditory performance.

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Finally, the neural patterns of processed motion information are provided to the central nervous system in the form of amplitude-modulated electrical currents delivered via the vestibular electrodes. (Figure 2)

Figure 2 -- The vestibular implant concept: head fixed motion sensors capture head motion and gravity. A regular cochlear implant processor is fed with this motion information and controls via telemetry the implanted stimulator, which consists of a modified cochlear implant stimulator with 1 up to 3 electrodes retrieved from the main cochlear array. The cochlear array will be inserted into the cochlea; the vestibular electrodes will be implanted in the vicinity of the ampullary branches of the vestibular nerve using an intralabyrinthine or extralabyrinthine surgical approach. Finally, using electrical stimulation the motion information will be transmitted to the central nervous system through the vestibular pathways.

Although the aim of the vestibular implant is eventually to restore the complete vestibular function, we first focused on the semicircular canal function. The aim was to reproduce the natural, physiological functioning. In physiological conditions, in a static condition, the vestibular nerve has a resting discharge rate of about 90 action potentials per seconds.(Goldberg and Fernandez 1971) This resting discharge rate is then modulated by the activity of the vestibular hair cells which is determined by head movements and gravity. The integration of this principle together with the laws of Ewald is the fundament of the vestibular implant functioning. Indeed, each canal is highly sensitive to rotations around an axis perpendicular to their plane. As rotations in one direction induce a decrease (inhibitory) of the resting discharge rate, the opposite happens (excitatory) for rotations in the opposite direction. For example, the right lateral semicircular canal has the highest sensitivity for head rotations in the

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horizontal plane. In this plane, as head rotations to the right will induce an increase of the discharge rate of the vestibular nerve, head rotation to the left will induce a

decrease its discharge rate. Therefore, in this case, head rotations to the right are considered as excitatory and head rotations to the left as inhibitory (Figure 3).

Figure 3 – Mechano-transduction in the vestibular endorgans. Hair cells are connected to vestibular neurons which have a constant resting discharge rate. When subjected to an angular acceleration, according to its direction, the stereocilias of the hair cells are deflected to one or the other side, inducing an increase or a decrease of the discharge rate of the vestibular neurons. This allows for the bidirectional coding of rotations. The concept of the vestibular implant is based on this fundamental physiological property. Indeed, a constant baseline electrical stimulation of the vestibular neurons is first restored and then, up or down modulated according to the direction and magnitude of rotations. (Reproduced from

https://neupsykey.com/the-vestibular-system-3/#filepos3930092 )

Motion modulation of the resting discharge rate elicits, via the vestibulo-ocular reflex, compensatory eye movements of opposite direction to head movements. Each canal has the ability to generate bidirectional eye movements. This is fundamental as we aim at an unilateral restoration of the vestibular function. Practically, to restore the function of a semicircular canal with a vestibular implant, the first step is to restore the resting discharge rate. This is achieved by delivering a constant electrical

stimulation (baseline stimulation). By using incremental stimulation profiles, it can be done without discomfort for the patients. Finally, the amplitude or the rate of this baseline stimulation can be increased or decreased, in function of the direction and

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magnitude of the rotation, inducing eye movements of one or the other direction perpendicular to the plane of the stimulated canal.

1.5 Implantation procedures

Currently there are 2 different surgical approaches to the ampullary branches of the vestibular nerve. The extralabyrinthine approach was the first to be developed.(Feigl et al. 2009) By reaching the ampullary nerves outside the labyrinth, it was

hypothesized that the hearing preservation rate would be highest. The surgical approach to the posterior ampullary nerve, also called the singular nerve, was already known and mainly used for intractable benign paroxysmal positional vertigo (BPPV).(Pournaras, Kos, and Guyot 2008; Gacek 1974) The rate of hearing loss after this procedure was less than 4%.(Gacek and Gacek 2002) Note that, although for obvious ethical reasons in this project, all implanted ears were deaf, hearing preservation is a crucial issue in the population of patients with bilateral vestibular loss as the majority of them has a normal or residual hearing.(Guinand, Boselie, et al.

2012) In a second step, extralabyrinthine approaches to the lateral and superior ampullary nerves were developed.(Feigl et al. 2009) All the extralabyrinthine approaches can be done transmeatally (through the external auditory canal). They can be performed in local anesthesia. This allowed conducting per-operative assessment in the conscious patient, which was important to confirm the project’s feasibility. Later when the first vestibular implant prototypes were implanted the procedure was done in general anesthesia. Nevertheless the extralabyrinthine approaches are technically challenging and stabilization of lateral and superior ampullary nerve electrodes is still to be optimized.

As all the promising results reported by research groups working in the same field on animals were obtained by using more intuitive intralabyrinthine approaches (Dai, Fridman, Davidovics, et al. 2011; Lewis et al. 2009; Nie et al. 2013), we also

developed intralabyrinthine approaches in humans.(van de Berg et al. 2012) For this approach, a regular mastoidectomy is performed, all 3 semicircular canals are

exposed, an inframillimetric fenestration is made in each of the canal, and finally the electrodes are inserted in the labyrinth. Promisingly, hearing preservation as well as preservation of residual vestibular function has been shown to be possible in animals and humans, at least in certain cases.(Bierer et al. 2012; Rubinstein et al. 2012; Dai,

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Fridman, and Della Santina 2011; Tang, Melvin, and Della Santina 2009; Tran et al.

2012) Although this is in line with results obtained after canal plugging procedures for intractable BPPV(Agrawal and Parnes 2001), intractable Menière Disease(Charpiot, Rohmer, and Gentine 2010) or dehiscence of the superior semicircular canal(Ward et al. 2012; Wilms, Ernst, and Mittmann 2018; Van Haesendonck, Van de Heyning, and Van Rompaey 2016), long term results after vestibular implant implantation will be needed.

In contrast to the vestibular implant prototypes developed by two American teams(Phillips et al. 2013) (personal communication for the second team), our vestibular implant prototype is a hybrid system (vestibulo-cochlear). Therefore all patients had a simultaneous cochlear implantation. In their everyday life, they all benefit from the hearing rehabilitation provided by the cochlear implant. The vestibular implant is only activated in laboratory conditions.

1.6 Early “proof-of-concept”, acute experiments in patients

Using the above mentioned extralabyrinthine surgical approach, the first electrical stimulations were done in local anesthesia in 3 deaf patients before cochlear implantation. One patient had concomitant unilateral vestibular loss and the two others were diagnosed with a bilateral Menière disease. In this first experiment, only the posterior ampullary nerve was targeted. It could be shown that it is possible to elicit robust nystagmic responses predominantly in the vertical plane, which corresponds to the activation of the vestibulo-ocular reflex (VOR). Amplitude (µA) modulation showed a fairly linear positive correlation with the slow phase velocity of the nystagmus. For the frequency (pulse rate) modulation, an almost linear rise was observed until a peak, possibly representing the “optimal” frequency, followed by a progressive decline of the nystagmic response (slow phase velocity).

In patients, acute stimulations elicited different subjective percepts: “a feeling of surprise”, “an impression of rotating without nausea” and “a sensation similar to motion sickness”. Those experiments done in local anesthesia were followed by a standard insertion of a cochlear implant in general anesthesia..(Wall, Kos, and Guyot 2007)

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A similar extralabyrinthine procedure targeting the lateral and superior ampullary nerves was performed in deaf ears of three patients with unilateral intractable Menière disease before labyrinthectomy. The nystagmic responses were mainly in the horizontal plane and no co-activation of the facial nerve was observed.(Guyot, Sigrist, Pelizzone, Feigl, et al. 2011)

Later, the first acute intra-operative intralabyrinthine electrical stimulation trials of the different ampullary nerves were performed in general anesthesia in 3 deaf ears of patients with a bilateral vestibular loss prior to cochlear implantation (van de Berg et al. 2012). Drugs used for general anesthesia have a significant inhibithory effect on the VOR, particullary its fast phase. (Birns and Honrubia 1980; Nakao, Markham, and Curthoys 1980). For example,propofol (2,6-diisopropylphénol), which is a short acting hypnotic agent and is very often used to induce and maintain general anesthesia is known to have a strong inhibitory effect on the activity of the vestibular nuclei in rats.(Cavazzuti et al. 1991) Therefore, before starting our experiments with

peroperative electrical stimulations, propofol was stopped and general anesthesia was maintained with remiphentanil, a short-acting synthetic opioid. Remiphentanil is similar to fentanyl, which induces a complete inhibition of the fast phase of the VOR responses (Janeke, Jongkees, and Oosterveld 1969). Therefore, the VOR responses consisted in tonic deviations of the eyes, predominantly in the plane of the stimulated canal. When the electrical stimulation was stopped, the eyes returned to the neutral position. We hypothesized that this was a passive eye movement induced by elastic forces of the eye ball.

No short or long term complication was observed in the group of patients having participated in the above mentioned experiments.

1.7 Chronic implantations

In 2007, the first permanent implantation of a vestibular implant prototype was performed in a 69 years old male, in Geneva. The patient was diagnosed with an idiopathic bilateral vestibular loss and a concomitant severe to profound bilateral sensorineural hearing loss. This first vestibular implant prototype was a modified cochlear implant provided by MED-EL (Innsbruck, Austria). It was composed of one

“vestibular” electrode and of a cochlear array comprising 11 electrodes. The

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“vestibular” electrode was put in the vicinity of the posterior ampullary nerve using an extralabyrinthine approach. The first activation was done several weeks after the implantation. Unexpectedly, electrical stimulation of the posterior ampullary nerve induced a nystagmus predominantly in the horizontal plane. We hypothesized that a possible current spread to adjacent neural structures could have explained this misalignment. During the stimulation, the patient perceived a high pitch sound and felt dizzy. Both percepts increased with increasing current amplitude. After about half an hour of constant stimulation, the nystagmus had ceased. For the first time ever, a constant discharge rate of the vestibular nerve had been artificially restored with the vestibular implant and even more importantly the subject had adapted to it. When the electrical stimulation was finally stopped, a nystagmus of opposite direction had been observed for duration of approximatively 10 minutes. This was a further indication that adaptation had taken place. The adaptation time was decreased to few minutes by exposing the patients to successive stimulations with intervals without stimulation.

This “adapted” state maintained up to 24 hours after the vestibular implant had been switched off. (Guinand et al. 2011) This was significantly faster that previously

shown in animal research.(Merfeld et al. 2006) Those results had a significant impact as they strongly suggested that permanent activation of the vestibular implant in order to avoid long lasting unpleasant symptoms each time the device was switched on or off would not be necessary.

Furthermore, it was demonstrated that smooth eye movements could be elicited by a sinusoidal modulation of the amplitude or the frequency of the baseline electrical stimulation. The largest vestibular responses were obtained when using amplitude modulation.(Guyot, Sigrist, Pelizzone, and Kos 2011)

Since the first implantation in2007, 12 other patients (i.e., 13 successful implantations in total) have received a vestibular implant with one up to three vestibular electrodes.

(Table 1). All patients had a severe bilateral vestibular loss and the implanted ear was deaf (details on the inclusion criteria can be found in (Perez Fornos et al. 2014)).

Etiologies of the bilateral vestibular loss, and its duration were heterogeneous among the patients. Until now, no surgical complications or adverse events related to the implantations have been reported. Details regarding the first 11 implantations can be found in a previous publication.(Guinand et al. 2015)

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Table 1. Demographic 13 implanted patients.

Patient

(N=13) Sex Etiology Onset Age

(implant)

Year

implanted Side Vestibular electrodes^*

Surgical approach^•

BVL1 m Idopathic Progressive 68 2007 left PAN EL

BVL2 m Congenital/idopat

hic Progressive 34 2008 right PAN EL

BVL3 m Congenital/idopat

hic Progressive 46 2008 left PAN EL

BVL4 m

Sudden hearing loss right/

Menière disease left

Progressive 71 2011 left PAN EL

BVL5 m Traumatic Acute

(<1 year) 63 2012 right PAN/LAN EL

BVL6 f

St.p.

mastoidectomy in childhood right/traumatic

Acute

(<1 year) 67 2013 left PAN/LAN/

SAN IL

BVL7 f St.p. meningitis at age of 1

Acute

(47 years) 48 2012 right PAN/LAN/

SAN IL

BVL8 m DFNA9 Progressive 67 2012 left PAN/LAN/

SAN IL

BVL9 f DFNA9 Progressive 68 2013 left PAN/LAN/

SAN IL

BVL10 m DFNA9 Progressive 66 2013 left PAN/LAN/

SAN IL

BVL11 m DFNA9 Progressive 64 2013 left PAN/LAN/SA

N IL

BVL12 m Traumatic Acute

(3 years) 53 2015 right PAN/LAN/

SAN IL

BVL13 f Idopathic Progressive 56 2016 Left PAN/LAN/

SAN IL

*PAN- posterior ampullary nerve; LAN – lateral ampullary nerve; SAN- superior ampullary nerve

•EL – extralabyrinthic; IL – intralabyrinthic; BVL- bilateral vestibular loss

To our knowledge, three other teams have performed vestibular implantations in humans. The team of Della Santina at the Johns Hopkins University in Baltimore (USA), the team of Rubinstein at the University of Washington in Seattle (USA) and the team of Ramos from Spain. The two American teams have developed vestibular

“only” implant prototypes. Those prototypes are also modified cochlear implants, however without any cochlear electrodes. Both teams use intralabyrinthine approaches.

The Rubinstein’s group has developed a specially designed nine-channel vestibular implant based on a Nucleus Freedom cochlear implant (Cochlear, Sydney, Australia).

The devices had three leads that were implanted in each canal. Every lead had three stimulation sites. (Golub et al. 2014; Phillips, Ling, Nie, et al. 2015) Their initial

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concept was different from ours. Indeed, their vestibular device was concieved to act as a pace maker that could regulate the vestibular attacks in patients with severe Menière disease. They initally implanted 4 patients with intractable Menière disease.

Only one patient sufferedexperienced a characteristictypical Menière’s crisis after having been implanted. The vestibular implant was activated during this crisis, which led to a decrease of the symptoms’ severity. Although promising, no other attack of Menière’s disease had been observed. This was most likely due to the significant loss of the vestibular function reported in those 4 patients after the implantation...

Moreover the pre-operative residual hearing could not be preserved in any of the 4 implanted patients. Still, the principle of a vestibular pacemeker developed to control the fluctuation of the vestibular function in patients suffering handicapping Menière’s disease is an interesting concept and represents a potential therapeutic application of the vestibular implant. More recently the same team has decided to target the

population of patients with a bilateral vestibular loss. They have slightly modified their prototype and have implanted additional patients (personnal communication). We are not aware of already published results.

The group of Della Santina works with the company MED-EL (Innsbruck, Austria).

Like us they target patients with bilateral vestibular loss, predominantly following ototoxic treatments (gentamicin). However in contrast to our candidates who must have a severe bilateral vestibular loss and at least a deaf ear, their inclusion criteria allow enrollement of candidates with variable residual vestibular function and a normal hearing. Up to now they have implanted between 5 and 10 patients. All or most of the implanted patients wear the device permanently outside of the hospital.

Some patients have reported a subjective improvement. Moreover, promisingly, Della Santina reported a certain level of hearing preservation in some implanted patients (personnal communication). However, we are not aware of published results.

A consortium, led by Ramos, from Spain, has obtained a significant European grant for the developpment of a vestibular implant aiming to restore the otolithic function (https://cordis.europa.eu/project/rcn/216320/factsheet/en). They work with the companty Cochlear (Sydney, Australia). Apparently, they have recently implanted patients. We are not aware of any available data.

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2-Artificial angular Vestibulo-ocular reflex (VOR)

After having shown that, in static conditions, using a sinusoidal signal to modulate the restored baseline electrical stimulation of the ampullary branches of the vestibular nerve, it was possible to generate bidirectional smooth eye movements(Guyot, Sigrist, Pelizzone, and Kos 2011), the next step was to demonstrate that the VOR could be generated by a real movement. This was explored, first by using a conventional rotatory chair generating rotations around an earth vertical axis and secondly by using the video head impulse test. The range of frequencies and angular velocities explored is different in the two tests. Although both tests only assess a limited range of the functional spectrum of the vestibular system, they are essential for the clinical assessment of patients with impairment of the balance system.

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2.1 Low to high frequencies and low to medium angular velocities

In this milestone paper, for the first time, restoration of an artificial VOR in response to a natural movement was demonstrated in three patients with a vestibular implant prototype using current clinical tests. Patients sat on a rotatory chair which generated sinusoidal earth vertical rotations in the frequency range of 0.1Hz to 2Hz and a peak angular velocity of 30°/s. While 0.1Hz is considered as a low frequency for the vestibular system, 2Hz already lies in the high frequency domain. Compared to the head impulse test where angular velocities above 200°/s are reached, 30°/s can be considered as a rather low to medium angular velocity.

In this experiment, the aim was to restore an almost purely horizontal (around an earth vertical axis) VOR, therefore the motion information was transmitted to the central nervous system by modulation of the baseline electrical stimulation delivered to the sole lateral ampullary nerve. In the three patients the placement of the

vestibular electrodes was intralabyrinthine. All tests were performed in complete darkness to suppress the contributions of the visual system. Eye movements were recorded using a bidimensional video eye-tracker in two conditions: 1) with the active vestibular implant (“System ON”) and 2) with the inactive vestibular implant (“system OFF”). The VOR gains were computed for each tested frequency. With the “System ON”, the VOR gain significantly increased for rotation frequencies of 0.5, 1 and 2Hz, but not for lower frequencies of 0.1 and 0.25Hz. A positive correlation between the modulation depth (stimulation intensity) and the electrically evoked VOR gains was found. In the best case, when the stimulation depth was increased to 75% of the available dynamic range, the electrically evoked VOR gain became close to normal.

Althgough only three patients were involved and only a limited range of motion profiles were tested, those results represents the first demonstration of a functional restoration of the VOR using a vestibular implant in human patients.

A consecutive experiment later demonstrated that the frequency dependency of the artificially electrically evoked VOR was similar to that observed in age matched healthy subjects.(van de Berg et al. 2014)

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ORIGINAL RESEARCH ARTICLE published: 29 April 2014 doi: 10.3389/fneur.2014.00066

Artificial balance: restoration of the vestibulo-ocular reflex in humans with a prototype vestibular neuroprosthesis

Angelica Perez Fornos¹*^†, Nils Guinand¹^†, Raymond van de Berg², Robert Stokroos², Silvestro Micera^3,4, Herman Kingma², Marco Pelizzone¹and Jean-Philippe Guyot¹

1Service of Otorhinolaryngology and Head and Neck Surgery, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland

2Division of Balance Disorders, Department of Otorhinolaryngology and Head and Neck Surgery, Faculty of Health Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, Netherlands

3Translational Neural Engineering Laboratory, Center for Neuroprosthetics, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

4The BioRobotics Institute, Scuola Superiore Sant’Anna, Pisa, Italy

Edited by:

Michael Strupp,

Ludwig-Maximilians-Universität München, Germany

Reviewed by:

Michael Strupp,

Ludwig-Maximilians-Universität München, Germany

Alexandre Bisdorff, Centre Hospitalier Emile Mayrisch, Luxembourg Klaus Jahn, University of Munich, Germany

*Correspondence:

Angelica Perez Fornos, Service of Otorhinolaryngology and Head and Neck Surgery, Department of Clinical Neurosciences, Cochlear Implant Center for French Speaking Switzerland, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland e-mail: angelica.perez-fornos@

hcuge.ch

†Angelica Perez Fornos and Nils Guinand are shared first authors.

The vestibular system plays a crucial role in the multisensory control of balance. When vestibular function is lost, essential tasks such as postural control, gaze stabilization, and spatial orientation are limited and the quality of life of patients is significantly impaired.

Currently, there is no effective treatment for bilateral vestibular deficits. Research efforts both in animals and humans during the last decade set a solid background to the concept of using electrical stimulation to restore vestibular function. Still, the potential clinical benefit of a vestibular neuroprosthesis has to be demonstrated to pave the way for a translation into clinical trials. An important parameter for the assessment of vestibular function is the vestibulo-ocular reflex (VOR), the primary mechanism responsible for maintaining the perception of a stable visual environment while moving. Here we show that the VOR can be artificially restored in humans using motion-controlled, amplitude modulated electrical stimulation of the ampullary branches of the vestibular nerve.Three patients received a vestibular neuroprosthesis prototype, consisting of a modified cochlear implant providing vestibular electrodes. Significantly higher VOR responses were observed when the prototype was turned ON. Furthermore, VOR responses increased significantly as the intensity of the stimulation increased, reaching on average 79% of those measured in healthy volunteers in the same experimental conditions. These results constitute a fundamental milestone and allow us to envision for the first time clinically useful rehabilitation of patients with bilateral vestibular loss.

Keywords: vestibular implant, balance, sensory neuroprostheses, rehabilitation, vestibulo-ocular reflex

INTRODUCTION

Balance can be considered as the sixth human sense. It is the result of the synergistic processing of multisensory information that allows for the unconscious automatization of essential tasks such as postural control, gaze stabilization, and spatial orientation.

The peripheral vestibular system is part of the inner ear and it is composed of multi-dimensional motion sensors, located in the semicircular canals and in the otolithic organs. These end organs are connected to the branches of the vestibular nerve and provide information crucial to balance tasks, and any limitation in their function can significantly affect balance control. This is par- ticularly true in the case of a bilateral loss of vestibular function (BVL). Recent studies have clearly demonstrated that there are significant functional consequences to this deficit (1,2) and that these have a significant adverse impact on the quality of life of affected patients (3). Currently, there is no evidence of an effective treatment for patients with BVL. Despite intensive balance retraining, most patients show no long-term improvement of their symptoms or recovery of their vestibular function (4).

The idea of electrically stimulating the vestibular system in an attempt to rehabilitate patients with a BVL is based on a concept very similar to that of cochlear implants, which are very successful for rehabilitating patients with profound hearing loss (5). Extensive animal studies provided the first evidence sup- porting the feasibility of the idea. Already in 1963, Cohen and Suzuki showed that electrical stimulation of an ampullary branch of the vestibular nerve induces a nystagmic response predominantly in the plane of the stimulated branch (6). Several decades later, Merfeld’s team at the Jenks Vestibular Physiology Laboratory (Massachusetts Eye and Ear Infirmary, Boston, MA, USA) provided the first demonstration of the ability to generate smooth eye movements in response to bilateral (7,8) and unilateral (9,10) electrical stimulation of the ampullary branches of the vestibular nerve. The possibility of coupling motion sensors to the head and using this information to modulate the electrical stimulation delivered to the vestibular system was also systematically investigated and verified in animal models by the same authors (8,9,11) and also by Della Santina’s team at the Vestibular NeuroEngineering

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Perez Fornos et al. Artificial restoration of the VOR

Laboratory [Johns Hopkins School of Medicine, Baltimore, MA, USA; Ref. (12–15)].

Although these studies have achieved important steps in demonstrating the feasibility of the concept, it is very difficult to assess the true functional benefits that humans could derive from such a system via animal studies. First, in all animals the BVL was induced chemically or mechanically (canal plugging), which might differ significantly from the natural BVL pathophysiology. Indeed, BVL can be of various etiologies, of different durations, and thus with different levels of neurosensory involvement (16). Second, for obvious reasons it is difficult to assess the true functional benefits of a vestibular neuroprosthesis in animals. These limitations high- light the need of human research to verify the potential clinical benefit of this approach.

To our knowledge, there are only two groups in the world inves- tigating the use of electrical stimulation of the vestibular system in human patients: our group and the team lead by Rubinstein at the University of Washington (Washington, DC, USA). How- ever, their concept is fundamentally different from ours and from the one developed by Merfeld’s and Della Santina’s teams. Instead, their first approach was to develop a “vestibular pacemaker,” not intended to code motion (17). This device was directed at patients with Menière disease, in the hope to control the repeated, transient episodes of vertigo associated with the disease, but should preserve vestibular function, which is close to normal in this group of patients. They have also conducted preliminary animal studies confirming the possibility to electrically elicit eye movements (and thus effectively activate the vestibular system) with their device, and suggested that it was possible to preserve hearing and pre-existing vestibular function after implantation (18). Unfortu- nately, this was not verified in humans and both the auditory and vestibular function of implanted patients deteriorated consider- ably (17,19). Recently, this group shifted focus to a motion coding device, as mentioned in a recent publication exploring the possibility to induce body sway upon computer-controlled electrical stimulation (19).

Our research consortium has fulfilled several important prereq- uisites for the development of a system allowing for the chronic stimulation of the peripheral vestibular system in human patients (20). Special surgical techniques have been developed (21–24) and the feasibility of electrical stimulation of the three different ampullary branches of the vestibular nerve has been demonstrated both in acute (25,26) and chronic settings (27). Yet, a fundamental milestone to establish the validity of the approach should be

accomplished: to investigate whether electrical stimulation of the ampullary branches of the vestibular nerve could provide a means to effectively rehabilitate patients with BVL.

In this context, the vestibulo-ocular reflex (VOR) is of particular interest. It is one of the gold standards in vestibular testing since it can be easily quantified (gain, phase, and axis) and since it provides objective evidence of the ability to restore gaze stabilization mechanisms in patients with BVL in specific conditions.

The VOR is a reflex eye movement that allows maintaining stable gaze on the object of interest by producing an eye movement in the direction opposite to the head movement. When bilateral vestibular function is lost, the mechanisms generating these compensatory eye movements for image stabilization are inadequate. A direct functional consequence of this lack of image stabilization is an abnormal decrease of dynamic visual acuity, which makes face recognition and sign reading difficult while walking (1,2). There- fore, as a first step in the evaluation of the rehabilitation prospects of a vestibular neuroprosthesis, we decided to investigate whether the artificial restoration of the VOR is possible via electrical stimulation of an ampullary branch of the vestibular nerve, in humans suffering from BVL of different etiologies and different disease durations. For practical reasons, we focused on the stimulation of the lateral ampullary nerve (LAN), which generates in theory a one-dimensional horizontal angular VOR. Indeed, it is much easier to deliver horizontal than vertical whole-body rotations.

MATERIALS AND METHODS

We investigated whether it is possible to artificially restore the VOR in patients with BVL. We hypothesized that this could be achieved using motion-controlled, amplitude modulated electrical stimulation. Tests were performed without any electrical stimulation (system OFF) and upon electrical stimulation of the LAN (system ON). In the system ON condition, the amplitude of the electrical stimulation was modulated via the motion signal captured by an inertial sensor (gyroscope).

PATIENTS

Three patients with BVL (seeTable 1) participated in the experiments. Patients were recruited at the Service of Otorhinolaryngol- ogy and Head and Neck Surgery at the Geneva University Hospitals and at the Division of Balance Disorders at the Maastricht Univer- sity Medical Center. They fulfilled the following inclusion criteria:

(1) mean peak slow phase velocity of 5°/s or less in bilateral bither- mal (30 and 44°C) caloric irrigations with water, (2) pathologic

Table 1 | Demographics and stimulation details of the three implanted patients.

Sex Age

(implantation)

BVL etiology

Deafness Implanted ear Vestibular threshold (µA)

UCL (µA) Steady-state stimulation amplitude (µA)

BVL1 Female 58 Meningitis Unilateral Right 100 225 160

BVL2 Male 66 DFNA9 Bilateral Left 145 345 245

BVL3 Female 67 Trauma Bilateral Left 175 425 300

UCL, upper comfortable level.

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Multidimensional restitution of the vestibular function with a vestibular implant

Thesis

Reference

Multidimensional restitution of the vestibular function with a vestibular implant

" Multidimensional restitution of the

vestibular function with a vestibular implant "

Summary

Table of contents

1-Introduction

2-Artificial angular Vestibulo-ocular reflex (VOR)

Artificial balance: restoration of the vestibulo-ocular reflex in humans with a prototype vestibular neuroprosthesis