Incremental Velocity Error As A New Treatment In Vestibular Rehabilitation (INVENT VPT Trial): Study Protocol For A Randomized Controlled Crossover Trial

Background: A clinical pattern of damage to the auditory, visual, and vestibular sensorimotor systems, known as multi-sensory impairment, affects a significant percent of the US population. Within the population of US military service members exposed to mild traumatic brain injury (mTBI), 15 – 44% will develop multi-sensory impairment following a mild traumatic brain injury. In the US civilian population, multi-sensory impairment related symptoms are also a common sequela of damage to the vestibular system and affect ~ 300-500/100,000 population. Vestibular rehabilitation is recognized as a critical component of the management of multi-sensory impairment. Unfortunately, the current clinical practice guidelines for the delivery of vestibular rehabilitation are not evidence-based and primarily rely on expert opinion. The focus of the INVENT VPT trial is gaze stability training, which represents the unique component of vestibular rehabilitation. The aim of the INVENT VPT trial is to assess the efficacy of a non-invasive, incremental vestibular adaptation training device for normalizing the response of the vestibulo-ocular reflex. Methods: The INVENT VPT trial is a multicenter randomized controlled crossover trial in which military service members with mTBI and civilian patients with vestibular hypofunction are randomized to begin traditional vestibular rehabilitation or incremental vestibular adaptation and then cross over to the alternate intervention after a prescribed washout period. Vestibulo-ocular reflex function and other functional outcomes are measured to identify the best means to improve delivery of vestibular rehabilitation. We incorporate ecologically valid outcome measures that address the common symptoms experienced in those with vestibular pathology and multi-sensory impairment. Discussion: The INVENT VPT Trial will directly impact the health care delivery of vestibular rehabilitation in patients suffering from multi-sensory impairment in three critical ways: 1) Compare optimized traditional methods of vestibular rehabilitation to a novel device that is hypothesized to improve vestibulo-ocular reflex performance; 2) Isolate the ideal dosing of vestibular rehabilitation considering patient burden and compliance rates; 3) Examine whether recovery of the vestibulo-ocular reflex can be predicted in participants with vestibular symptoms. Trial registration: ClinicalTrials.gov, NCT03846830. Registered 20 February 2019,https://clinicaltrials.gov/ct2/show/NCT03846830

Rapid cross-sensory adaptation of self-motion perception

Perceptual adaptation is often studied within a single sense. However, our experience of the world is naturally multisensory. Here, we investigated cross-sensory (visual vestibular) adaptation of self motion perception. It was previously found that relatively long visual self-motion stimuli (greater or equal to 15s) are required to adapt subsequent vestibular perception, and that shorter duration stimuli do not elicit cross sensory (visual vestibular) adaptation. However, it is not known whether several discrete short duration stimuli may lead to cross sensory adaptation (even when their sum, if presented together, would be too short to elicit cross sensory adaptation). This would suggest that the brain monitors and adapts to supra modal statistics of events in the environment. Here we investigated whether cross sensory (visual vestibular) adaptation occurs after experiencing several short (1s) self-motion stimuli. Forty five participants discriminated the headings of a series of self motion stimuli. To expose adaptation effects, the trials were grouped in 140 batches, each comprising three prior trials, with headings biased to the right or left, followed by a single unbiased test trial. Right, and left biased batches were interleaved pseudo randomly. We found significant adaptation in both cross sensory conditions (visual prior and vestibular test trials, and vice versa), as well as both unisensory conditions (when prior and test trials were of the same modality, either visual or vestibular). Fitting the data with a logistic regression model revealed that adaptation was elicited by the prior stimuli (not prior choices). These results suggest that the brain monitors supra modal statistics of events in the environment, even for short duration stimuli, leading to functional (supra modal) adaptation of perception.

Drug treatment of acute vertigo

Acute vertigo is a severe condition that requires urgent treatment. Vertigo can be caused by peripheral or central vestibular disorders of various etiopathology. Whatever the reason of vestibular dizziness, it is characterized by severe attacks with imbalance, nausea and vomiting in the acute period. Symptomatic treatment consists of vestibular suppressants and antiemetic drugs. There are several key principles regarding management of patients with vertigo that includes combined use of vestibular suppressants and antiemetics, which allows potentiation of their effects, limitation the use of symptomatic therapy to 2–3 days and perhaps earlier initiation of vestibular rehabilitation which effectiveness can be improved with agents that stimulate central vestibular adaptation.

The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex

Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in α9-knockout mice. These mice carry a missense mutation of the gene encoding the α9 nicotinic acetylcholine receptor (nAChR) subunit. The α9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 α9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5×), gain-decrease adaptation (0.5×), or no adaptation (baseline, 1×). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20°/s), we measured the sinusoidal (0.2–10 Hz, 20–100°/s) and transient (1,500–6,000°/s2) VOR in complete darkness. α9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (∼5% <1 Hz to ∼25% >1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in α9-knockout mice (17%) compared with control mice (53%), a reduction of ∼70%. Our results show that the loss of α9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity.