Analysis of Vestibular Compensation Following Clinical Intervention for Vestibular Schwannoma

Study Overview
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Brief Summary
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Multiple sensory cues are typically generated by discrete events, and while they do not reach the cerebrum simultaneously, the brain can bind them temporally if they are interpreted as corresponding to a single event. The temporal binding of vestibular and non-vestibular sensory cues is poorly understood and has not been studied in detail, despite the fact that the vestibular system operates in an inherently multimodal environment. In this study, the researchers are investigating the physiology and pathophysiology of vestibular temporal binding by studying normal subjects, patients with peripheral and central vestibular dysfunction, and patients with vestibular and cochlear signals provided by prosthetic implants in the inner ear.

Detailed Description
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Multiple sensory cues are generated by discrete events (e.g., the vestibular-visual signals after hitting a pothole) and while they do not reach the cerebrum simultaneously, the brain can synthesize them if they are interpreted as corresponding to a single event. This is critical because the central representation of an event is improved if two or more relevant cues are integrated but conversely is degraded if unrelated inputs are synthesized. Little research has focused on temporal binding of vestibular signals with other sensory cues, even though the vestibular system operates in an inherently multimodal environment, and virtually nothing is known about temporal binding abnormalities in patients with peripheral or central vestibular disorders. The investigators will use psychophysical tests (quantifying the PSS [point of subjective simultaneity] and TBW [temporal binding window]) to study vestibular temporal binding in normal people, patients with combined vestibular and cochlear prostheses, and patients with peripheral or central vestibular dysfunction. The researchers will investigate two fundamental aspects of temporal binding: its dependence on signal precision and adaptation driven by habitual exposure to sensory patterns. Furthermore, the researchers will investigate how and why temporal binding differs from normal in patients with peripheral and central vestibular dysfunction.

Official Title
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Temporal Synthesis of Vestibular and Extra-Vestibular Sensory Signals

Conditions
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Migraine, Vestibular Migraine, Vestibular Schwannoma, Motion Sickness, Dizziness, Vestibular Disorder

Intervention / Treatment
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* Behavioral: Temporal Binding Adaptation - TBW training
* Behavioral: Temporal Binding Adaptation - PSS training
* Behavioral: Temporal Binding Adaptation - PSS adaptation with VI stimulation
* Behavioral: Chronic Motion-modulated Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal subjects normal vestibular-oculomotor exams normal low-frequency standard rotational testing normal hearing Migraine meets International Headache Society (IHS) criteria for migraine with or without aura tested more than 2 weeks after most recent migraine headache Vestibular Migraine meets Barany Society criteria for vestibular migraine, which includes: episodic vestibular symptoms that occur with headaches that meet the IHS criteria for migraine tested more than 2 weeks after most recent migraine headache or vestibular episode Vestibular Schwannoma existence of unilateral vestibular schwannoma (pre & post clinical intervention e.g. surgical resection) must plan to have clinical intervention such as sub-occipital surgical approach with complete sectioning of the vestibular nerve rotational testing to assess pre-surgical vestibular function audiogram brain MRI consistent with vestibular schwannoma audiography in each ear Vestibular (VI) and Cochlear (CI) Implant subjects scheduled for CI surgery because of deafness minimum 5 year history of documented absence of auditory and vestibular function, based on review of their audiograms and vestibular tests specific vestibular criteria: peak ice water caloric response of less than 3deg/s for each ear; yaw VOR time constant <3s and gain <0.25; and reduced head impulse gain (<0.25) for all canal planes specific audiographic criteria: 80dB or greater sensorineural hearing loss in both ears Exclusion Criteria: Normal subjects history of otologic or neurologic disease on vestibular suppressant medication (benzodiazepine, antihistamine, anticholinergic) pregnant or recently (<6mos) pregnant Migraine history of vestibular symptoms (other than motion sickness) evidence of other neurologic or otologic dysfunction on migraine prophylactic medications on vestibular suppressant medication (benzodiazepine, antihistamine, anticholinergic) Vestibular Migraine (VM) other neurologic or otologic dysfunction as defined above except for central eye movement findings that are consistent with VM and therefore not exclusionary. on migraine prophylactic medication on vestibular suppressant medication (benzodiazepine, antihistamine, anticholinergic) Vestibular Schwannoma other otologic disease (other than presbycusis) or any neurologic disease (other than migraine) on vestibular suppressant medication (benzodiazepine, antihistamine, anticholinergic)

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Controls<br>normal control subjects - no history of neurologic or inner ear disease The investigators will characterize vestibular spatial and temporal precision by calculating perceptual thresholds and reaction times for vestibular (yaw rotation, ytranslation) stimuli in normal subjects over a wide age range. Vestibular-visual temporal binding is then performed on each subject and the relationship between the principal parameters (vestibular perceptual thresholds [inversely related to spatial precision], vestibular reaction time variability [inverse of temporal precision], and the PSS and TBW from the temporal binding paradigm) will be examined. The investigators will collect qualitative assessments of dizziness/disbalance (DHI: dizziness handicap index) and quantitative measurements of balance and vestibular function (FGA: functional gait analysis, postural sway, and standard rotational testing - VOR gain, time constant, asymmetry). | Behavioral: Temporal Binding Adaptation - TBW training<br>* The investigators will use a temporal order judgment (TOJ) with a visual (light) cue and a motion (yaw rotation, y-translation) cue. The relative timing of the motion onset and the light are varied and subjects indicate which occurred first by pressing a button after the motion ends. The TOJ task will generate a psychometric curve and the PSS (point of subjective simultaneity) and TBW (temporal binding window) are calculated. Then training focuses on SOAs (stimulus onset asynchronies) near the TBW borders (e.g., PSS +/- 0.5xTBW), starting from 50 ms outside the TBW and moving randomly towards the PSS. The goal of the training is to narrow the TBW -- training trials will be provided for 30 min and after each response the subject is told if their response was right or wrong. After training, the TOJ task is repeated to determine how the TBW has changed. Sham training will be the same as the actual training except that verbal feedback of response accuracy will not be provided.<br>Behavioral: Temporal Binding Adaptation - PSS training<br>* After the PSS and TBW are calculated with the standard TOJ paradigm, 100 training trials are provided where the SOA is set to [PSS - 200 ms], with the goal of shifting the PSS more negative. Then the TOJ task will be repeated but every 10 testing trials will be followed by 10 training trials (SOA = PSS - 200), and this pattern will be repeated 10 times to 100 more training trials interspersed with the Post TOJ data. Subjects will respond after all trials and testing and training will not be distinguished. After this is completed, the new PSS and TBW are calculated. Sham PSS training will be identical to the above except that the 'training' period will consist of random SOAs rather than a series of fixed SOAs.<br>|
| Experimental: Central Vestibular Dysfunction<br>Migraine and Vestibular Migraine patients The investigators intend to evaluate vestibular (yaw rotation or y-translation) - visual temporal binding in people with a wide range of motion sickness sensitivities (as quantified with standard questionnaires), including normal subjects, people with migraine and with vestibular migraine. The investigators will use our standard adaption method to narrow the TBW in these subjects, and will also employ PSS adaptation if a consistent pattern emerges that relates MS sensitivity to the PSS. The investigators will induce motion sickness using a pseudo-Coriolis task (so susceptibility can be quantified pre and post training). | Behavioral: Temporal Binding Adaptation - TBW training<br>* The investigators will use a temporal order judgment (TOJ) with a visual (light) cue and a motion (yaw rotation, y-translation) cue. The relative timing of the motion onset and the light are varied and subjects indicate which occurred first by pressing a button after the motion ends. The TOJ task will generate a psychometric curve and the PSS (point of subjective simultaneity) and TBW (temporal binding window) are calculated. Then training focuses on SOAs (stimulus onset asynchronies) near the TBW borders (e.g., PSS +/- 0.5xTBW), starting from 50 ms outside the TBW and moving randomly towards the PSS. The goal of the training is to narrow the TBW -- training trials will be provided for 30 min and after each response the subject is told if their response was right or wrong. After training, the TOJ task is repeated to determine how the TBW has changed. Sham training will be the same as the actual training except that verbal feedback of response accuracy will not be provided.<br>Behavioral: Temporal Binding Adaptation - PSS training<br>* After the PSS and TBW are calculated with the standard TOJ paradigm, 100 training trials are provided where the SOA is set to [PSS - 200 ms], with the goal of shifting the PSS more negative. Then the TOJ task will be repeated but every 10 testing trials will be followed by 10 training trials (SOA = PSS - 200), and this pattern will be repeated 10 times to 100 more training trials interspersed with the Post TOJ data. Subjects will respond after all trials and testing and training will not be distinguished. After this is completed, the new PSS and TBW are calculated. Sham PSS training will be identical to the above except that the 'training' period will consist of random SOAs rather than a series of fixed SOAs.<br>|
| Experimental: Peripheral Vestibular Dysfunction<br>Vestibular Schwannoma patients The basic approach is to characterize the precision of their vestibular information (perceptual thresholds for spatial precision, reaction times for temporal precision), and their temporal binding characteristics for vestibular (yaw rotation or y-translation)-visual inputs, in three states: pre-op, sub-acute post-op (2-6 weeks), and chronic post-op (6 months+). At each state the investigators will also assess the quality of their vestibular-mediated behaviors through questionnaires (e.g. DHI), postural sway, functional gait analysis, and standard rotational testing (VOR gain, time constant, and asymmetry). | Behavioral: Temporal Binding Adaptation - TBW training<br>* The investigators will use a temporal order judgment (TOJ) with a visual (light) cue and a motion (yaw rotation, y-translation) cue. The relative timing of the motion onset and the light are varied and subjects indicate which occurred first by pressing a button after the motion ends. The TOJ task will generate a psychometric curve and the PSS (point of subjective simultaneity) and TBW (temporal binding window) are calculated. Then training focuses on SOAs (stimulus onset asynchronies) near the TBW borders (e.g., PSS +/- 0.5xTBW), starting from 50 ms outside the TBW and moving randomly towards the PSS. The goal of the training is to narrow the TBW -- training trials will be provided for 30 min and after each response the subject is told if their response was right or wrong. After training, the TOJ task is repeated to determine how the TBW has changed. Sham training will be the same as the actual training except that verbal feedback of response accuracy will not be provided.<br>Behavioral: Temporal Binding Adaptation - PSS training<br>* After the PSS and TBW are calculated with the standard TOJ paradigm, 100 training trials are provided where the SOA is set to [PSS - 200 ms], with the goal of shifting the PSS more negative. Then the TOJ task will be repeated but every 10 testing trials will be followed by 10 training trials (SOA = PSS - 200), and this pattern will be repeated 10 times to 100 more training trials interspersed with the Post TOJ data. Subjects will respond after all trials and testing and training will not be distinguished. After this is completed, the new PSS and TBW are calculated. Sham PSS training will be identical to the above except that the 'training' period will consist of random SOAs rather than a series of fixed SOAs.<br>|
| Experimental: Implant Subjects<br>Cochlear Implant (CI)/Vestibular Implant (VI) patients A causative role for vestibular precision in temporal binding will be investigated in the VI patients, since the noise characteristics of the vestibular channel will be varied and to determine how this affects thresholds and temporal binding. As part of a second aim, the investigators will use VI and CI prosthetic signals in patients who have never received them together to see how the brain process sensory cues to which it is essentially naïve. Finally, after the acute experiments the investigators will provide 8 hours of 'physiologic' VI and CI stimulation by turning both implants on, sound modulates activity in the CI as usual, and angular head motion modulates activity in the VI while the subject actively explores the hospital environment. | Behavioral: Temporal Binding Adaptation - PSS adaptation with VI stimulation<br>* The adaptation will utilize the same approach used in non-implanted patients. The investigators will provide a repeated, fixed SOA with either the CI or VI leading the other stimulus by 220 ms. After the training period, which will match the number of stimuli pairs provided to our normal vestibular-auditory control subjects undergoing PSS adaptation, the TOJ study is repeated to recalculate the PSS and TBW.<br>Behavioral: Chronic Motion-modulated Stimulation<br>* To provide 8 hours of 'physiologic' CI and VI inputs during normal activities, the investigators will employ standard motion-modulated stimulation with the VI. This requires pre-adaptation to a 200 pps tonic stimulation rate (to emulate the push-pull design of the native vestibular system allowing modulating stimulation upward or downward with opposite directions of motion). The three electrodes are connected to the head-mounted prosthetic circuit, which consists of three angular velocity sensors (one aligned with the sensitive axis of each canal) such that head rotations in the plane of the given canal modulate the stimulation rate of the corresponding electrode, upward (for ipsi) or downward (for contralateral) head rotations, thereby simulating normal canal-mediated modulations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in postural sway/balance | Measurements of postural sway during Romberg testing on floor and foam (including an extra 60s balance test during which subject stands on foam and shakes head left and right at 1hz frequency while fixating on a point a set distance away) pre & post temporal binding adaptation (TBW & PSS training). | baseline and post temporal binding adaptation (1 hour) | 
| Change in rapid measure of gait | This measure is scored before and after PSS and TBW adaptation in UVD (unilateral vestibular dysfunction) patients. Gait is scored by performance on a task derived from the FGA (walking 40 feet while turning the head from side to side). It is scored on a 0 to 10 visual scale and provides a rapid assessment of vestibular function pre and post adaptation. | baseline and post temporal binding adaptation (1 hour) | 
| Change in measure of inducible dizziness | Looking at the change between before and after PSS and TBW adaptation in UVD (unilateral vestibular dysfunction) patients. Inducible dizziness is the symptom severity provoked by a task derived from the FGA (walking 40 feet while turning the head from side to side). It is scored on a 0 to 10 visual scale and provides a rapid assessment of vestibular function pre and post adaptation. | baseline and post temporal binding adaptation (1 hour) | 
| Change in Motion Sickness (MS) Susceptibility | The investigators will use a well-validated variant of the classic Coriolis task, a pseudo-Coriolis task where subjects view a strong yaw-axis OKN stimulus while the head is tilted passively in roll at 1.0 Hz (starting 5 s after the vection illusion begins). The investigators found empirically that 40 roll tilts of the head were adequate to induce a range of MS symptoms, from virtually none in people with minimal MS sensitivity to severe nausea in people with more prominent MS sensitivity. Subjects grade their MS symptoms before and after the pseudo-Coriolis task using a simple visual analog (0 to 10) scale. | baseline and post temporal binding adaptation (1 hour) | 
| Change in Point of Subjective Simultaneity (PSS) | Pre and post chronic motion-modulated stimulation in CI/VI patients - the PSS will be measured during temporal binding testing | baseline and 1 hour post 8-hour VI-CI 'physiologic' stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sensory integration, cochlear implant, vestibular implant, balance, dizziness, vestibular disorders