Paolo Colagiorgio

A New Tool for Investigating the Functional Testing of the VOR

Peripheral vestibular function may be tested quantitatively, by measuring the gain of the angular vestibulo-ocular reflex (aVOR), or functionally, by assessing how well the aVOR performs with respect to its goal of stabilizing gaze in space and thus allow to acquire visual information during the head movement. In recent years, several groups have developed clinical and quantitative approaches to functional testing of the vestibular system based on the ability to identify an optotype briefly displayed on screen during head rotations. Although the proposed techniques differ in terms of the parameters controlling the testing paradigm, no study has thus far dealt with understanding the role of such choices in determining the effectiveness and reliability of the testing approach. Moreover, recent work has shown that peripheral vestibular patients may produce corrective saccades during the head movement (covert saccades), yet the role of these eye movements toward reading ability during head rotations is not yet understood. Finally, no study has thus far dealt with measuring the true performance of their experimental setups, which is nonetheless likely to be crucial information for understanding the effectiveness of functional testing approaches. Thus we propose a new software and hardware research tool allowing the combined measurement of eye and head movements, together with the timing of the optotype on screen, during functional testing of the vestibulo-ocular reflex (VOR) based on the Head Impulse Test. The goal of such tool is therefore that of allowing functional testing of the VOR while collecting the experimental data necessary to understand, for instance, (a) the effectiveness of the covert saccades strategy toward image stabilization, (b) which experimental parameters are crucial for optimizing the diagnostic power of the functional testing approach, and (c) which conditions lead to a successful reading or an error trial.

The Effect of Vestibulo-Ocular Reflex Deficits and Covert Saccades on Dynamic Vision in Opioid-Induced Vestibular Dysfunction

Patients with bilateral vestibular dysfunction cannot fully compensate passive head rotations with eye movements, and experience disturbing oscillopsia. To compensate for the deficient vestibulo-ocular reflex (VOR), they have to rely on re-fixation saccades. Some can trigger “covert” saccades while the head still moves; others only initiate saccades afterwards. Due to their shorter latency, it has been hypothesized that covert saccades are particularly beneficial to improve dynamic visual acuity, reducing oscillopsia. Here, we investigate the combined effect of covert saccades and the VOR on clear vision, using the Head Impulse Testing Device – Functional Test (HITD-FT), which quantifies reading ability during passive high-acceleration head movements. To reversibly decrease VOR function, fourteen healthy men (median age 26 years, range 21–31) were continuously administrated the opioid remifentanil intravenously (0.15 µg/kg/min). VOR gain was assessed with the video head-impulse test, functional performance (i.e. reading) with the HITD-FT. Before opioid application, VOR and dynamic reading were intact (head-impulse gain: 0.87±0.08, mean±SD; HITD-FT rate of correct answers: 90±9%). Remifentanil induced impairment in dynamic reading (HITD-FT 26±15%) in 12/14 subjects, with transient bilateral vestibular dysfunction (head-impulse gain 0.63±0.19). HITD-FT score correlated with head-impulse gain (R = 0.63, p = 0.03) and with gain difference (before/with remifentanil, R = −0.64, p = 0.02). One subject had a non-pathological head-impulse gain (0.82±0.03) and a high HITD-FT score (92%). One subject triggered covert saccades in 60% of the head movements and could read during passive head movements (HITD-FT 93%) despite a pathological head-impulse gain (0.59±0.03) whereas none of the 12 subjects without covert saccades reached such high performance. In summary, early catch-up saccades may improve dynamic visual function. HITD-FT is an appropriate method to assess the combined gaze stabilization effect of both VOR and covert saccades (overall dynamic vision), e.g., to document performance and progress during vestibular rehabilitation.

A device for the functional evaluation of the VOR in clinical settings

We developed the head impulse testing device (HITD) based on an inertial sensing system allowing to investigate the functional performance of the rotational vestibulo-ocular reflex (VOR) by testing its gaze stabilization ability, independently from the subject’s visual acuity, in response to head impulses at different head angular accelerations ranging from 2000 to 7000 deg/s2. HITD was initially tested on 22 normal subjects, and a method to compare the results from a single subject (patient) with those from controls was set up. As a pilot study, we tested the HITD in 39 dizzy patients suffering, non-acutely, from different kinds of vestibular disorders. The results obtained with the HITD were comparable with those from the clinical head impulse test (HIT), but an higher number of abnormalities was detectable by HITD in the central vestibular disorders group. The HITD appears to be a promising tool for detecting abnormal VOR performance while providing information on the functional performance of the rotational VOR, and can provide a valuable assistance to the clinical evaluation of patients with vestibular disorders.

A Wearable and Modular Inertial Unit for Measuring Limb Movements and Balance Control Abilities

Measuring human movement has many useful applications ranging from fall risk assessment, quantifying sports exercise, studying people habits, and monitoring the elderly. Here, we present a versatile, wearable device based on a 9-degrees-of-freedom inertial measurement unit conceived for providing objective measurements of trunk or limb movements for the assessment of motor and balance control abilities. The proposed device measures linear accelerations, angular velocities, and heading and can be configured to either wirelessly transmit the raw or preprocessed data to a computer for online use, e.g., visualization or further processing, or to store the acquired data locally for long-term monitoring during free movement. Furthermore, the device can work in either single sensor or multiple sensors configuration, to simultaneously record several body parts for monitoring full body kinematics. Here, we compare body sway and trunk kinematic data computed based on our sensor with those based on the data from a force platform and a marker-based motion tracker, respectively, during the evaluation of both static and dynamic exercises drawn from clinical balance scales. Results from these experiments on two populations of healthy subjects are encouraging and suggest that the proposed device can effectively be used for measuring limb movements and to assess balance control abilities.

Multiple timescales in the adaptation of the rotational VOR.

Goal-directed movements, such as pointing and saccades, have been shown to share similar neural architectures, in spite of the different neuromuscular systems producing them. Such structure involve an inverse model of the actuator being controlled, which produces the commands innervating the muscles, and a forward model of the actuator, which predicts the sensory consequences of such commands and allows online movement corrections. Recent studies have shown that goal-directed movements also share similar motor-learning and motor-memory mechanisms, which are based on multiple timescales. The hypothesis that also the rotational vestibulo-ocular reflex (rVOR) may be based on a similar architecture has been presented recently. We hypothesize that multiple timescales are the brains solution to the plasticity-stability dilemma, allowing adaptation to temporary and sudden changes while keeping stable motor-control abilities. If that were the case, then we would also expect the adaptation of reflex movements to follow the same principles. Thus we studied rVOR gain adaptation in eight healthy human subjects using a custom paradigm aimed at investigating the existence of spontaneous recovery, which we considered as the hallmark of multiple timescales in motor learning. Our experimental results show that spontaneous recovery occurred in six of eight subjects. Thus we developed a mathematical model of rVOR adaptation based on two hidden-states processes, which adapts the cerebellar-forward model of the ocular motor plant, and show that it accurately simulates our experimental data on rVOR gain adaptation, whereas a single timescale learning process fails to do so.

New insights into vestibular-saccade interaction based on covert corrective saccades in patients with unilateral vestibular deficits

In response to passive high-acceleration head impulses, patients with low vestibulo-ocular reflex (VOR) gains often produce covert (executed while the head is still moving) corrective saccades in the direction of deficient slow phases. Here we examined 23 patients using passive, and 9 also active, head impulses with acute (< 10 days from onset) unilateral vestibular neuritis and low VOR gains. We found that when corrective saccades are larger than 10°, the slow-phase component of the VOR is inhibited, even though inhibition increases further the time to reacquire the fixation target. We also found that 1) saccades are faster and more accurate if the residual VOR gain is higher, 2) saccades also compensate for the head displacement that occurs during the saccade, and 3) the amplitude-peak velocity relationship of the larger corrective saccades deviates from that of head-fixed saccades of the same size. We propose a mathematical model to account for these findings hypothesizing that covert saccades are driven by a desired gaze position signal based on a prediction of head displacement using vestibular and extravestibular signals, covert saccades are controlled by a gaze feedback loop, and the VOR command is modulated according to predicted saccade amplitude. A central and novel feature of the model is that the brain develops two separate estimates of head rotation, one for generating saccades while the head is moving and the other for generating slow phases. Furthermore, while the model was developed for gaze-stabilizing behavior during passively induced head impulses, it also simulates both active gaze-stabilizing and active gaze-shifting eye movements.NEW & NOTEWORTHY During active or passive head impulses while fixating stationary targets, low vestibulo-ocular gain subjects produce corrective saccades when the head is still moving. The mechanisms driving these covert saccades are poorly understood. We propose a mathematical model showing that the brain develops two separate estimates of head rotation: a lower level one, presumably in the vestibular nuclei, used to generate the slow-phase component of the response, and a higher level one, within a gaze feedback loop, used to drive corrective saccades.

A role for NMDAR-dependent cerebellar plasticity in adaptive control of saccades in humans

BACKGROUND Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated. OBJECTIVE To test the role of cerebellar plasticity phenomena on adaptive saccade control. METHODS We evaluated the effect of continuous theta burst stimulation (cTBS) over the posterior vermis on saccade amplitude adaptation and spontaneous recovery of the initial response. To further identify the substrate of synaptic plasticity responsible for the observed adaptation impairment, subjects were pre-treated with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. RESULTS Amplitude adaptation was altered by cTBS, suggesting that cTBS interferes with cerebellar plasticity involved in saccade adaptation. Amplitude adaptation and spontaneous recovery were not affected by cTBS when recordings were preceded by memantine administration. CONCLUSION The effects of cTBS are NMDAR-dependent and are likely to involve long-term potentiation or long-term depression at specific synaptic connections of the granular and molecular layer, which could effectively take part in cerebellar motor learning.

Extraction of traditional COP-based features from COM sway in postural stability evaluation

Postural control during quiet standing is evaluated by analyzing CoP sway, easily measured using a force platform. However, recent proliferation of motion tracking systems made easily available an estimate of the CoM location. Traditional CoP-based measures presented in literature provide information about age-related changes in postural stability and fall risk. We investigated, on an age-matched group of subjects, the relationship between classical CoP-based measures computed on sway path and statistical mechanics parameters on diffusion plot, with those extracted from CoM time-series. Our purpose is to understand which of these parameters, computed on CoM sway, can discriminate postural abnormalities, in order to use a video tracking system to evaluate balance in addition to motor capabilities.

A wearable system for measuring limb movements and balance control abilities based on a modular and low-cost inertial unit.

Monitoring balance and movement has proven useful in many applications ranging from fall risk assessment, to quantifying exercise, studying people habits and monitoring the elderly. Here we present a versatile, wearable instrument capable of providing objective measurements of limb movements for the assessment of motor and balance control abilities. The proposed device allows measuring linear accelerations, angular velocities and heading either online, through wireless connection to a computer, or for long-term monitoring, thanks to its local storage abilities. One or more body parts may be simultaneously monitored in a single or multiple sensors configuration.

Bilateral vestibular impairment in Vogt Koyanagi Harada syndrome: a case report

Vogt Koyanagi Harada (VKH) syndrome is an autoimmune disorder that targets melanocytes and melanocyte-associated antigens. It is characterized by chorioretinitis, but may include neurological, dermatological, and audio-vestibular manifestations. Hypoacusis and tinnitus may be so severe that a cochlear implant is needed, while vestibular impairment is usually mild andmost often revealed only by clinical or instrumental findings. A 58-year-old Caucasian woman was referred to our attention for vertigo and severe bilateral visual loss which had started 7 years before. At that time, there was no evidence of past or current neurological, auditory, or cutaneous manifestations. Based on the results of fundus examination, OCT, and fluorescein angiography, and in the absence of a previous penetrating ocular trauma or surgery, and the negative laboratory findings, the diagnosis of probable VKH (isolated ocular disease) was made. The vertigo sensation was explained as a consequence of the visual loss. Her HLA was DR7/DRw53 and DRB1*07. After steroid and cyclosporine therapy, the visual symptoms recovered, but they relapsed each time the immunosuppressive treatment was tapered. When we saw her, visual acuity was normal and she described her vertigo as a sensation of unsteadiness that probably started before the onset of visual symptoms and had slowly worsened over the years until it became difficult for her to stand steadily in conditions of dim or no light, and she complained of oscillopsia while walking or moving her head. On neurological examination, the head impulse test (HIT) showed corrective overt saccades in all directions, suggesting that the vestibulo-ocular reflex (VOR) was hypoactive. There were no signs of neuropathy or cerebellar dysfunction. The vestibular instrumental testing showed no response in either direction for perand post-rotatory evaluation in the dark (step velocity 100 deg/s initial acceleration, 140 deg/s constant velocity for 30 s before stopping the chair abruptly) and normal visual-vestibular interaction. The head impulse test (HIT) [1, 2] (Fig. 1) showed a significantly reduced VOR gain both for clockwise (CW 0.33) and counterclockwise (CCW 0.11) passive head rotation (normal values 0.9 and 0.95 respectively). The functional HIT showed a reduced capability to read the orientation of Landolt’s C during head rotation (correct answers CW 0.65and CCW 0.32; normal values 0.87 and 0.89 respectively), in keeping with the complaint of oscillopsia. Subjective visual vertical [3], cervical vestibular evoked myogenic potentials (VEMPs) and N3 potential [4], pure tone audiometry, and brainstem auditory evoked potential were normal. The ocular VEMPswere normal after right ear stimulation, but were not detectable after left ear stimulation. An MRI brain scan showed some microangiopathic white matter lesions, without any abnormality within the posterior fossa and the inner ear. A clinical and vestibular instrumental re-evaluation after 18 months was unmodified. The balance disorder in our patient was attributable to a bilateral, peripheral, vestibular failure (BVF): the left side was more affected than the right, and the canal more than the otolith function. This discrepancy may reflect the * Maurizio Versino mversino@unipv.it