Traditional and Non-Traditional Inputs to the Vestibular System

One of the primary functions of the vestibular system is to provide stabilizing reflexes to the eye, head, and body. These reflexes are often coordinated with inputs from the visual and proprioceptive systems. More recently, research has shown that other, non-traditional, stimuli also affect the vestibular system, though the scope of this research has been limited. This thesis explores the effect of both traditional and non-traditional inputs on the vestibular system by characterizing their influence compensatory movements. We begin by looking at the influence of the vestibular periphery and efference copy on compensatory eye movements (Chapter 2). While each of these has been described individually (as the vestibular-ocular reflex (VOR) and pre-programmed eye movements (PPEM) respectively), there is currently controversy in the field regarding 1) to what extent PPEM influence gaze stabilization in healthy animals, and 2) how these two inputs interact with each other. We propose a model of gaze stability in which VOR and PPEM work cooperatively, and compare model predictions to our data as well as data others have reported. We found that our model accurately predicted eye movements for all behavioral contexts tested. In Chapter 3, we describe the effect of single high-intensity noise exposure on the vestibular system. Currently, controversy surrounds whether, and to what extent, noise damages the semi-circular canals. We characterized changes to both ocular and head stability to better answer this question and found that after noise exposure there was loss of both ocular and head stability. However, the exact nature of this deficit was not as expected and the influence of cervical pathways after vestibular lesion is discussed. Finally, in Chapter 4, we examine the effect of galvanic vestibular stimulation (GVS) and optokinetic stimulation on standing posture. We propose a model of postural stability inspired by the velocity storage model of ocular stability. While others have proposed more complex models that make similar predictions, those predictions have not been explicitly tested and, further, it’s not clear if the added complexity is necessary. We found that, while simple, our model could correctly predict subjects’ responses to both stimuli, suggesting that the body interprets and uses sensory information for postural stability in a manner similar to that for ocular stability. Taken together these findings demonstrate that the influence of non-traditional inputs and pathways to vestibular system is substantial and should be considered both in laboratory and clinical settings. Specifically, we showed in Chapter 2 that PPEM are not merely an enhanced or adapted VOR, but part of a unique gaze stabilization system that merits independent consideration. In Chapter 3, we showed that a single noise exposure can cause significant functional damage to the vestibular system, suggesting that patients with noise-induced hearing loss should be tested for vestibular loss as well. Finally, in Chapter 4, we showed that GVS can be integrated like natural vestibular stimulation but only if it is properly conditioned first. This is of particular importance for vestibular prosthetic design, which uses GVS to substitute for lost vestibular input.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143914/1/hastepha_1.pd

Evidence for a reference frame transformation of vestibular contributions to voluntary reaching movements

Les estimations des mouvements de soi provenant des signaux vestibulaires contribuent à la planification et l’exécution des mouvements volontaires du bras lorsque le corps se déplace. Cependant, comme les senseurs vestibulaires sont fixés à la tête alors que le bras est fixé au corps, les signaux vestibulaires doivent être transformés d’un système de référence centré sur la tête à un système centré sur le corps pour pouvoir contribuer de façon appropriée au contrôle moteur du bras. Le but premier de ce travail était d’étudier l’évidence d’une telle transformation. La stimulation galvanique vestibulaire (SGV) a été utilisée pour activer les afférences vestibulaires et simuler une rotation autour d’un axe naso-occipital fixe pendant que des sujets humains faisaient des mouvements du bras dans le plan horizontal, avec la tête dans différentes orientations. Une transformation des signaux vestibulaires implique que la SVG devrait simuler une rotation autour d’un axe horizontal lorsque la tête est droite et autour d’un axe vertical lorsque la tête est en flexion antérieure. La SGV devrait ainsi perturber les mouvements du bras en fonction de l’orientation de la tête. Nos résultats démontrent que les signaux vestibulaires contribuant aux mouvements d’atteinte sont effectivement transformés en un système de référence centrée sur le corps. Le deuxième but de ce travail était d’explorer les mécanismes utilisant ces signaux vestibulaires transformés. En comparant les effets de la SGV appliquée avant ou pendant les mouvements d’atteinte nous avons montré que les signaux vestibulaires transformés contribuent à des mécanismes de compensation distincts durant la planification des mouvements d’atteinte comparativement à l’exécution.Vestibular signals provide self-motion estimates that contribute to the planning and execution of voluntary reaching movements during body motion. However, because the vestibular sensors are fixed in the head whereas the arm is fixed to the trunk vestibular signals must be transformed from a head-centered to a body-centered reference frame to contribute appropriately to limb motor control. The first goal of the current work was to investigate the evidence for such a transformation. To do so we used galvanic vestibular stimulation (GVS) to selectively activate vestibular afferents and simulate rotation about a fixed roughly naso-occipital axis as human subjects performed reaching movements with the head in different orientations. If vestibular signals that contribute to reaching are transformed to body-centered coordinates, then with the head upright GVS should simulate mainly tilt about an earth-horizontal axis (roll), whereas with the head pitched forward the same stimulus should simulate rotation about an earth-vertical axis (yaw). We therefore predicted that GVS should perturb horizontal-plane reach trajectories in a head-orientation dependent manner. Our results demonstrate that vestibular signals which contribute to reaching are indeed transformed to a body-centered reference frame. The second goal of this work was to explore the mechanisms that use these transformed vestibular signals. By comparing the effect of GVS applied during versus prior to reaching we also provide evidence that transformed vestibular signals contribute to distinct compensation mechanisms for body motion during reach planning versus execution

Septal Modulation of the Hippocampus

The medial septum (MS) is the main source of acetylcholine to the hippocampus, a structure involved in memory and Alzheimer’s disease (AD). Learning and memory involve long-term changes in synaptic strengths, and are suggested to be facilitated by a brain wave, theta rhythm in the hippocampus. Since medial septal neurons influence hippocampal neural activity, lesion of two neuronal populations in the MS, cholinergic and GABAergic, was performed by intraseptal infusion of 192 IgG-saporin and orexin-saporin, respectively. I hypothesized that 1) activation of cholinergic cells by vestibular stimulation induces an atropine-sensitive theta rhythm, modulates synaptic transmission and enhances long-term potentiation (LTP), a model of synaptic plasticity, in the hippocampus and 2) GABAergic neurons regulate granule cell activity by inhibiting interneurons in the dentate gyrus (DG). Vestibular stimulation by passive whole-body rotation induced an atropine-sensitive theta rhythm that was not present in awake immobility. Following systemic cholinergic blockade, septal 192 IgG-saporin or bilateral vestibular lesion, rotation-induced theta and rotation-induced modulation of evoked potential were attenuated. LTP was enhanced when tetanus was delivered during rotation as compared to during immobility. Systemic cholinergic blockade or 192 IgG-saporin lesion abolished LTP enhancement by rotation. I provided the first report investigating the role of septal GABAergic neurons on dentate neuronal unit activity in vivo. In urethane-anesthetized sham-lesion rats, pontis nucleus oralis (PNO) stimulation induced a theta rhythm, increased spontaneous granule cell activity, facilitated DG population spike and increased paired-pulse depression (PPD) of population spikes. In freely moving rats, PPD was larger during walking as compared to during immobility. Orexin-saporin lesion attenuated theta, and blocked PNO-induced population spike facilitation and PPD in anesthetized rats. Spontaneous granule cell activity decreased while spontaneous interneuronal activity increased in orexin-saporin lesion rats as compared to sham-lesion rats. It is inferred that tonic interneuronal inhibition is increased and granule cells are less likely to be activated in orexin-saporin lesion rats, as compared to sham-lesion rats. Therefore, vestibular stimulation provides a physiological method to activate septal cholinergic neurons, consistent with improvement of cognition in humans. Vestibular stimulation may ameliorate cholinergic dysfunction deficits and targeting septal GABAergic neurons may improve behavioral functions in AD

Electrophysiological profile and monosynaptic circuitry of efferent vestibular nucleus neurons

As with other sensory modalities, the vestibular system recruits efferent circuitry to transport information from the central nervous system (CNS) to the sensory periphery. This efferent vestibular system (EVS) originates in the brainstem and terminates on vestibular hair cells and afferent fibres in the semicircular canals and otolith organs. Understanding how this central component outputs to the vestibular organs, and mediates motor and vestibular coordination, could potentially impact clinical treatment of vestibular disorders. Previous EVS work has primarily focused on the anatomy, pharmacology, synaptic mechanisms, and peripheral effects of efferent vestibular nucleus (EVN) activation. Although this work is fundamental to understanding this system and its mechanism of action, the behavioural function of the EVS is yet to be ascribed. For this, we need to appreciate the physiology of EVN neurons, and their context of activation within the CNS. In this thesis, I characterise the electrophysiological profile of EVN neurons, and trace their direct monosynaptic circuitry. My methodology includes whole-cell current- and voltage- clamp electrophysiology, and glycoproteindeficient rabies virus tracing techniques. Using these, I enrich understanding of EVN action, and hint at potential functional roles from their CNS partners. The data presented in this thesis provides novel insights into the EVS. EVN neurons are characterised with a homogeneous output, but a heterogeneous synaptic input profile. Inputs to the EVN originate from diverse areas in the brainstem and cortex. These findings suggest that the EVN modulates vestibular end organs in multiple different behavioural contexts. This work forms the basis of subsequent EVS behavioural investigations such as loss of function experiments targeting input regions via optogentic means and subsequent EVS recordings, or silencing of EVN activity and subsequent behavioural testing. Collectively, my results, these future directions, and the existing body of EVS literature, brings us closer than ever to understanding and ascribing a functional role for the EVS

Human visual-vestibular interactions during postural responses to brief falls

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1980.MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING.Bibliography: leaves 263-276.by Roger William Wicke.Ph.D

Évaluation du contrôle sensorimoteur chez les patients ayant une scoliose idiopathique de l'adolescent : vers un biomarqueur des troubles sensorimoteur basé sur la stimulation vestibulaire galvanique

La scoliose est la pathologie déformante du rachis la plus courante de l'adolescence. Dans 80 % des cas, elle est idiopathique, signifiant qu'aucune cause n'a été associée. Les scolioses idiopathiques répondent à un modèle multifactoriel incluant des facteurs génétiques, environnementaux, neurologiques, hormonaux, biomécaniques et de croissance squelettique. Comme hypothèse neurologique, une anomalie vestibulaire provoquerait une asymétrie d'activation des voies vestibulospinales et des muscles paravertébraux commandés par cette voie, engendrant la déformation scoliotique. Certains modèles animaux permettent de reproduire ce mécanisme. De plus, des anomalies liées au système vestibulaire, comme des troubles de l'équilibre, sont observées chez les patients avec une scoliose. La stimulation vestibulaire galvanique permet d'explorer le contrôle sensorimoteur de l'équilibre puisqu'elle permet d'altérer les afférences vestibulaires. L'objectif de cette thèse est d'explorer le contrôle sensorimoteur en évaluant la réaction posturale provoquée par cette stimulation chez les patients et les participants contrôle. Dans la première étude, les patients sont plus déstabilisés que les contrôles et il n'y a pas de lien entre l'ampleur de l'instabilité et la sévérité de la scoliose. Dans la deuxième étude, à l’aide d’un modèle neuromécanique, un poids plus grand aux signaux vestibulaires a été attribué aux patients. Dans la troisième étude, un problème sensorimoteur est également observé chez les jeunes adultes ayant une scoliose, excluant ainsi que le problème soit dû à la maturation du système nerveux. Dans une étude subséquente, des patients opérés pour réduire leur déformation du rachis, montrent également une réaction posturale de plus grande amplitude à la stimulation comparativement à des participants contrôle. Ces résultats suggèrent que l’anomalie sensorimotrice ne serait pas secondaire à la déformation. Finalement, un algorithme a été développé pour identifier les patients ayant un problème sensorimoteur. Les patients montrant un contrôle sensorimoteur anormal ont également une réponse vestibulomotrice plus grande et attribuent plus de poids aux informations vestibulaires. Globalement, les résultats de cette thèse montrent qu’un déficit sensorimoteur expliquerait l’apparition de la scoliose mais pas sa progression. Le dysfonctionnement sensorimoteur n’est pas présent chez tous les patients. L’algorithme permettant une classification de la performance sensorimotrice pourrait être utile pour de futures études cliniques.Scoliosis is the most frequent spinal deformity in adolescence. In 80% of the cases, it is idiopathic, meaning that no cause has been associated with the patient's case. Idiopathic scoliosis seems to respond to a multifactorial model including genetic, environmental, neurological, hormonal, biomechanical and skeletal growth factors. A neurological assumption is that an anomaly of the vestibular system would cause asymmetrical activation of the vestibulospinal pathway and of paraspinal muscles. This cascade would generate the scoliotic deformity. Animal models have demonstrated this possibility. In addition, many vestibular related anomalies are observed in adolescents with scoliosis as vestibulo-ocular reflex abnormalities or balance control disorders. Galvanic vestibular stimulation allows exploring sensorimotor control by faltering the vestibular afferents. The objective of this thesis is to explore the sensorimotor control through vestibular-evoked postural response in patients with scoliosis and healthy controls. The results of the first study show that the vestibular-evoked postural response is larger in patients compared to controls. Moreover, the amplitude of the postural response is not scaled to the spinal deformation amplitude. In a second study, through a neuromechanical feedback control model, we demonstrate that patients assigned a larger weight to vestibular signal compared to controls. Results of the third study reveal that young adults with idiopathic scoliosis, compared to controls, have a larger postural response. This observation excludes a transient response due to the maturation of the nervous system. Then, balance control impairment seems secondary to a neurosensory phenomenon as balance control dysfunction is observed in patients who had surgery reducing spine deformation. Ultimately, an algorithm has been developed to distinguish patients with or without sensorimotor control problems compared to healthy adolescents. Remarkably, the amplitude of the feedforward vestibular response of these patients is larger and they assign a larger weight to vestibular than proprioceptive information. Overall, this thesis proposes a procedure to identify patients with scoliosis having sensorimotor control impairment. In the end, it is believed that the classification procedure may help future clinical studies as patients with sensorimotor dysfunction could be identified. Hopefully, future research will enhance this procedure and lead to an efficient biomarker

The Intrinsic Plasticity Of Medial Vestibular Nucleus Neurons During Vestibular Compensation: A Systematic Review And Meta-Analysis

The diversity of activity displayed by neurons of the central nervous system is unmatched by any other cell in the body. Each neuron displays a characteristic, stereotypic pattern of firing which often defines its functional role (Llinas, 1988). Some neurons are spontaneously active at rest, displaying pacemaker-like properties, while others are very quiescent until stimulated by synaptic inputs. Some neurons fire rapid, regular action potential trains which show little deterioration in frequency over time. Others fire only short bursts of action potentials and reduce their rate of firing quickly, producing very little response to even large inputs (Bean, 2007). These discharge characteristics are fundamentally determined by two main features: the intrinsic membrane properties of the neuron and the nature of the synaptic inputs the neuron receives. Intrinsic properties are those relating to the architecture of the neuronal membrane, intracellular ionic buffers that regular electrolyte concentrations and the types of ion channels expressed on the membrane and their pattern of distribution (Wijesinghe & Camp, 2011). Meanwhile, synaptic properties are determined by the types of transmitters arriving at the neuronal surface, the distribution of these synapses and their density over various functionally specialised regions of the neuron (Spruston, 2008). From the various permutations of these different properties emerges the vast array of different firing characteristics observed of individual neurons from different regions of the brain (Llinas, 2014). Despite the prevalent stereotypy observed across different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum & Kandel, 2012; Sweatt, 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck & Yaari, 2008; Camp, 2012; Vitureira, Letellier & Goda, 2012; Yin & Yuan, 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Bailey, Kandel & Harris, 2015; Kandel, 2001). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously attributed to synaptic mechanisms alone (Desai, 2003; Hanse, 2008; Mozzachiodi & Byrne, 2010; Titley, Brunel & Hansel, 2017). A number of studies in the past 30 years have demonstrated important activity-dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Beraneck & Idoux, 2012; Camp & Wijesinghe, 2009). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties (for example see previous work in Camp & Wijesinghe, 2009; Wijesinghe & Camp, 2011; Wijesinghe, Solomon & Camp, 2013; Wijesinghe et al., 2015). In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains our sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg et al., 2012). It mediates basic reflexes that maintain gaze stability during head movement and stabilises dynamic posture (Bronstein, Patel & Arshad, 2015). This sensory modality also has a unique property of near immediate recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys & Halmagyi, 1995). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient model to bridge in vitro findings to clinical observations (Straka, Zwergal & Cullen, 2016). Recent studies have suggested that vestibular compensation may be behavioural correlate of a form of experience-dependent plasticity occurring within the vestibular nuclei of the brainstem (Dutia, 2010; Lacour & Tighilet, 2010; Macdougall & Curthoys, 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons in a way that is necessary for the process to occur. In the thesis that follows, I present the first comprehensive systematic review of the scientific literature searching for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during the acute phase of vestibular compensation. To determine the methodological quality of studies discovered through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 17 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is evidence in favour of the hypothesis. Then, pooling quantitative data from this evidence, I performed a meta-analysis which demonstrates a moderate, statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, their spontaneous discharge rate increases by 4 spikes/sec on average and their sensitivity (or gain) in response to current stimuli increases. Using this novel approach, I demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental studies with similar aims. I also identify a number of areas in which the reporting of experimentation in field of vestibular research can be improved to strengthen the quality and validity of future work. Despite the prevalent stereotypy observed different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum et al. 2012, Sweatt 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck and Yaari 2008, Camp 2012, Vitureira, Letellier et al. 2012, Yin and Yuan 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Kandel 2001, Bailey, Kandel et al. 2015). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously solely attributed to synaptic mechanisms (Desai 2003, Hanse 2008, Mozzachiodi and Byrne 2010, Titley, Brunel et al. 2017). A number of studies in the past 20 years have demonstrated important activity dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Camp and Wijesinghe 2009, Beraneck and Idoux 2012). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties. In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains an animal’s sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg, Wilson et al. 2012). It mediates basic reflexes that maintain gaze stability during head movement (vestibuloocular reflex) and stabilises posture (vestibulospinal reflex) (Bronstein, Patel et al. 2015). This sensory modality also has a unique property of near immediate and complete recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys and Halmagyi 1995). For example, following unilateral peripheral vestibular lesions, the acute symptom of vertigo and its behavioural effects abate spontaneously within days (Fetter 2016). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient and ideal model to bridge in vitro findings to clinical observations (Straka, Zwergal et al. 2016). Recent studies have suggested that vestibular compensation may be a form of experience dependent plasticity which occurs within the brainstem vestibular reflex arc, most clearly in the vestibular nuclei (Dutia 2010, Lacour and Tighilet 2010, Macdougall and Curthoys 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons. Many of these changes are of the firing patterns and sensitivity to external stimuli, reflecting changes in the intrinsic properties of these. In the thesis that follows, I present a systematic review of the scientific literature looking for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during vestibular compensation. To determine the quality of studies revealed through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 16 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is moderate amount of moderate quality evidence, and a small amount of high quality evidence, in favour of the hypothesis. Further, using quantitative data from rodent models of compensation, I performed a meta-analysis which demonstrates strong, statistically significant evidence in favour of the hypothesis. In summary, published evidence to date supports the notion that unilateral vestibular lesions induce changes in the intrinsic membrane properties of medial vestibular nucleus neurons such that their spontaneous discharge rate increases and their sensitivity (or gain) in response to current stimuli increases