Subthreshold Vestibular Stimulation as a Strategy for Rehabilitation

Bilateral vestibular hypofunction affects more than 64,000 adults in the US and leads to a substantial decline in quality of life. Bilateral vestibular hypofunction (BVH) is a condition characterized by a bilateral impairment of vestibular sensory function2. BVH often occurs without a known cause but can result from a viral infection, exposure to ototoxic drugs, vestibulo-cochlear nerve tumors, Meningitis, or Meniere's disease2. The results of a nationally representative survey estimate that between 64,000 and 193,000 adults in the US (28 to 85 per 100,000) are affected2. However, due to a lack of standardized vestibular screenings in older adult populations, the true prevalence of BVH is likely underestimated. Aging is also capable of producing a bilateral reduction in vestibular function, yielding a sub-type of BVH labeled as "Presbyvestibulopathy". In fact, more than 50% of adults over the age of 65 show evidence of vestibular impairment3 and recent data suggest that age-related vestibular declines may begin as early as age 403.

The symptoms of BVH - oscillopsia (bouncing vision whilst the head is moved), imbalance, gait instability, and dizziness - manifest secondary to an insensitivity of the vestibular system to self-motion cues (i.e., rotation, translation, or tilting of the head). Relative to unilateral vestibular lesions, the symptoms of BVH lead to greater perceived disability and a worsened health-related quality of life4; the economic burden of BVH has been estimated to be $13,019 per patient, nearly 4-times the burden of unilateral vestibular disease4. Adding to the economic and health-related burden is the substantial increase in fall risk; Ward, et al. (2015) showed that patients with BVH display an age-adjusted fall risk that is 9.9x higher than patients without a diagnosis of BVH but who report imbalance/dizziness, and 31x higher than the asymptomatic general population2; Sun, et al. (2015) reported that patients with BVH experience an average of 19 falls per year and Herdman and colleagues showed that over half of patients with BVH aged 65-74 reported a history of falls5. Given the substantial burden of BVH, the identification of new approaches for improving the functional status of these individuals is critically important. To meet this need, we propose to investigate the use of subthreshold vestibular stimulation as a novel strategy for improving vestibular function in patients with bilateral vestibular dysfunction.

The nervous system responds to changes in external or internal conditions by altering the behavior of neurons through multiple forms of neural plasticity. A specific form of plasticity, "homeostatic plasticity", stabilizes neural activity by driving the excitability of neurons toward a "set-point" level of activity6. Over the last six years, new data have come to light showing that the vestibular system also possess a robust capacity to modulate sensitivity to self-motion cues in response to prolonged periods of motion. Dietrich and Straka showed direct evidence of a bidirectional modulation of neuronal firing rates in the oculomotor neurons of Xenopus laevis (i.e., via the lateral canal driven aVOR) following subthreshold and suprathreshold yaw rotations7. In a sample of healthy adults, Fitzpatrick and Watson (2015) showed a 248% decrease in perceptual sensitivity and a 50% decrease in the sensitivity of the descending vestibular pathways (elicited by galvanic vestibular stimulation) following a single ten-minute period of large amplitude (suprathreshold) rotations8. Recently, Keywan and colleagues found that the sensitivity to interaural (IA) translation cues was increased 28.8% immediately following a 20-minute block of low-amplitude (subthreshold) translations9; a follow up study using the same subthreshold IA translation stimulus yielded an average improvement in sensitivity (i.e., reduction in self-motion perceptual thresholds) of 39%10. Collectively, these results demonstrate a capacity to use motion perturbations (i.e., low, or high levels of vestibular stimulation) to dynamically adjust the sensitivity of the vestibular system on both the single neuron and behavioral levels. The ability to use subthreshold motion stimuli to drive plasticity in the vestibular system motivates this study. We aim to determine if the delivery of a subthreshold motion stimulus before balance training leads to greater improvements in postural control for individuals with bilateral vestibular hypofunction.

We aim to test if the enhancement of sensitivity to roll tilt self-motion cues, via a subthreshold motion stimulus, leads to improved outcomes following balance training. We hypothesize a greater improvement in balance (i.e., reduction in postural sway) when balance training is preceded by a subthreshold motion stimulus (i.e., primer). Thirty subjects with BVH (50% with age-related BVH) will be randomly assigned into either (1) an experimental group who will complete a standard balance training intervention preceded by 20-minutes of subthreshold 0.5 Hz tilts, (2) a "Balance-Only" control group who will complete the same standard balance training but preceded by a 20-minute placebo stimulus, or (3) a "Motion-Only" control group who will only receive 20-minutes of subthreshold 0.5 Hz tilts without additional balance training. Training will occur over 6 visits within a 2-week window, yielding a total of 6 hours of training. Balance performance, as well as alternative secondary outcome measures, will be measured on the day prior to training and the day following the training protocol.

Balance training will consist of progressive exposure to continuous pseudorandom platform perturbations. Participants will stand on a MOOG hexapod motion platform, secured using a harness and safety rails. Balance training will be progressed by (a) gradually increasing the number of degrees of freedom (e.g., 1DOF to 6DOF) in the perturbation, (b) removing visual cues, (c) narrowing the base of support, and (d) increasing the amplitude, velocity, and/ or acceleration of the platform motion. The experimental (Balance+Motion) group and the "Motion-Only" group will be sinusoidally tilted at an imperceptible subthreshold velocity (57.4% of baseline tilt thresholds) for a period of 20 minutes prior to balance training. The Balance-Only control group will complete an identical balance intervention; however it will be preceded by 20 minutes of a placebo stimulus (intermittent 1 mm translations of the motion platform).

The primary outcome measures will capture balance performance in conditions that rely primarily upon vestibular feedback including (A) standing on a sway referenced support with the eyes closed, and (B) standing with eyes closed on a motion platform delivering continuous pseudorandom balance perturbations. The root mean square distance (RMSD) of the CoP data captured will be used for each assessment. Secondary outcome measures include (A) 0.5 Hz tilt perceptual thresholds (a motion proﬁle that mirrors the subthreshold stimulus) which will be used to quantify changes in sensitivity to vestibular self-motion tilt cues and (B) the functional gait assessment (FGA) which will be used to measure dynamic ambulatory balance.

Eligibility Criteria:
Inclusion Criteria:

* Bilateral yaw aVOR gain of \< 0.8 on video head impulse testing OR bilateral positive bedside head impulse test
* Symptoms of at least 3-month duration that include (a) Unsteadiness with walking or standing, (b) Either oscillopsia or worsened balance on uneven ground or with vision removed, and (c) No symptoms sitting or lying down.
* Must be able to stand
* No leg or foot amputations
* No lower limb braces
* Not currently pregnant by self-report
* Weight \<= 300 pounds

Exclusion Criteria:

* Severe head trauma or traumatic brain injury
* History of seizures
* Alternative neurologic illness or condition known to impact vestibular or balance function (e.g., stroke, neurodegenerative disorders, demyelinating illness)
* Major psychiatric (e.g., panic disorder, psychosis, etc.) disorder
* Any of the following eye diseases or conditions: amblyopia (or "lazy eye") or history of amblyopia, diagnosis of age- related macular degeneration, retina dystrophy, glaucoma, cataracts,
* Recent (\<6 months) orthopedic injury to the lower extremities that may affect test performance
* Upper extremity injuries requiring current sling immobilization
* Recent surgery (\< 6 months) that may impact test performance.
* Any other severe health problem (heart disease, pulmonary disease, cancer, etc.) that may affect test performance
* Due to potentially nauseogenic nature of some motions and to protect fetus and mother, pregnant women will also be excluded from this study
* Since we cannot address every possible potential individual recruit in advance, additional exclusion criteria may be required.