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Background To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). Methods Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. Results The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. Conclusions/interpretation In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

Appalachian Kentucky is a region characterized by poor healthcare literacy and access. We investigate the disparities in demographic distribution and outcomes of penile squamous cell carcinoma (pSCC) in rural Kentucky.Data were retrieved for patients with pSCC from 1995-2015 from the Kentucky Cancer Registry and the Surveillance, Epidemiology and End Results Program (SEER) and were used to investigate differences between Appalachian Kentucky and the remainder of the state and country.The incidence of pSCC from 1995-2015 in Appalachian Kentucky was over 60% higher than non-Appalachian regions (2.6 vs. 1.6 cases/100,000 people). Nearly 40% were from Appalachian counties. They presented with similar grade and pT stage at diagnosis but were more likely to have pN+ disease (p0.001). Rates of cancer-specific mortality (CSM) were similar between the two regions, but patients with CSM exhibited shorter survival interval from diagnosis in Appalachia (median 20 vs. 26 months, p = 0.016). Compared to national SEER data, patients from Appalachian Kentucky presented with similar grade and stage but exhibited higher rates of CSM (24.0% vs. 20.1%, p = 0.029). African Americans (AA) comprised only 5% of patients but exhibited high pathologic stage at presentation (p = 0.041) and shorter survival intervals (median 12 vs. 23 months, p = 0.023) compared to Caucasians.There is a disproportionately high rate of pSCC in Appalachian Kentucky. Both Appalachian and AA men exhibited more advanced disease at presentation and shorter survival, identifying socioeconomic and racial disparities which can be targeted to improve outcomes in high risk individuals.

Multifocal pupillographic objective perimetry (mfPOP) has recently been shown to be able to measure cortical function. Here we assessed 44 regions of the central 60 degrees of the visual fields of each eye concurrently in 7 minutes/test. We examined how foveally- and peripherally-directed attention changed response sensitivity and delay across the 44 visual field locations/eye. Four experiments were completed comparing white, yellow and blue stimulus arrays. Experiments 1 to 4 tested 16, 23, 9 and 6 subjects, 49/54 being unique. Experiment 1, Experiments 2 and 3, and Experiment 4 used three variants of the mfPOP method that provided increasingly improved signal quality. Experiments 1 to 3 examined centrally directed attention, and Experiment 4 compared effects of attention directed to different peripheral targets. Attention reduced the sensitivity of the peripheral locations in Experiment 1, but only for the white stimuli not yellow. Experiment 2 confirmed that result. Experiment 3 showed that blue stimuli behaved like white. Peripheral attention showed increased sensitivity around the attentional targets. The results are discussed in terms of the cortical inputs to the pupillary system. The results agree with those from multifocal and other fMRI and VEP studies. mfPOP may be a useful adjunct to those methods.

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

We compared the diagnostic power of electrophysiologically and psychophysically measured contrast thresholds for the diagnosis of glaucoma. Additionally, we investigated whether combining results from the two methods improved diagnostic power. Seven-eight subjects between 40 and 88 years formed the main study group: 21 normal controls (9 males) and 57 glaucoma patients (30 males) were tested. Twenty-two younger control subjects were also tested. Contrast thresholds were determined for a 1 cpd sinusoidal grating, subtending 41° × 52° modulated at 14.3 rps. The thresholds were based on the same staircase method applied to visual evoked potential (VEP) and psychophysical responses (Psyc). Diagnostic power was assessed by the percent area under the curve (%AUC) of receiver operating characteristic plots. Psyc showed significant age dependence, −0.10 ± 0.02 dB, while VEPs did not. Diagnostic performance for moderate and severe eyes combined was modest: Psyc 74 ± 9.0 % and VEP 72 ± 9.1 %, but improved significantly (p

Objectives: The objective of this paper is to investigate the pattern of abnormalities and establish the diagnostic power of multifocal objective pupil perimetry (mfPOP) in multiple sclerosis (MS). Methods: A prospective study enrolling 35 normal (47.9 ± 16.8 years, 22 females) and 85 MS subjects (49.8 ± 11.3 years, 62 females; 72 relapsing–remitting (RR), and 13 primary or secondary progressives (PorS)). EDSS scores for the RR and PorS groups were 3.53 ± 1.04 (mean ± SD), and 5.9 ± 1.43, respectively. mfPOP responses were obtained from 44 regions/visual field. Each region was analysed according to response time-to-peak and standardised amplitude (AmpStd). Predictive power was measured by percentage area under the receiver operator curve (%AUC). Results: mfPOP responses showed a significant reduction of 0.69 ± 0.04 dB (mean ± SE) in AmpStd and significantly delayed time-to-peak of 25.95 ± 0.89 ms (mean ± SE) in MS subjects compared to control subjects ( pConclusions: mfPOP is well tolerated and potentially has a role in the diagnosis and assessment of patients with MS.

To evaluate the ability of multifocal visual evoked potentials (mfVEPs) to identify functional loss in patients with early and exudative age-related macular degeneration (AMD). A dichoptic multifocal stimulus presentation was employed to investigate the regional effects of AMD and the potential diagnostic utility in macular disease.MfVEP responses were recorded from 19 unilateral exudative AMD patients with non-exudative (n = 15) or normal (n = 4) presentations in the fellow eye and 28 age-matched controls. Root mean square (RMS) waveforms were pooled across selected EEG channels to produce global field RMS (gfRMS) waveforms. GfRMS amplitudes and response delays were analysed by multivariate linear models, and diagnostic capacity was measured using areas under the curve (AUC) of receiver operator characteristic plots.The mean gfRMS amplitude of the exudative eye of AMD patients was significantly reduced compared with the controls (-2.03 ± 0.08 dB, t = -12.9). Fellow non-exudative AMD eyes were less effected but still significantly reduced (-0.84 ± 0.07 dB, t = -11.5). No significant difference in mean gfRMS delay of AMD eyes across the central 46° was observed. AUC values of 100 ± 0.0% (mean ± SE) for exudative and 79.7 ± 6.5% for non-exudative eyes were obtained for response amplitudes.The study demonstrated that mfVEP identified retinal dysfunction in both exudative AMD and fellow non-exudative AMD eyes, but mostly affecting the macular field. The reduced testing duration and good diagnostic accuracy suggest that dichoptic mfVEPs may be a sensitive tool for monitoring progression in AMD.

We compared the diagnostic power of 10 stimulus variants that assessed the visual fields of both eyes by recording pupillary responses to multifocal stimuli. The 10 variants comprised 6 initial tests, and 4 subsequent variants whose design was informed by the initial results.Two study groups containing 16 normal and 22 primary open angle glaucoma subjects, and 15 normal and 20 primary open angle glaucoma subjects had their diagnostic status verified by a slit-lamp investigation, applanation tonometry, 3 forms of perimetry, and Stratus OCT. Stereoscopically arranged displays presented multifocal stimulus arrays having 24 stimulus regions/eye within the central 60 degrees. Pupil responses were recorded by video cameras under infrared illumination. The 10 stimulus conditions varied in presentation rate, duration, stimulus luminance, and flicker rate. Stimuli were 4 minutes in duration, presented in 8 segments of 30 seconds. Up to 15% of the data of a segment could be lost owing to blinks and fixation losses without repeating the segment.Each recording gave 96 direct and consensual responses/subject. The best performing stimulus method gave a sensitivity of 1.0 ± 0.0 (mean ± SE) for moderate and severe glaucomatous fields combined at a false positive rate of 0.05. Median signal to noise ratios for peak response amplitude expressed as t-statistics exceeded 4 for several variants.Stimulus delivery rates of about 1 presentation/region/s and test luminance around 150 cd/m performed best diagnostically. Unlike automated perimetry, the mfPOP method provides information on response delays and afferent and efferent defects at each region of the visual field.

We compared photopic and scotopic multifocal pupillographic stimuli in age-related macular degeneration (AMD). Both eyes of 18 normal and 14 AMD subjects were tested with four stimulus variants presented at photopic and 126 times lower luminances. The multifocal stimuli presented 24 test regions/eye to the central 60°. The stimulus variants had two different check sizes, and when presented either flickered (15 Hz) for 266 ms, or were steady for 133 ms. Mean differences from normal of 5 to 7 dB were observed in the central visual field for both photopic and scotopic stimuli (all p < 0.00002). The best areas under receiver operating characteristic plots for exudative AMD in the photopic and scotopic conditions were 92.9 ± 8.0 and 90.3 ± 5.7% respectively, and in less severely affected eyes 83.8 ± 9.7% and 76.9 ± 8.2%. Damage recorded at photopic levels was possibly more diffusely distributed across the visual field. Sensitivity and specificity was similar at photopic and scotopic levels.

PURPOSE To investigate retinal function in subjects with unilateral exudative age-related macular degeneration (AMD) using multifocal pupillographic objective perimetry (mfPOP) and to assess the diagnostic accuracy of this technique. METHODS We tested each of 20 exudative AMD patients and 20 control subjects with 4 different mfPOP stimulus variants. Multifocal stimuli consisting of 24 or 44 independent stimulus regions per eye extending from fixation to 15° eccentricity were presented dichoptically. The aperiodic stimuli were presented at 1 or 4 s mean intervals. Video cameras recorded pupil responses under infrared illumination. Test duration consisted of 8 segments of 30 s. Stimuli were presented at a luminance of 250 cd/m and a background of 10 cd/m. Peak regional contraction amplitudes, time to peaks, and a linear combination of these were used to produce receiver operator characteristic (ROC) curves to measure the diagnostic accuracy of this method. RESULTS Mean constriction amplitudes of exudative AMD subjects were decreased by 0.77 ± 0.15 dB (p < 5 × 10). Stimulus ensembles with 44 regions and faster presentation rates produced the largest effect on response sizes (t = 3.63; p < 0.0002). When comparing the control eyes to exudative AMD eyes, the area under the curve of ROC plots was 0.96 ± 0.03 (mean ± SE). This was achieved for asymmetry analysis of the difference in response amplitudes obtained from the two eyes at each point in the visual field. CONCLUSIONS The mean effect of exudative AMD on contraction amplitudes reflected the severity of disease, and ROC analysis from amplitude deviations improved the sensitivity of detection of exudative AMD. A longitudinal investigation into the mfPOP responses of patients with non-exudative AMD may detect and classify visual fields with poor prognosis.

Purpose: We investigated issues that could impair the capacity of multifocal pupilliographic perimetry to detect visual field damage. Differential blue light absorbance causes between-subject variance so we compared stimuli with differing blue content. We also quantified declining response gain at higher stimulus intensities (saturation), which can reduce sensitivity to changes in the visual field. Methods: Independent stimuli were delivered to 44 regions of both eyes whereas pupil responses were recorded under infrared illumination. Luminance-response functions were measured at 88 locations for white, yellow, and red stimuli at luminances ranging from 36 to 288 cd/m 2 . Response saturation was quantified by fitting power functions: Response=aLuminance z , z

Objective To examine the feasibility of a multifocal visual evoked potential (mfVEP) binocularly, using a variant of the multifocal frequency-doubling (FD) pattern-electroretinogram (MFP). Methods Stimuli were presented in both monocular and dichoptic conditions at eight visual field locations/eye. The incommensurate stimulus frequencies ranged from 15.45 to 21.51Hz. Five stimulus conditions differing in spatial frequency and orientation were examined for three viewing conditions. The resulting 15 stimulus conditions were examined in 16 normal subjects who repeated all conditions twice. Results Several significant independent effects were identified. Response amplitudes were reduced for dichoptic viewing (by 0.85 times, p −11 ); offset by increases in responses for between eye differences of one octave of spatial frequency: lower (1.15 times, 0.1cpd); higher (1.29 times, 0.4cpd), both p −7 . Crossed orientations produced significant effects upon response phase ( p =0.023) but not amplitude ( p =0.062). Conclusions The results indicated that dichoptic evoked potentials using multifocal frequency-doubling illusion stimuli are practical. The use of crossed orientation, or differing spatial frequencies, in the two eyes reduced binocular interactions. Significance The results indicate a method wherein several spatial or temporal and frequencies per visual field region can be tested in reasonable time using a multifocal VEP using spatial frequency-doubling stimuli.

PURPOSE This study investigated multifocal pupillographic objective perimetry (mfPOP) stimuli that target the intrinsic photosensitivity of melanopsin retinal ganglion cells. The diagnostic potential for glaucoma is compared between stimuli biased toward either cone input to these cells or their melanopsin response. METHODS Nineteen glaucoma patients and 24 normal subjects were tested using mfPOP stimulus protocols with either 33-ms yellow or 750-ms blue stimuli. Subjects' color discrimination was assessed using the Farnsworth 100-hue test. Pupillary responses were measured, and mixed-effects regression was used to quantify results. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis. RESULTS The mean reduction in moderate to severe glaucoma pupil responses using blue mfPOP stimuli was larger but more variable than that of the shorter yellow stimuli (blue: -1.32 dB [t(40) = -2.29; P = 0.027]; yellow: -0.93 dB [t(40) = -3.13; P = 0.003]). Color discrimination decreased significantly with age and glaucoma, with type III blue-yellow anomalies dominating. ROC analysis revealed similar diagnostic accuracies (AUC for eyes classified as moderate to severe; blue: 81.7%, yellow: 83.7). Slightly higher sensitivity and specificity were obtained using blue stimuli in mild disease (AUCs blue: 71.1, cf. yellow: 67.7), although this difference was not significant. CONCLUSIONS In moderate to severe glaucoma, diagnostic accuracy of yellow and blue was similar, but blue stimuli showed limited ability to resolve scotomas. Blue mfPOP stimuli, however, may have advantages over yellow in detecting early glaucoma.

PURPOSE Retinal light sensitivity loss has been shown to occur prior to other signs of retinopathy and may predict the sight-threatening sequelae. A rapid, objective perimetric test could augment diabetes care. We investigated the clinical use of multifocal pupillographic objective perimetry (mfPOP) to identify patients with and without diabetic retinopathy. METHODS Retinopathy severity was determined using the Early Treatment of Diabetic Retinopathy Study (ETDRS) standard for fundus photography. Pupillary responses were measured from both eyes of 25 adults with none to moderate diabetic retinopathy and 24 age-matched controls, using three mfPOP stimulus variants. Multifocal pupillographic objective perimetry stimulus variants tested 44 regions per eye arranged in a five-ring dartboard layout presented within either the central 30° or 60° of fixation. Receiver operator characteristic (ROC) curves were produced from contraction amplitudes and time to peak responses. RESULTS Regression analysis revealed that mean amplitude deviations were larger with severity of early retinopathy. On average, the longest delays were measured in patients with no retinopathy. The brightest wide-field stimuli produced the highest area under the ROC curve for differentiating eyes with no retinopathy from nonproliferative diabetic retinopathy (NPDR) and from healthy eyes (100 ± 0.0%, mean ± SE). The asymmetry in local delay deviations between eyes tended to produce higher sensitivity and specificity than amplitude deviations. CONCLUSIONS Asymmetry in local response delays measured by mfPOP may provide useful information regarding the severity of diabetic retinopathy and may have clinical use as a rapid, noninvasive method for identifying functional loss even in the absence of NPDR.

Purpose. To investigate the potential of multifocal pupillographic objective perimetry to assess changes in retinal function with clinical severity of age-related macular degeneration (AMD). Methods. Pupil responses were recorded from 40 subjects with AMD and 23 normal control subjects (mean T SD age, 71.3 T 5.1 years). Age-related macular degeneration subjects were classified according to the Age-Related Eye Disease Study (AREDS) classification system and allocated into one of four AMD severity groups. Three multifocal pupillographic objective perimetry stimulus variants that were identical in luminance but varied in spatiotemporal sequence were used. In one of the three protocols, stimuli were presented with a pedestal flicker for 266 milliseconds at 15 Hz. Results. On average, response amplitudes demonstrated a significant change in sensitivity with progression from earlystage (0.32 T 0.08 dB, t = 3.88) to late-stage (j1.60 T 0.12 dB, t = j12.7) age-related macular degeneration. Response delays followed a similar trend with the longest delays in AREDS4 (57.2T 1.9 milliseconds, t = 29.5). Ring analysis identified the largest mean effect on responses within the central 6 degrees of fixation. The NewStimuli protocol achieved the best diagnostic accuracy across all severity groups with area under the curve values of 0.85 T 0.066 (AREDS1), 0.908 T 0.085 (AREDS2), 0.929 T 0.040 (AREDS3), and 1.0 T 0.0 (AREDS4). Conclusions. The mean effect of AMD on contraction amplitudes and response delays reflected the severity of disease, and the NewStimuli protocol achieved good diagnostic accuracy across all AMD severity groups. Multifocal pupillographic objective perimetry may potentially be a useful method in monitoring progression of AMD and assessing change in retinal function with novel interventions in early AMD. Longitudinal studies are required to identify biomarkers that predict eyes at risk of progression. (Optom Vis Sci 2014;91:904Y915)

This study investigated the diagnostic utility for glaucoma of multifocal pupillographic objective perimetry stimuli targeting different components of the pupillary response: cortically derived colour responses and subcortical luminance responses.Observational cross-sectional study undertaken at the Australian National University.Thirty-five eyes of 24 glaucoma subjects and 46 eyes of 23 normal subjects.Subjects were tested with three multifocal pupillographic objective perimetry stimulus variants. The luminance-only variant (YYbal) utilized yellow stimuli on a yellow background; mixed colour and luminance protocols utilized green stimuli on a red background (RGbal, RG). Stimuli of 33 ms duration were presented at mean intervals of 4 s/region.Pupil constriction amplitude and time to peak. Area under the receiver operating characteristic curve was the main measure of sensitivity and specificity for glaucoma.Colour and luminance protocols were more accurate at differentiating glaucoma subjects from normal subjects than the luminance-only protocol, and produced the largest reductions in amplitudes. This type of protocol also produced the highest overall sensitivity and specificity for glaucoma (receiver operating characteristic % area under the curve: severe, 100%; moderate, 94.4%; mild, 71.0%). Pattern deviations tended to produce higher area under the receiver operating characteristic curves in eyes classified as mild. Significant differences in the means of the six worst amplitude deviations were observed between normal and severe glaucoma subjects only.Stimuli targeting both cortical pupillary colour response and subcortical pupillary luminance response components produced higher diagnostic accuracy than stimuli targeting subcortical pupillary luminance responses alone. Inclusion of constriction latencies further improved accuracy.

We are developing multifocal pupillographic objective perimetry (mfPOP) to assess localized changes in function within visual pathways. In this study, we investigate novel mfPOP stimuli designed to target neural components from either or both the sub-cortical pupillary luminance response and the cortically driven color response.Pupillary responses of 12 subjects were recorded to eight mfPOP stimulus variants (protocols). Forty-eight visual field test-regions (24/eye) were stimulated concurrently with uncorrelated sequences of either high or low luminance-contrast, luminance- plus color-contrast, or equiluminant color-exchange stimuli. Stimulus pulses were of 50 ms duration and were presented at mean intervals of 4 seconds/region. Test durations were 4 or 8 minutes; therefore, estimated responses were derived from 60 or 120 stimulus presentations to each test region.Pupillary response amplitudes were more influenced by luminance-contrast than the color-contrast of stimuli; response delays, however, were more closely linked to the proportion of color- versus luminance-contrast in each protocol. Significant differences (P0.05) in amplitudes but not delays were present between all three high luminance-contrast protocols and a low luminance-contrast luminance protocol, regardless of color content. The reverse pattern was observed between the equiluminant color exchange protocol and this same low luminance-contrast luminance protocol. Only the low luminance-contrast plus color exchange protocol differed significantly from the low luminance-contrast luminance protocol in both measures.Two protocols, utilizing low and high luminance-contrast plus color exchange, were identified as likely to incorporate both cortical and subcortical response components, and were deemed potential candidates for further investigation in clinical studies.

Early age-related macular degeneration (AMD) is common among the elderly. While only a small number progress to sight-threatening stages of AMD, identifying prognostic functional markers remains paramount. Here, we objectively evaluate retinal function in patients with large drusen by multifocal pupillographic objective perimetry (mfPOP). Different temporal presentation rates and luminances were compared to optimize parameters for high signal to noise ratios (SNR) and diagnosticity for early AMD. Pupil responses were recorded from 19 early AMD patients (30 eyes) and 29 age-matched control subjects. We compared a luminance-balanced stimulus ensemble and two unbalanced stimulus variants, each consisting of 44 independent stimulus regions per eye extending from fixation to 15˚ eccentricity. Video cameras recorded pupil responses for each eye under infrared illumination. The amplitudes and delays of the peak responses were analysed by multivariate linear models. The diagnostic accuracy of the stimulus variants was compared using areas under the curve (AUC) of receiver operator characteristic (ROC) plots. Early AMD eyes differed significantly from normal in their mean constriction amplitudes (−2.22 ± 0.15 dB, t = −14.8) and delays (17.92 ± 1.2 ms, t = 14.9). The brightest stimulus ensembles produced the highest median SNRs of 3.45 z-score units; however, the balanced method was found to be the most diagnostic. AUC values of 0.95 ± 0.03 (mean ± SE) for early AMD were obtained when the asymmetry of response amplitudes between eyes was considered. The mfPOP responses of early AMD eyes showed significant abnormality in response amplitudes and peak time. The ROC AUCs of 95 % suggest that mfPOP is a sensitive tool for detecting early abnormalities in AMD and longitudinal studies measuring progression of retinal dysfunction are warranted.

Multifocal pupillographic objective perimetry was compared using 24 and 44 regions per visual field.Experimental design in a university setting.Twenty-seven normal control and 36 age-matched glaucoma patients.The four test variants differed in the mean interval between stimuli: 4, 1 or 0.25 s; and the number of visual field regions tested within the central 60 degrees: 24 or 44. All subjects had their diagnostic status confirmed by optical coherence tomography, two forms of perimetry and slit-lamp biomicroscopy. Both eyes were measured concurrently in 2.73 ± 0.45 min/eye (mean ± standard deviation), and tests were repeated about 2 weeks apart.The main outcome measures were: (i) mean change in light sensitivity due glaucoma; and (ii) areas under Receiver Operator Characteristic plots for detecting glaucoma.For all four variants, consensual responses, female gender and age produced small but significant sensitivity differences, and sensitivity declined with age by ≤-0.27 dB/decade (all P0.0003). The best diagnostic accuracy (area under curve 93.2 ± 3.89%) was produced by the one-presentation/s 44-region protocol. Across the four protocols, the effect of repeat testing was small (all methods ≤0.15 dB).Presentation rate had little effect, but increasing the tested density from 24 to 44 regions/field improved diagnostic power. Given that multifocal pupillographic objective perimetry also provides information on response delay and afferent versus efferent defects at every visual field region, it may be a useful adjunct to perimetry.

PURPOSE: To investigate the neural basis of contraction anisocoria and any implications for assessments using pupillary responses, through analysis of topographic variation in amplitudes of direct and consensual pupil responses. METHODS: Direct and consensual pupillary contraction amplitudes were analyzed from six studies in which 120 normal subjects were tested with 24 different stimulus variants. The dichoptically presented multifocal stimulus arrays subtended ± 30° of visual field but varied in color (achromatic or yellow), number of test regions (24 to 60/eye), mean regional presentation interval (0.25 to 16 s), and pulse time-course (33 to 150 ms, flickered or steady). The 290 cd/m(2) test-regions were displayed on a 10 cd/m(2) background. Ratios between mean direct and consensual responses were calculated for each region. Results were quantified using multivariate linear analysis. RESULTS: Direct responses within the temporal hemifield were significantly larger than consensual for all stimulus protocols. Across the 24 protocols these differences ranged between 13.8% (t(1415)=3.06, P

Multifocal pupillographic objective perimetry (mfPOP) has the advantage of being a non-invasive, objective method for measuring up to 88 visual field responses from both eyes concurrently within 5min. To date mfPOP has been used to assess the peripheral visual field. Here we examine the practicality of mfPOP for testing the macular region of the visual field. This study examines variations in temporal presentation rate, spatial stimulus layout and luminance intensity in a group of normal subjects to determine the optimal parameters for achieving high signal to noise ratios for a macular version of mfPOP. Responses to multifocal stimuli comprising 24 or 44 stimulus regions per eye were measured dichoptically achieving median signal to noise ratios of 2.47 z-score units. Long stimulus presentation intervals combined with 24 region non-overlapping layouts produced the largest contraction amplitudes and shortest response delays.

Purpose: This preliminary study investigated a means of concurrently assessing the visual field defects of both eyes by recording pupillary responses to multifocal stimuli. Methods: Twenty normal subjects and 26 primary open angle glaucoma patients, age and sex matched, were examined by slit-lamp, Humphrey Field Analyser II achromatic 24-2 perimetry and fundus photography. The patients had moderate to severe fields in at least one eye. Two stereoscopically arranged displays presented an array of 24 stimulus regions per eye extending from fixation to 30 degrees eccentricity. Pupil responses were recorded by video cameras under infrared illumination. Four stimulus conditions were tested: each stimulus region containing either a single or a 2 × 2 array of patches, presented either steadily for 133 ms or flickered at 15 Hz for 266 ms. Mean presentation rate was 1/s/region. The 4-min duration stimuli were presented in 8 segments of 30 s. Segments did not need to be repeated unless more than 15% of a segment record was lost as a result of blinks or fixation losses. Results: The 48 stimuli produced 96 direct and consensual responses per subject. The single patch, non-flickered stimulus condition produced the best diagnostic performance, an area under the curve of 84%. The contraction amplitudes for that stimulus gave a median z-score of 3.2. Conclusions: The method produced diagnostic accuracy approaching that of automated perimetry, but unlike perimetry provides standard errors for every point in each field as well as information on response delay and efferent defects. Only one pupil needs to function to measure both visual fields.

Purpose Multifocal pupillographic perimetry was used to examine differences in the visual fields of 23 subjects with early type 2 diabetes (T2D) and 23 age- and sex-matched control subjects. Methods Independent stimuli were delivered to 44 regions of each eye while pupil responses were recorded with infrared cameras. The stimuli were presented in 8 segments of 30 seconds, and both eyes of each subject were tested twice. The direct and consensual responses provided 88 responses per eye. The diagnostic power of the method was then examined by applying receiver operator analysis to the peak regional contraction amplitudes, time to peaks, and linear combinations of those. Results Dichoptic multifocal pupillography provided response amplitudes with a median z-score of 2.63 +/- 0.26 (SE). The diagnostic performance (expressed as areas under ROC plots) of the eight subjects (32 fields) who had had T2D for at least 10 years was 0.87 +/- 0.06 (mean +/- SE) for response amplitude deviations from normative data, rising to 0.95 +/- 0.04 when between-eye symmetry was considered. Mean pupil size did not have diagnostic power. Comparison of direct and consensual response fields indicated that the observed localized field defects were afferent. Conclusions Reasonable diagnostic power was obtained, especially for the 16 eyes that had had T2D for more than 10 years, inferring that even in the near absence of visible diabetic retinopathy, some retinal damage had been sustained. This result, if confirmed in a wider group, suggests the that the method may be clinically useful in screening for early damage to the retina in T2D diabetes.

Multifocal functional magnetic resonance imaging has recently been introduced as an alternative method for retinotopic mapping, and it enables effective functional localization of multiple regions‐of‐interest in the visual cortex. In this study we characterized interactions in V1 with spatially and temporally identical stimuli presented alone, or as a part of a nine‐region multifocal stimulus. We compared stimuli at different contrasts, collinear and orthogonal orientations and spatial frequencies one octave apart. Results show clear attenuation of BOLD signal from the central region in the multifocal condition. The observed modulation in BOLD signal could be produced either by neural suppression resulting from stimulation of adjacent regions of visual field, or alternatively by hemodynamic saturation or stealing effects in V1. However, we find that attenuation of the central response persists through a range of contrasts, and that its strength varies with relative orientation and spatial frequency of the central and surrounding stimulus regions, indicating active suppression mechanisms of neural origin. Our results also demonstrate that the extent of the signal spreading is commensurate with the extent of the horizontal connections in primate V1. Hum Brain Mapp, 2008. © 2008 Wiley‐Liss, Inc.

In non-human primates at least three anatomically and functionally distinct channels convey signals from the retina to the primary visual cortex (V1). Two of these channels, the parvocellular and the koniocellular, are sensitive to chromatic contrasts and form the basis of color vision. In humans, common phylogenetic history with other primates and psychophysical experiments suggest identical retinocortical mechanisms but separate evaluation of the distinct anatomical channels has been difficult because signals are already combined in V1. We studied the spatial distribution of activation to chromatic stimuli along the two opponent chromatic axes in human V1 with multifocal functional magnetic resonance imaging. The signal strength was quantified from three experiments with stimuli up to 20 degrees eccentricity. The hypothesis was that, although the parvo- and koniocellular signals are mixed in V1, distinct distributions of signal strength would be evident. We found that whereas different conditions activated the same areas of cortex, indicating that they have identical magnification factors, the responses to red/green stimulation were stronger close to the fovea whereas the blue/yellow responses were much less diminished with increasing eccentricity. Both chromatic axes showed saturating contrast response functions. Our measure directly from human V1 is in line with earlier psychophysical studies suggesting relatively stronger parvocellular channel representation close to the fovea, and more uniform distribution of the koniocellular and achromatic channels. In addition, our study presents a way to rapidly quantify retinotopic signal transmission in distinct retinocortical pathways of individual subjects.

We examined frequency doubling (FD) illusion based automated perimetry (FDT) and dichoptic FD multifocal visual evoked potentials (FDmfVEPs) in Normal and multiple sclerosis (MS) subjects. Contrast thresholds were determined at 17 visual field locations using an FDT perimeter. The stimuli presented to each location were 0.25 cpd gratings presented with rapid (25 Hz) counterphase flicker and thus displayed the spatial FD illusion. Dichoptic mfVEPs were recorded by concurrently stimulating eight regions/eye with FD stimuli presented at 95% contrast. Recordings were obtained from 27 Normal subjects, 26 MS patients who had experienced Optic Neuritis (MSON) and 24 MS patients without a history of ON (MSNON). The FDT thresholds showed enhanced contrast sensitivity for MSON patients (P0.0001) but not for MSNON patients. Response amplitudes for the central four regions of the mfVEP stimulus were reduced in both patient groups (P0.005). A classification model based upon the FDT thresholds performed at a specificity of 96% for a sensitivity of 97% in MSON patients, but the accuracy (simultaneously largest sensitivities and specificities) was poor (approximately 60%) in MSNON patients. Discriminant models based on the FDT thresholds and FDmfVEPs were able to diagnose more that 90% MSON patients but performed poorly for MSNON patients.

We compared the diagnostic capabilities of contrast reversal and sparse pattern pulse stimulation for dichoptic multifocal visual evoked potentials (mfVEPs) measured in normal subjects and multiple sclerosis (MS) patients. Multifocal responses were obtained from 27 normal subjects and 50 relapsing-remitting patients, 26 of whom had experienced optic neuritis (ON+). The patient groups were matched for length of disease and number of clinical attacks. Compared with the responses of normal subjects those of MS patients had significantly smaller response amplitudes, lower signal-to-noise ratios, more complex response waveforms, and longer response delays. The effects were larger for sparser stimuli. Sensitivities and specificities for the different stimulus types were estimated from receiver operator characteristic (ROC) plots. Bootstrap estimates of the accuracies of the ROCs for the most promising measure, the template delays, indicated the sparsest stimulus would deliver 92% sensitivity at a false-positive rate of 0%. In contrast, at 92% sensitivity the conventional mfVEP stimulus misdiagnosed more than 20% of the normal population. The results were similar for patients with no history of ON (ON-). In performing well in patients with no history of ON, the sparse mfVEPs seem to measure progressive damage associated with axon and gray matter losses rather than damage associated with a history of serious inflammation.

Visual evoked responses to dichoptically presented multifocal stimuli were recorded for 92 eyes. Two stimulus variants were explored: temporally sparse and rapidly contrast reversing. We used hierarchal decomposition (HD) to represent the multifocal responses in terms of a small number of potentially unique component waveforms that are interrelated in a multivariate linear autoregressive (MLAR) relationship. The HD method exploits temporal correlations over a range of delays in the responses to estimate parallel, feedforward and feedback relationships between the HD components. Three HD components having temporal interrelationships constrained (at P < 0.05) to a moving ∼20 ms window could describe the multifocal responses well (median r2-values up to 90%). HD components were similar for both stimulus types and the component waveforms were temporally correlated, especially the first and third components. The data set was large enough to estimate separate HD components for each multifocal stimulus region. The component waveforms differed somewhat by region but the MLAR relationships were similar. At short delays parallel processing dominated. At longer delays the proportion of response drives that were attributed to feedback and feedforward relationships grew. Overall HD analysis seems to provide an informed summary of multifocal responses and insights into their sources.

Temporally sparse stimuli have been found to produce larger multifocal visual evoked potentials than rapid contrast-reversal stimuli. We compared the contrast-response functions of conventional contrast-reversing (CR) stimuli and three grades of temporally sparse stimuli, examining both the changes in response amplitude and signal-to-noise ratio (SNR). All stimuli were presented dichoptically to normal adult human subjects. One stimulus variant, the slowest pattern pulse, had interleaved monocular and binocular stimuli. Response amplitudes and SNRs were similar for all stimuli at contrast 0.4 but grew faster with increasing contrast for the sparser stimuli. The best sparse stimulus provided an SNR improvement that corresponded to a recording time improvement of 2.6 times relative to that required for contrast reversing stimuli. Multiple regression of log-transformed response metrics characterized the contrast-response functions by fitting power-law relationships. The exponents for the two sparsest stimuli were significantly larger (P < 0.001) than for the CR stimuli, as were the mean response amplitudes and signal-to-noise ratios for these stimuli. The contrast-dependent response enhancement is discussed with respect to the possible influences of rapid retinal contrast gain control, or intracortical and cortico-geniculate feedback.

The multifocal mapping of electroretinograms and visual evoked potentials has established an important role in both basic research and in diagnostic procedures. We have developed a multifocal mapping method for fMRI, which allows detailed analysis of multiple local visual field representations in the cortex with excellent spatial resolution. Visual field was divided into 60 regions in a dartboard configuration, scaled according to the human magnification factor. Within blocks of 7 s, half of the regions were stimulated with checkerboard patterns contrast reversing at 8 reversals per second, while the other half remained inactive at uniform luminance. The subset of active regions changed with each 7-s block, according to an orthogonal design. Functional MRI was done with a 3-T GE Signa and analyzed with SPM2. A general linear model was fitted producing activation maps for each of the 60 regions, and local signal changes were quantified from V1. These activation maps were next assigned to 3D surface models of the cortical sheet, and then unfolded, using the Brain a la Carte software package. Phase-encoded retinotopic analysis of conventional design served as qualitative comparison data. With multifocal fMRI, all regions were mapped with good signal-to-noise ratio in V1, and subsets of regions showed activation in V2 and V3. This method allows rapid and direct exploration of multiple local visual responses, and is thus able to give complementary information to phase encoded mapping of retinotopic areas.

PURPOSE To investigate the efficacy of multifocal pupillographic objective perimetry (mfPOP) to quantify the effects of intravitreal ranibizumab injection for choroidal neovascularization (CNV) secondary to exudative age-related macular degeneration (AMD). METHODS mfPOP visual fields from 20 patients with unilateral exudative AMD treated with intravitreal ranibizumab were measured before and after 3 months of treatment and were compared with that in 30 normal subjects. Two stimulus types consisting of ensembles of 24 or 44 independent stimuli per eye had a mean presentation interval at each region of 1 second. Pupil responses were recorded with video cameras under infrared illumination. Multiple linear models were fitted to contraction amplitudes and delay to peak responses, to determine the independent effects of exudative AMD before and after ranibizumab therapy. RESULTS After 3 months of treatment, mean additional response delays compared to normal subjects for the 24-region stimulus improved significantly (P < 5 × 10⁻⁹) from a mean of 18.82 ± 3.0 ms at baseline to 7.45 ± 3.15 ms. The mean effect of exudative AMD at baseline decreased constriction amplitude by -1.11 ± 0.24 dB (P < 0.00001) with little improvement after ranibizumab therapy. Small pretreatment elevations of extrafoveal sensitivity correlated with improvements in central retinal thickness (CRT) after treatment (P < 0.0005). CONCLUSIONS Improvements in mfPOP contraction amplitudes and time to peak responses were measured in eyes treated with intravitreal ranibizumab; however, response delays appeared to be the most indicative of functional improvement. Confirmation of hypersensitivity in the extrafoveal field in a larger group may support this finding as a prognostic marker for good treatment outcomes.

PURPOSE. The recent development of an objective and noninvasive perimetric technique using pupillary responses to sparse multifocal visual stimuli shows promise for the assessment of visual function in glaucoma. This study assesses the sensitivity and specificity of four variants of dichoptic multifocal pupillographic objective perimetry (mfPOP) with a highresolution, 40-region/field stimulus. METHODS. Nineteen normal subjects and 17 with open-angle glaucoma were tested with four 4-minute stimulus protocols, presented in eight segments of 30 seconds each. Achromatic multifocal stimuli comprised 40 test regions per eye arranged in a four-ring dartboard layout subtending 60° of visual field. Background luminance was 10 cd/m 2 with active stimulus regions displaying steady or flickered stimuli at 290 cd/m 2 . Stimulus durations were between 33 and 150 ms, mean intervals between presentations to each test region ranged from 1 to 16 seconds. Fixation was monitored in real time. RESULTS. Longer mean intervals and durations resulted in better diagnostic performance. Best results were obtained with 150-ms flickered stimuli and a discriminant function that incorporated both amplitude and width of responses: ROC area under the curve 0.86 0.05 (mean SE) across all visual field severities, (n 34) and 1.00 0.00 for moderate and severe fields (n 10). CONCLUSIONS. mfPOP produces separate information on response delay and afferent and efferent defects at every point in the field. The diagnostic accuracy of the 40-region, 150-ms stimulus is comparable to that of commonly used subjective perimeters and encourages further investigation of this technique. (Invest Ophthalmol Vis Sci. 2011;52:604‐610) DOI:10.1167/iovs.10-5737

At about the time of eye opening, one eye of seven tammar wallaby pouch young was surgically rotated about the optic axis by approximately 90 degrees. In adulthood the projection of the visual field through the rotated eye onto the contralateral superior colliculus was mapped electrophysiologically. Although apparently distorted, the projection could be coherently re-rotated mathematically to a reasonable copy of the normal projection from the opposite eye of the same animal, including details such as regional variations of the magnification factor. The same was true of three adult animals in which the eye rotation was done after anaesthesia immediately before the electrophysiological mapping. In animals in which the visual field seen through one eye, the other being normal, was rotated for the entire period of visual experience, there was no sign of compensation or rearrangement of the topographic map. Retinocollicular synaptic connections appear unmoved by such discordant visual experience.

Multifocal VEP (mfVEP) responses were obtained from 13 normal human subjects for nine test conditions, covering three viewing conditions (dichoptic and left and right monocular), and three different temporal stimulation forms (rapid contrast reversal, rapid pattern pulse presentation, and slow pattern pulse presentation). The rapid contrast reversal stimulus had pseudorandomized reversals of checkerboards in each visual field region at a mean rate of 25 reversals/s, similar to most mfVEP studies to date. The rapid pattern pulse presentation had pseudorandomized presentations of a checkerboard for one frame, interspersed with uniform grey frames, with a mean rate of 25 presentations/s per region per eye. The slow pattern pulse stimulus had six presentations/s per region per eye. Recording time was 5.3 min/condition. For dichoptic presentation slow pattern pulse responses were 4.6 times larger in amplitude than the contrast reversal responses. Binocular suppression was greatest for the contrast reversal stimulus. Consideration of the signal-to-noise ratios indicated that to achieve a given level of reliability, slow pattern pulse stimuli would require half the recording time of contrast reversal stimuli for monocular viewing, and 0.4 times the recording time for dichoptically presented stimuli. About half the responses to the slow pattern pulse stimuli had peak value exceeding five times their estimated standard error. Responses were about 20% smaller in the upper visual field locations. Space–time decomposition showed that responses to slow pattern pulse were more consistent across visual field locations. We conclude that the pattern pulse stimuli, which we term temporally sparse, maintain the visual system in a high contrast gain state. This more than compensates for the smaller number of presentations in the run, and provides signal-to-noise advantages that may be valuable in clinical application.