Comparing multifocal pupillographic objective perimetry (mfPOP) and multifocal visual evoked potentials (mfVEP) in retinal diseases

Multifocal pupillographic objective perimetry (mfPOP) shows regions of slight hypersensitivity away from retinal regions damaged by diabetes or age-related macular degeneration (AMD). This study examines if such results also appear in multifocal visual evoked potentials (mfVEPs) recorded on the same day in the same patients. The pupil control system receives input from the extra-striate cortex, so we also examined evidence for such input. We recruited subjects with early type 2 diabetes (T2D) with no retinopathy, and patients with unilateral exudative AMD. Population average responses of the diabetes patients, and the normal fellow eyes of AMD patients, showed multiple regions of significant hypersensitivity (p < 0.05) on both mfPOP and mfVEPs. For mfVEPs the occipital electrodes showed fewer hypersensitive regions than the surrounding electrodes. More advanced AMD showed regions of suppression becoming centrally concentrated in the exudative AMD areas. Thus, mfVEP electrodes biased towards extra-striate cortical responses (surround electrodes) appeared to show similar hypersensitive visual field locations to mfPOP in early stage diabetic and AMD damage. Our findings suggest that hypersensitive regions may be a potential biomarker for future development of AMD or non-proliferative diabetic retinopathy, and may be more informative than visual acuity which remains largely undisturbed during early disease

Comparison of unifocal, flicker, and multifocal pupil perimetry methods in healthy adults

To this day, the most popular method of choice for testing visual field defects (VFDs) is subjective standard automated perimetry. However, a need has arisen for an objective, and less time-consuming method. Pupil perimetry (PP), which uses pupil responses to onsets of bright stimuli as indications of visual sensitivity, fulfills these requirements. It is currently unclear which PP method most accurately detects VFDs. Hence, the purpose of this study is to compare three PP methods for measuring pupil responsiveness. Unifocal (UPP), flicker (FPP), and multifocal PP (MPP) were compared by monocularly testing the inner 60 degrees of vision at 44 wedge-shaped locations. The visual field (VF) sensitivity of 18 healthy adult participants (mean age and SD 23.7 ± 3.0 years) was assessed, each under three different artificially simulated scotomas for approximately 4.5 minutes each (i.e. stimulus was not or only partially present) conditions: quadrantanopia, a 20-, and 10-degree diameter scotoma. Stimuli that were fully present on the screen evoked strongest, partially present stimuli evoked weaker, and absent stimuli evoked the weakest pupil responses in all methods. However, the pupil responses in FPP showed stronger discriminative power for present versus absent trials (median d-prime = 6.26 ± 2.49, area under the curve [AUC] = 1.0 ± 0) and MPP performed better for fully present versus partially present trials (median d-prime = 1.19 ± 0.62, AUC = 0.80 ± 0.11). We conducted the first in-depth comparison of three PP methods. Gaze-contingent FPP had best discriminative power for large (absolute) scotomas, whereas MPP performed slightly better with small (relative) scotomas

Detection of higher visual function deficits and validation of multifocal pupillography in stroke, chiasmal compression and anterior ischemic optic neuropathy.

It is well established that neural damage can result in visual dysfunction, both visual field loss and in higher visual function (HVF) loss such as perceptions of depth, colour, motion and faces. This thesis examines these visual deficits in the common neurological diseases of stroke, chiasmal compression, and anterior ischemic optic neuropathy (AION). While it is established that isolated complete HVF deficits do occur in stroke, they are also known to be rare. However, as HVFs are not routinely tested in clinical practice, it is unknown how common more subtle defects are, and what tools are effective in detecting these. Chapter 3 explores these questions, outlining that colour and depth perceptions are the most commonly affected, that Ishihara (colour) and stereofly and randot (depth), are the most useful tests, and outlines recommendations for improvement in some of these tools. The relatively new invention of multifocal pupillographic objective perimetry (mfPOP) provides a number of benefits from other forms of perimetry. It measures both eyes at once, allowing measures of direct and consensual responses, it is objective, and it allows repeat measures of each region giving a measure of error. This advancement opens up new opportunities to investigate pupillary physiology in neurological disorders and adds new challenges in how to combine these signals into a single meaningful measure. Chapter 4 investigates the physiology of the pupil in stroke, chiasmal compression, and AION, and investigates how these components can be appropriately combined into a single measure. Results show naso-temporal differences are consistent with known physiology in control subjects and provides evidence that denser nasal retinal input may underpin the greater contraction anisocoria seen in temporal fields than in nasal fields. With the intention that mfPOP be used in clinical practice, it must demonstrate it can perform as well as traditional perimetry, such as Humphrey and Matrix devices, in a wide range of disorders. Currently mfPOP testing neurological disorders has been very limited, and this represents a large gap in the literature. Chapter 5 compares mfPOP to Humphrey and Matrix perimeters, showing they mfPOP does not correlate well with these devices, and compares their utility in neurological disease. It shows that Humphrey appears the most useful device overall, with Matrix being exceptionally good in chiasmal compression, while mfPOP does not appear effective in these disorders. With the first mfPOP approach having limitations in its diagnostic ability, a second stimulus protocol was designed using colour opponency with the measure of response latency (rather than amplitude), thought to preferentially stimulate cortical input to the pupil response, and may allow detection of cortical lesions. Chapter 6 investigates this new colour exchange protocol and latency measure, contrasting with the more common luminance approach used in chapter 5. It shows that the colour protocol shows a number of subtle differences compared to the luminance protocol, but does not show any greater utility in neurological disease. It reveals that latency and amplitude appear to have a weak positive relationship, and that mfPOP repeats appear to correlate well, but all measures have substantial variation. These finding open up a number of future directions, from a larger and more focused HVF study into colour and depth perception, to considering retinal density as contributing towards biases in pupillary components, exploring hemifield ratios as a measure of early detection of chiasmal compression, and trialling other mfPOP methods to determine whether neurological disorders can be detected through pupillometry

Pupil Size as a Gateway Into Conscious Interpretation of Brightness

Although retinal illumination is the main determinant of pupil size, evidence indicates that extra-retinal factors, including attention and contextual information, also modulate the pupillary response. For example, stimuli that evoke the idea of brightness (e.g., pictures of the sun) induce pupillary constriction compared to control stimuli of matched luminance. Is conscious appraisal of these stimuli necessary for the pupillary constriction to occur? Participants' pupil diameter was recorded while sun pictures and their phase-scrambled versions were shown to the left eye. A stream of Mondrian patterns was displayed to the right eye to produce continuous flash suppression, which rendered the left-eye stimuli invisible on some trials. Results revealed that when participants were aware of the sun pictures their pupils constricted relative to the control stimuli. This was not the case when the pictures were successfully suppressed from awareness, demonstrating that pupil size is highly sensitive to the contents of consciousness

Localization of Neuronal Gain Control in the Pupillary Response

Multifocal pupillographic objective perimetry (mfPOP) is being developed as an alternative to standard visual perimetry. In mfPOP, pupil responses to sparse multifocal luminance stimuli are extracted from the overall composite response. These individual test-region responses are subject to gain-control which is dependent on the temporal and spatial density of stimuli. This study aimed to localize this gain within the pupil pathway. Pupil constriction amplitudes of 8 subjects (41.5 ±12.7 y, 4 male) were measured using a series of 14 mfPOP stimulus variants. The temporal density of stimulus signal at the levels of retina, pretectal olivary nuclei (PON), and Edinger-Westphal nuclei (EWN) were controlled using a combination of manipulation of the mean interval between stimulus presentations (3 or 6 stimuli/s/hemiretina) and the restriction of stimuli to specific subsets of the 24 visual field test-regions per eye (left or right eye, left or right hemifield, or nasal or temporal hemifield). No significant difference was observed between mfPOP variants with differing signal density at the retina or PON but matched density at the other levels. In contrast, where signal density differed at the EWN but was the same at the retinal and PON levels e.g., between 3 stim/s homonymous hemifield and all test-region variants, significant reductions in constriction amplitudes were observed [t(30) = −2.07 to −2.50, all p &lt; 0.05]. Similar, although more variable, relationships were seen using nasal, and temporal hemifield stimuli. Results suggest that the majority of gain-control in the subcortical pupillary pathway occurs at the level of the EWN

Aspects of the pupil light response and colour vision using pupillometric and psychophysical tests

The pupil light reflex response (PLR) has been used as an indicator of visual function in neuro-ophthalmology but its usefulness is limited by the use of large light sources and gross measurement techniques. In this study, sophisticated recording equipment (the P SCAN 100 system) and computer-generated stimuli have been used to study certain aspects of the PLR. Luminance masking techniques have been developed which affect the PLR in different ways. In normal observers, local luminance masking eliminates some but not all of the PLR, while light flux changes over a larger area completely eliminate the PLR. Two components of the PLR have been proposed, based on experiments involving normal observers and subjects with cortical damage and optic nerve damage. The first component appears to involve cortical mechanisms as it is absent in subjects with cortical damage. This component has a high contrast gain, but saturates at contrasts above about 30%. The second component may equate with the classical subcortical pupil pathway. It has a lower contrast gain and exhibits extensive spatial summation, and may be involved with the control of steady state pupil size. The pupil has also been shown to respond to spectral changes. This study measures the pupil colour response (PCR) using the P SCAN 100 system and computer-generated stimuli. Luminance masking techniques were again used to ensure that the pupil was responding only to colour change, and not to any increase in light flux when the stimulus was presented. Significant PCRs were measured for a range of colours in normal subjects, but were not present in dichromats when the stimuli were chosen to fall in the same isochromatic zone as the background for each class of dichromat. PCRs were also investigated in subjects with damage to VI and V4. Small but significant responses were measured when large saturated stimuli were used. It is proposed that these responses may involve subcortical mechanisms. A psychophysical colour vision test has been used to investigate the processing of chromatic signals in normal subjects and patients with damage to the early-stage visual pathways. Two stimulus configurations were used - the first involves the detection of vertical bars defined only by chromatic signals (the ‘pattern’ test), and the second involves the detection of a colour change of a large target already defined by luminance contrast (the ‘colour’ test). In normal subjects, there is no difference between the chromatic discrimination thresholds found for the two types of test. In this study, two subjects were investigated who performed worse on the pattern test than the colour test. A group of patients who had previously suffered optic neuritis was also investigated to see if the same pattern of results was obtained, but this group showed a great variation in performance. It was proposed that performance at the two tests, indicating the use of chromatic signals, is mediated by two separable neural substrates. These two neural mechanisms can be affected differently but not specifically in optic neuritis. Type I colour-opponent centre-surround cells could be responsible for performance at the pattern test, while Type II colour-opponent spatially co-extensive cells could mediate colour detection when larger targets are used