Linking vestibular function and sub-cortical grey matter volume changes in a longitudinal study of aging adults

Abstract Emerging evidence suggests a relationship between impairments of the vestibular (inner ear balance) system and decline in visuospatial cognitive performance in older adults. However, it is unclear whether age-related vestibular loss is associated with volume loss in brain regions known to receive vestibular input. To address this gap, we investigated the association between vestibular function and the volumes of four structures that process vestibular information (the hippocampus, entorhinal cortex, thalamus, and basal ganglia) in a longitudinal study of 97 healthy, older participants from the Baltimore Longitudinal Study of Aging. Vestibular testing included cervical vestibular-evoked myogenic potentials (cVEMP) to measure saccular function, ocular VEMP (oVEMP) to measure utricular function, and video head-impulse tests to measure the horizontal semi-circular canal vestibulo-ocular reflex (VOR). Participants in the sample had vestibular and brain MRI data for a total of 1 (18.6%), 2 (49.5%) and 3 (32.0%) visits. Linear mixed-effects regression was used to model regional volume over time as a function of vestibular physiological function, correcting for age, sex, intracranial volume, and inter-subject random variation in the baseline levels of and rates of change of volume over time. We found that poorer saccular function, characterized by lower cVEMP amplitude, is associated with reduced bilateral volumes of the thalamus and basal ganglia at each time point, demonstrated by a 0.0714 cm3 ± 0.0344 (p=0.038; 95% CI: 0.00397-0.139) lower bilateral-mean volume of the basal ganglia and a 0.0440 cm3 ± 0.0221 (p=0.046; 95% CI: 0.000727-0.0873) lower bilateral-mean volume of the thalamus for each 1 unit lower cVEMP amplitude. There were no significant associations between volume and oVEMP or mean VOR gain. These findings provide insight into the potential neural substrates for the observed link between age-related vestibular loss and spatial cognition. Comprehensive Summary Humans rely on their vestibular, or inner ear balance, system to manage everyday life. In addition to sensing head motion and head position with respect to gravity, the vestibular system helps to maintain balance and gaze stability. Furthermore, the evidence is mounting that vestibular function is linked to spatial cognition: the capacity to mentally represent the world and navigate through it. Yet, the exact processes by which vestibular function enables spatial cognition are unclear. One promising mechanism is through changes of the sizes and shapes of the brain anatomies that support spatial cognitive function. The intuition is that, as vestibular function declines with aging, less vestibular information is distributed throughout the brain, leading to a loss of neurons in areas that receive those inputs. In support of this putative mechanism, recent discoveries underscore the association of vestibular impairment with spatial cognitive declines and with atrophy of brain areas that support spatial cognition, the hippocampus and entorhinal cortex, in older adults. This work investigates the extent over time to which age-related vestibular loss contributes to the atrophy of four brain regions that receive vestibular input and subserve spatial cognition: the hippocampus, entorhinal cortex, thalamus, and basal ganglia. Using data from a cohort of healthy, older adults between 2013 and 2017 from the Baltimore Longitudinal Study of Aging, we assessed regional brain volume as a function of vestibular function, while accounting for common confounds of brain volume change (e.g. age, sex, head size). We found that poor vestibular function is associated with significantly reduced volumes of the thalamus and basal ganglia. Notably, this study is one of the first to demonstrate relationships between age-related vestibular loss and brain atrophy in brain regions that receive vestibular input and promote spatial cognition. But more research is needed to understand the observed connection between vestibular function, neuroanatomy, and spatial cognition. Which brain areas suffer from age-related vestibular loss? How and in what sequence are they affected? As the world’s aging population—and likely the prevalence of age-related vestibular impairment—increases, answering questions like these becomes increasingly important. One day, these answers will provide targets for preemptive interventions, like physical or cognitive pre-habilitation, to stave off malignant cognitive changes before they occur and progress into clinical significance.