Central Adaptation after Peripheral Vestibular Injury

This thesis examines how the human brain adapts after peripheral vestibular injury. Vestibular perceptual function is used as a probe of cortical vestibular function. A paradigm determining vestibular perceptual thresholds to yaw axis rotation by a method of limits is described. Asymmetry in the thresholds is induced in normal subjects with galvanic vestibular stimulation. In patients with acute vestibular neuritis, perceptual thresholds were bilaterally elevated, with less asymmetry when compared to the brainstem reflexive function. Thresholds were measured in a prospective longitudinal study in vestibular neuritis patients, assessed acutely and at follow-­‐up (n=16). Assessments comprised vestibular caloric testing, visual dependency measures, questionnaire measures of symptom load, anxiety, depression and fear of body sensations. Clinical recruitment found a low rate of correct diagnoses by referring clinicians. Symptomatic outcome at follow-up was associated with increased visual dependence, asymmetric caloric function, increased anxiety and depression. It was also associated with increased fear and anxiety of body sensations present acutely, suggesting this may be predisposing. The anatomical substrate of central compensation was investigated in patients with bilateral vestibular failure (n=12) and normal controls (n=15) using functional MRI. A novel air turbine-powered vibrating device was developed to provide high and low levels of proprioceptive stimulus to neck rotator muscles. This was combined with a horizontal visual motion paradigm in a factorial design. A lateralised interaction was found in the lateral occipital visual processing areas in the avestibular patients. In addition to the known visual-vestibular interaction, this demonstrates a visuo-proprioceptive interaction, which may reflect compensation after vestibular injury. Conclusions: Vestibular perceptual function can be measured in disease, and is elevated in patients with acute peripheral vestibulopathy. Specific psychological and physiological factors associated with clinical recovery after vestibular neuritis are proposed. Functional MRI shows that proprioceptive signals interact with visual motion signals in patients with vestibular failure

Vestibular Perception following Acute Unilateral Vestibular Lesions.

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2) and velocity steps of 90°/s (acceleration 180°/s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions

Visual Dependency and Dizziness after Vestibular Neuritis

Symptomatic recovery after acute vestibular neuritis (VN) is variable, with around 50% of patients reporting long term vestibular symptoms; hence, it is essential to identify factors related to poor clinical outcome. Here we investigated whether excessive reliance on visual input for spatial orientation (visual dependence) was associated with long term vestibular symptoms following acute VN. Twenty-eight patients with VN and 25 normal control subjects were included. Patients were enrolled at least 6 months after acute illness. Recovery status was not a criterion for study entry, allowing recruitment of patients with a full range of persistent symptoms. We measured visual dependence with a laptop-based Rod-and-Disk Test and severity of symptoms with the Dizziness Handicap Inventory (DHI). The third of patients showing the worst clinical outcomes (mean DHI score 36–80) had significantly greater visual dependence than normal subjects (6.35° error vs. 3.39° respectively, p = 0.03). Asymptomatic patients and those with minor residual symptoms did not differ from controls. Visual dependence was associated with high levels of persistent vestibular symptoms after acute VN. Over-reliance on visual information for spatial orientation is one characteristic of poorly recovered vestibular neuritis patients. The finding may be clinically useful given that visual dependence may be modified through rehabilitation desensitization techniques

Experimental set up and rod tilt in normals and high DHI patient group. A.

<p>Rod and Disk test experimental set up. Laptop-based Rod-and-Disk test to measure visual dependency, showing a subject viewing the screen through a field-restricting cone. Subjects carried out the test in a darkened room. <b>B.</b> Rod tilt in normals and high DHI patient group. Figure showing similar mean rod tilt (deg; ± SE) in the static condition for the normal control and high DHI patient groups. Also shown is visually induced rod tilt for both normal and High DHI groups, which is higher in the unrecovered patient group, despite similar values in the static condition.</p

Visually induced rod tilt for all patient groups and normals.

<p>Figure showing visually induced rod tilt (mean, ±SE) for all patient groups (High DHI; Low DHI; Asymptomatic). Shaded grey area represents 95% confidence interval of the mean for normal controls. Note, rod tilt values for Low DHI and Asymptomatic patient groups are within normal range, where as High DHI patients show significantly higher than normal rod tilts in the moving disk condition.</p

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer’s dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer’s disease

Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes

BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo