Postural impairments in unilateral and bilateral vestibulopathy.

Chronic imbalance is a major complaint of patients suffering from bilateral vestibulopathy (BV) and is often reported by patients with chronic unilateral vestibulopathy (UV), leading to increased risk of falling. We used the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation contributions to standing balance control, to determine whether CSMI measures could distinguish between healthy control (HC), UV, and BV subjects and to characterize vestibular, proprioceptive, and visual contributions expressed as sensory weights. We also hypothesized that sensory weight values would be associated with the results of vestibular assessments (vestibulo ocular reflex tests and Dizziness Handicap Inventory scores). Twenty HCs, 15 UVs and 17 BVs performed three CSMI conditions evoking sway in response to pseudorandom (1) surface tilts with eyes open or, (2) surface tilts with eyes closed, and (3) visual surround tilts. Proprioceptive weights were identified in surface tilt conditions and visual weights were identified in the visual tilt condition. BVs relied significantly more on proprioception. There was no overlap in proprioceptive weights between BV and HC subjects and minimal overlap between UV and BV subjects in the eyes-closed surface-tilt condition. Additionally, visual sensory weights were greater in BVs and were similarly able to distinguish BV from HC and UV subjects. We found no significant correlations between sensory weights and the results of vestibular assessments. Sensory weights from CSMI testing could provide a useful measure for diagnosing and for objectively evaluating the effectiveness of rehabilitation efforts and future treatments designed to restore vestibular function such as hair cell regeneration and vestibular implants.

Vestibular damage affects the precision and accuracy of navigation in a virtual visual environment.

Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed, which either activated dynamic idiothetic cues ('dynamic task', navigate by turning, walking in place) or eliminated them ('static task', navigate with key presses, head stationary). For both protocols, we employed a standard 'triangle completion task' in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear 'accuracy' (derived from response error) and 'precision' (derived from response variability) were calculated. Comparing performance 'within tasks', navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm, vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance 'between tasks', normal men performed better on the dynamic than the static paradigm while vestibular-deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage, they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.

The Next Challenges of Vestibular Implantation in Humans.

Patients with bilateral vestibulopathy suffer from a variety of complaints, leading to a high individual and social burden. Available treatments aim to alleviate the impact of this loss and improve compensatory strategies. Early experiments with electrical stimulation of the vestibular nerve in combination with knowledge gained by cochlear implant research, have inspired the development of a vestibular neuroprosthesis that can provide the missing vestibular input. The feasibility of this concept was first demonstrated in animals and later in humans. Currently, several research groups around the world are investigating prototype vestibular implants, in the form of vestibular implants as well as combined cochlear and vestibular implants. The aim of this review is to convey the presentations and discussions from the identically named symposium that was held during the 2021 MidWinter Meeting of the Association for Research in Otolaryngology, with researchers involved in the development of vestibular implants targeting the ampullary nerves. Substantial advancements in the development have been made. Yet, research and development processes face several challenges to improve this neuroprosthesis. These include, but are not limited to, optimization of the electrical stimulation profile, refining the surgical implantation procedure, preserving residual labyrinthine functions including hearing, as well as gaining regulatory approval and establishing a clinical care infrastructure similar to what exists for cochlear implants. It is believed by the authors that overcoming these challenges will accelerate the development and increase the impact of a clinically applicable vestibular implant.

Visuospatial Cognitive Dysfunction in Patients with Vestibular Loss.

OBJECTIVE: To characterize visuospatial and nonvisuospatial cognitive domains affected by vestibular loss and determine whether patient-reported outcomes measures (PROMs) correlate with performance on neuropsychological tests. STUDY DESIGN: Cross-sectional study. SETTING: University-based tertiary medical center. PATIENTS: Sixty-nine age-matched subjects: 25 patients with bilateral vestibular loss (BVL), 14 patients with unilateral vestibular loss (UVL), and 30 normal controls (NC). INTERVENTIONS: Neuropsychological tests used to assess visuospatial and auditory short-term and working memory, number magnitude representation, executive function, and attention. Validated PROMs used to evaluate quality of life and subjective cognitive impairment. MAIN OUTCOME MEASURES: Performance on neuropsychological tests and scores on PROM surveys. RESULTS: BVL and UVL patients performed significantly worse than NC subjects on tasks requiring visuospatial representation compared with NC subjects ( p < 0.01). BVL patients demonstrated decreased performance on spatial representation tasks compared with UVL and NC subjects ( p < 0.05 and p < 0.05, respectively). All subject groups performed similarly on tasks assessing nonvisuospatial cognitive domains, such as auditory short-term and working memory, executive function, and attention. PROMs did not seem to correlate with performance on neuropsychological tasks. CONCLUSION: Patients with vestibular loss exhibit impairments in tasks requiring visuospatial representation but perform similarly to NC subjects in tasks of auditory working memory, executive function, or attention. Currently available questionnaires may be insufficient to screen patients for cognitive deficits.

The Role of Interstitial Fluid Pressure in Cerebral Porous Biomaterial Integration.

Recent advances in biomaterials offer new possibilities for brain tissue reconstruction. Biocompatibility, provision of cell adhesion motives and mechanical properties are among the present main design criteria. We here propose a radically new and potentially major element determining biointegration of porous biomaterials: the favorable effect of interstitial fluid pressure (IFP). The force applied by the lymphatic system through the interstitial fluid pressure on biomaterial integration has mostly been neglected so far. We hypothesize it has the potential to force 3D biointegration of porous biomaterials. In this study, we develop a capillary hydrostatic device to apply controlled in vitro interstitial fluid pressure and study its effect during 3D tissue culture. We find that the IFP is a key player in porous biomaterial tissue integration, at physiological IFP levels, surpassing the known effect of cell adhesion motives. Spontaneous electrical activity indicates that the culture conditions are not harmful for the cells. Our work identifies interstitial fluid pressure at physiological negative values as a potential main driver for tissue integration into porous biomaterials. We anticipate that controlling the IFP level could narrow the gap between in vivo and in vitro and therefore decrease the need for animal screening in biomaterial design.

Speech Perception With Novel Stimulation Strategies for CombinedCochleo-Vestibular Systems.

Cochlear implants are very well established in the rehabilitation of hearing loss and are regarded as the most successful neuroprostheses to date. While a lot of progress has also been made in the neighboring field of specific vestibular implants, some diseases affect the entire inner ear, leading to both hearing and vestibular hypo- or dysfunction. The proximity of the cochlear and vestibular organs suggests a single combined implant as a means to alleviate the associated impairments. While both organs can be stimulated in a similar way with electric pulses applied through implanted electrodes, the typical phase durations needed in the vestibular system seem to be substantially larger than those typically needed in the cochlear system. Therefore, when using sequential stimulation in a combined implant, the pulse stream to the cochlea is interrupted by comparatively large gaps in which vestibular stimulation can occur. We investigate the impact of these gaps in the auditory stream on speech perception. Specifically, we compare a number of stimulation strategies with different gap lengths and distributions and evaluate whether it is feasible to use them without having a noticeable decline in perception and quality of speech. This is a prerequisite for any practicable stimulation strategy of a combined system and can be investigated even in recipients of a normal cochlear implant. Our results show that there is no significant deterioration in speech perception for the different strategies examined in this paper, leaving the strategies as viable candidates for prospective combined cochleo-vestibular implants.

Simultaneous activation of multiple vestibular pathways upon electrical stimulation of semicircular canal afferents.

BACKGROUND AND PURPOSE: Vestibular implants seem to be a promising treatment for patients suffering from severe bilateral vestibulopathy. To optimize outcomes, we need to investigate how, and to which extent, the different vestibular pathways are activated. Here we characterized the simultaneous responses to electrical stimuli of three different vestibular pathways. METHODS: Three vestibular implant recipients were included. First, activation thresholds and amplitude growth functions of electrically evoked vestibulo-ocular reflexes (eVOR), cervical myogenic potentials (ecVEMPs) and vestibular percepts (vestibulo-thalamo-cortical, VTC) were recorded upon stimulation with single, biphasic current pulses (200 µs/phase) delivered through five different vestibular electrodes. Latencies of eVOR and ecVEMPs were also characterized. Then we compared the amplitude growth functions of the three pathways using different stimulation profiles (1-pulse, 200 µs/phase; 1-pulse, 50 µs/phase; 4-pulses, 50 µs/phase, 1600 pulses-per-second) in one patient (two electrodes). RESULTS: The median latencies of the eVOR and ecVEMPs were 8 ms (8-9 ms) and 10.2 ms (9.6-11.8 ms), respectively. While the amplitude of eVOR and ecVEMP responses increased with increasing stimulation current, the VTC pathway showed a different, step-like behavior. In this study, the 200 µs/phase paradigm appeared to give the best balance to enhance responses at lower stimulation currents. CONCLUSIONS: This study is a first attempt to evaluate the simultaneous activation of different vestibular pathways. However, this issue deserves further and more detailed investigation to determine the actual possibility of selective stimulation of a given pathway, as well as the functional impact of the contribution of each pathway to the overall rehabilitation process.

Influence of systematic variations of the stimulation profile on responses evoked with a vestibular implant prototype in humans.

OBJECTIVE: To explore the impact of different electrical stimulation profiles in human recipients of the Geneva-Maastricht vestibular implant prototypes. APPROACH: Four implanted patients were recruited for this study. We investigated the relative efficacy of systematic variations of the electrical stimulus profile (phase duration, pulse rate, baseline level, modulation depth) in evoking vestibulo-ocular (eVOR) and perceptual responses. MAIN RESULTS: Shorter phase durations and, to a lesser extent, slower pulse rates allowed maximizing the electrical dynamic range available for eliciting a wider range of intensities of vestibular percepts. When either the phase duration or the pulse rate was held constant, current modulation depth was the factor that had the most significant impact on peak velocity of the eVOR. SIGNIFICANCE: Our results identified important parametric variations that influence the measured responses. Furthermore, we observed that not all vestibular pathways seem equally sensitive to the electrical stimulus when the electrodes are placed in the semicircular canals and monopolar stimulation is used. This opens the door to evaluating new stimulation strategies for a vestibular implant, and suggests the possibility of selectively activating one vestibular pathway or the other in order to optimize rehabilitation outcomes.

Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.