Behavioural correlates of ocular accomodation and the autonomic nervous system

The binding issue of th is thesis was the examination of workload, induced by relinotopic and spatiotopic stimuli, on both the ocu lomotor and cardiovascular systems together with investigating the covariation between the two systems - the 'eye-heart' link. Further, the influence of refractive error on ocular accommodation and cardiovascular function was assessed. A clinical evaluation was undertaken to assess the newly available open-view infrared Shin-Nippon NVision-K 5001 optometer, its benefit being the capability to measure through pupils = 2.3 mm. Measurements of refractive error taken with the NVision-K were found to be both accurate (Difference in Mean Spherical Equivalent: 0.14 ± 0.35 D; p = 0.67) and repeatable when compared to non-cycloplegic subjective refraction. Due to technical difficulties, however, the NVision-K could not be used for the purpose of the thesis, as such, measures of accommodation were taken using the continuously recording Shin-Nippon SRW-5000 openview infrared optometer, coupled with a piezo-electric finger pulse transducer to measure pulse. Heart rate variability (HRV) was spectrally analysed to determine the systemic sympathetic and parasympathetic components of the autonomic nervous system (ANS). A large sample (n = 60), cross-sectional study showed late-onset myopes (LOMs) display less accurate responses when compared to other refractive groups at high accommodative demand levels (3 .0 0 and 4.0D). Tonic accommodation (TA) was highest in the hypermetropes, fo llowed by emmetropes and early-onset myopes while the LOM subjects demonstrated statistically significant lower levels of TA. The root-meansquare (RMS) value of the accommodative response was shown to amplify with increased levels of accommodative demand. Changes in refractive error only became significant between groups at higher demand levels (3.0 D and 4.0 D) with the LOMs showing the largest magnification in oscilIations. Examination of the stimulus-response cross-over point with the unit ratio line and TA showed a correlation between the two (r = 0.45, p = 0.001), where TA is approximately twice the dioptric value of the stimulus-response cross-over point. Investigation of the relationship between ocular accommodation and systemic ANS function demonstrated covariation between the systems. Subjects with a faster heart rate (lower heart period) tended to have a higher TA value (r = -0.27, p < 0.05). Further, an increase in accommodative demand accompanies a faster heart rate. The influence of refractive error on the cardiovascular response to changes in accommodative demand, however, was equivocal. Examination of the microfluctuations ofacconunodation demonstrated a correlation between the temporal frequency location of the accommodative high Frequency component (HFC) and the arterial pulse frequency. The correlation was present at a range of accommodative demands from 0.0 D to 4.0 D and in all four refractive groups, suggesting that the HFC was augmented by physiological factors. Examination of the effect of visual cognition on ocular accommodation and the ANS confirmed that increasing levels of cognition affect the accommodative mechanism. The accommodative response shifted away from the subject at both near and far. This shift in accommodative response accompanied a decay in the systemic parasympathetic innervation to the heart. Differences between refractive groups also existed with LOMs showing less accurate responses compared to emmetropes. This disparity, however, appeared to be augmented by the systemic sympathetic nervous system. The investigations discussed explored Ihe role of oculomotor and cardiovascular fu nction in workload enviromnents, providing evidence for a behavioural link between the cardiovascular and oculomotor systems.

The effect of beta-adrenergic receptor antagonists on the temporal accommodative response

In this thesis a modified Canon IR optometer was used to record static and continuous responses of accommodation during sustained visual tasks. The instrument was assessed with regard to the ocular exit pupil used, its frequency response and noise levels. Experimental work concerned essentially the temporal characteristics and neurological basis of the accommodative mechanism. In the absence of visual stimuli, the accommodative system assumes a resting or tonic accommodative (TA) position, which may be modified by periods of sustained fixation. The rate of regression from a near task to TA in darkness has exhibited differences between regression rates for enunetropes (EMMs) compared with late-onset myopes (WMs). The rate of accommodative regression from a task set at 3D above TA was examined for a group of 10 EMMs and 10 LOMs for 3 conditions: saline, timolol and betaxolol. Timolol retarded the regression to TA for a sub-group of EMMs. The patterns of regression for the remaining emmetropes mirrored that for the LOMs, the drugs showing no difference in rate of regression compared with the saline condition. This provides support for the conjecture that LOMs and certain EMMs appear to be deficient in a sympathetic inhibitory component to the ciliary muscle which may attenuate adaptational changes in tonus and which leave them susceptible to the development of LOM. It is well established that the steady-state accommodative response is characterised by temporal changes in lens power having 2 dominant frequency components: a low frequency component (LFC: < 0.6Hz) and a high frequency component (HFC: 1.0-2.2Hz). This thesis investigates various aspects of these microfluctuations of accommodation.The HFC of accommodative fluctuations was shown to be present in central and peripheral lens zones, although the magnitude of the rms of accommodative microfluctuations was found to be reduced in the lens periphery. These findings concur with the proposal that the lens capsule acts as a force distributor, transmitting the tension from the zonules evenly over the whole of the lens surface.An investigation into the correlation between arterial pulse and the HFC of accommodative fluctuations showed that the peak frequency of the HFC was governed by the arterial pulse frequency. It was proposed that the microflucutations comprised a combination of neurological control (LFC) and physiological variations (HFC).The effect of timolol maleate on the steady-state accommodative response for a group of 10 emmetropes showed that timolol reduced significantly the rms of accommodative microfluctuations in treated but not untreated eyes. Consequently, the effect was considered to be locally, rather than systemically induced.The influence of the sympathetic system on within-task measurements of accommodation was examined by recording the accommodative response of 3 subjects to a sinusoidally moving target at 6 temporal frequencies from 0.05Hz to 0.5Hz for 3 drug conditions: saline, timolol and betaxolol. Timolol caused a reduced gain for frequencies below 0.3 whereas betaxolol reduced accommodative gain for all frequencies. It was proposed that the results for timolol were consistent with temporal response characteristics of sympathetic innervation of the ciliary muscle whereas the betaxolol results were thought to be a manifestation of fatigue resulting from the CNS depressant effect of the drug.

Novel pMDI formulations for pulmonary delivery of proteins

In this paper, we demonstrate that co-spray-drying a model protein with sodium carboxymethylcellulose (NaCMC) protects protein integrity during spray-drying, and that the resultant spray-dried powders can be successfully dispersed in hydrofluoroalkane (HFA) propellant to prepare pressurised metered dose (pMDI) formulations that exhibit high respirable fractions. The spray-dried powders were formulated as HFA-134a pMDI suspensions in the absence of any other excipients (e.g. surfactants) or co-solvents (e.g. ethanol). The in vitro aerosolisation profile of these systems was assessed using the twin stage impinger; fine particle fractions (FPF) ≥50% of the recovered dose were obtained. Following storage for five months, the aerosolisation performance was reassessed; the NaCMC-free formulation demonstrated a significant decrease in FPF, whereas the performance of the NaCMC-modified formulations was statistically equivalent to their initial performance. Thus, formulation of pMDI suspensions using NaCMC-based spray-dried powders is a promising approach for the pulmonary delivery of proteins and peptides. © 2009 Elsevier B.V. All rights reserved.