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Purpose: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. Experimental design: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/− salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. Results: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1–2), 25% nausea (grade 1–2), and 20% fatigue (grade 1–2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). Conclusion: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Objective: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. Materials and Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson’s chi-squared tests and the Kaplan–Meier method, respectively. Results: A total of 87 MIBC patients were included. The median age was 66 (39–84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2–14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. Conclusion: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

Multifocal pupillographic objective perimetry (mfPOP) is being developed as an alternative to subjective threshold perimetry for the management of visual and neurological disorders. Here, we evaluate, in normal subjects, differences in signal quality between the original mfPOP method of spatially sparse Continuous stimulus presentation and the new Clustered Volleys (CVs) method. We hypothesized that the CVs method would lead to increased signal-to-noise ratios (SNRs) over the original method due to the stabilization of gain within the pupillary system.Data were collected from six separate studies where otherwise-identical pairs of mfPOP tests using either the original Continuous stimulus presentation method or the new CVs method were undertaken; 440 6-minute tests from 96 normal subjects of varying ages were included. Per-region SNRs were compared between the two methods.Mean SNRs for the CVs mfPOP variants were between 35% and 57% larger than the original Continuous mfPOP variants (P0.001 in five of six studies). Similarly, the goodness-of-fit measure (r2) demonstrated large and significant fold increases of between 2.3× and 3.4× over the original method (all P0.001). Significant improvements in SNRs were present in all of the 88 test regions (44/eye), ranging between 8.4% and 93.7%; mean SNRs were significantly larger in 98% of test subjects.The CVs mfPOP stimulus presentation method produced substantial increases in signal quality over the original method. This is likely due to the stabilization of pupillary gain during stimulus presentation.These improvements increase diagnostic accuracy and have enabled shorter, 80-second mfPOP tests to be developed.

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.

Despite evoked potentials' (EP) ubiquity in research and clinical medicine, insights are limited to gross brain dynamics as it remains challenging to map surface potentials to their sources in specific cortical regions. Multiple sources cancellation due to cortical folding and cross-talk obscures close sources, e.g. between visual areas V1 and V2. Recently retinotopic functional magnetic resonance imaging (fMRI) responses were used to constrain source locations to assist separating close sources and to determine cortical current generators. However, an fMRI is largely infeasible for routine EP investigation. We developed a novel method that replaces the fMRI derived retinotopic layout (RL) by an approach where the retinotopy and current estimates are generated from EEG or MEG signals and a standard clinical T1-weighted anatomical MRI. Using the EEG-RL, sources were localized to within 2 mm of the fMRI-RL constrained localized sources. The EEG-RL also produced V1 and V2 current waveforms that closely matched the fMRI-RL's (n = 2) r(1,198) = 0.99, P < 0.0001. Applying the method to subjects without fMRI (n = 4) demonstrates it generates waveforms that agree closely with the literature. Our advance allows investigators with their current EEG or MEG systems to create a library of brain models tuned to individual subjects' cortical folding in retinotopic maps, and should be applicable to auditory and somatosensory maps. The novel method developed expands EP's ability to study specific brain areas, revitalizing this well-worn technique. Hum Brain Mapp 37:1696-1709, 2016. © 2016 Wiley Periodicals, Inc.

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

This work was supported by the Australian Research Council through the ARC Centre of Excellence in Vision Science(CE0561903).

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.

Background Multifocal pupillographic objective perimetry was compared using 24 and 44 regions per visual field. Design Experimental design in a university setting. Participants Twenty-seven normal control and 36 age-matched glaucoma patients. Methods 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. Main Outcome Measures The main outcome measures were: (i) mean change in light sensitivity due glaucoma; and (ii) areas under Receiver Operator Characteristic plots for detecting glaucoma. Results 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 P

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.

Despite evoked potentials' (EP) ubiquity in research and clinical medicine, insights are limited to gross brain dynamics as it remains challenging to map surface potentials to their sources in specific cortical regions. Multiple sources cancellation due to cortical folding and cross‐talk obscures close sources, e.g. between visual areas V1 and V2. Recently retinotopic functional magnetic resonance imaging (fMRI) responses were used to constrain source locations to assist separating close sources and to determine cortical current generators. However, an fMRI is largely infeasible for routine EP investigation. We developed a novel method that replaces the fMRI derived retinotopic layout (RL) by an approach where the retinotopy and current estimates are generated from EEG or MEG signals and a standard clinical T1‐weighted anatomical MRI. Using the EEG‐RL, sources were localized to within 2 mm of the fMRI‐RL constrained localized sources. The EEG‐RL also produced V1 and V2 current waveforms that closely matched the fMRI‐RL's (n = 2) r ((1,198)) = 0.99, P < 0.0001. Applying the method to subjects without fMRI (n = 4) demonstrates it generates waveforms that agree closely with the literature. Our advance allows investigators with their current EEG or MEG systems to create a library of brain models tuned to individual subjects' cortical folding in retinotopic maps, and should be applicable to auditory and somatosensory maps. The novel method developed expands EP's ability to study specific brain areas, revitalizing this well‐worn technique. Hum Brain Mapp 37:1696–1709, 2016. © 2016 Wiley Periodicals, Inc.

This paper describes multifocal visual evoked potentials (mfVEPs) recorded to different levels of temporal sparseness. It presents the usefulness and diagnostic value of mfVEPs in multiple sclerosis (MS) and optic neuritis (ON). The paper also discusses the usefulness of frequency doubling (FD) illusion and the effect of binocularity in Normal and MS study groups.

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)

Functional development of thalamic input to the cortex in anaesthetised wallaby pouch young between postnatal day 25 (P25) and P153 has been studied by electrical stimulation of the optic nerve, current source density (CSD) analysis, and histologic identification of recording sites. Conduction in the optic nerve was recorded prior to P39, by which time responses from the superior colliculus appeared. No evoked potential of cortical origin was recorded until P46, even though thalamic fibres grew into the cortical plate from P15. The first cortical synaptic responses were recorded at the margin of the subplate and the developing cortical plate, where cells that later comprise the adult layer 6 settle. At about P66, an additional short-latency, superficial response appeared, coinciding with the formation of layer 4. The deep response was retained in layer 6. Evoked activity in the presumed layer 4 was found progressively deeper in the cortex over the next few weeks, which would be expected from the addition of layer 3 above it. By P113, a new sink was added superficial in the cortex. Thalamocortical connections follow the same deep-to-superficial order in development as the cellular layers of the cortex. J. Comp. Neurol. 418:441–456, 2000. © 2000 Wiley-Liss, Inc.

Several lines of evidence are provided indicating that our visual percept can be dominated by spatial aliasing for viewing conditions near those needed to see the spatial frequency doubled illusion. The apparent aliasing effect indicates that the underlying sampling array has a density 15–30% of that of M-cells, in agreement with the known proportion of Y-like M-cells (My-cells). The presence of aliasing indicates, that there is a separate irregular array of My-cells, and that their role is to rapidly convey information on retinal gain control to the brain rather than to act primarily as inputs to image motion computation.

The chemical management of the black leaf streak disease in banana caused by Mycosphaerella fijiensis (Morelet) requires numerous applications of fungicides per year. However this has led to fungicide resistance in the field. The present study evaluated the activities of six fungicides against the mycelial growth by determination of EC50 values of strains collected from fields with different fungicide management programs: Rustic management (RM) without applications and Intensive management (IM) more than 25 fungicide application/year. Results showed a decreased sensitivity to all fungicides in isolates collected from IM. Means of EC50 values in mg L(-1) for RM and IM were: 13.25 ± 18.24 and 51.58 ± 46.14 for azoxystrobin, 81.40 ± 56.50 and 1.8575 ± 2.11 for carbendazim, 1.225 ± 0.945 and 10.01 ± 8.55 for propiconazole, 220 ± 67.66 vs. 368 ± 62.76 for vinclozolin, 9.862 ± 3.24 and 54.5 ± 21.08 for fludioxonil, 49.2125 ± 34.11 and 112.25 ± 51.20 for mancozeb. A molecular analysis for β-tubulin revealed a mutation at codon 198 in these strains having an EC50 greater than 10 mg L(-1) for carbendazim. Our data indicate a consistency between fungicide resistance and intensive chemical management in banana fields, however indicative values for resistance were also found in strains collected from rustic fields, suggesting that proximity among fields may be causing a fungus interchange, where rustic fields are breeding grounds for development of resistant strains. Urgent actions are required in order to avoid fungicide resistance in Mexican populations of M. fijiensis due to fungicide management practices.

It has been proposed that the spatial frequency doubled (FD) illusion may originate from Y-like non-linear retinal ganglion cells. If the contrast of multi-frequency stimuli is increased, Y cells show a phase advance in the self-sum frequencies but not in other output frequencies. We looked for these effects with a multi-region pattern electroretinogram (PERG) displaying the sum of two temporal frequencies in each visual field location. Regional variation was found in the recorded sum and difference frequencies. The results indicate that PERG signals become dominated by responses from Y-like cells when the FD illusion is seen.

When do the developing connections between mammalian retinal ganglion cells and the superior colliculus become functional? Evoked potentials elicited by optic nerve stimulation in the pouch young of the wallaby were used to answer the question. Up to 42 days after birth, the evoked potentials in the colliculus appeared to be generated by axon conduction. Synaptic activity was first recorded from the rostral colliculus at 45 days, and was found to be progressively more caudal, spreading to cover the colliculus, by 65 days. From the earliest indication of synaptic activity until eye opening at 140 days, current source density (CSD) analysis consistently showed the same basic pattern: an initial deep sink from synaptic activity of fast (Y type) fibres, and a more superficial longer-latency sink from slower (W type) fibres. All features became more clearly delineated with age. The indirect retinocorticocollicular connection appeared between 134 days and 146 days. The ability of optic nerve fibres to sustain action potentials precedes their formation of functional synapses with collicular neurons, which happens abruptly at three months before eye opening. CSD analysis showed that the relationship between the conduction velocity of optic nerve fibres and their depth of termination is evident from the first signs of synapse formation.

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.

ABC transporters are membrane proteins that use the energy released from the hydrolysis of ATP to drive the transport of compounds across biological membranes. In some plants, pathogenic fungi ABC transporters play a role as virulence factors by mediating the export of plant defense compounds or fungal virulence factors. Mycosphaerella fijiensis, the causal agent of black Sigatoka disease in banana, is the main constraint for the banana industry worldwide. So far, little is known about molecular mechanism that it uses to infect the host. In this study, degenerated primers designed from fungal ABC transporters known to be involved in virulence were used to isolate homologs from M. fijiensis. Here, we reported the full cloning of MfAtr4 a putative ortholog of MgAtr4 , an ABC transporter of the related Mycosphaerella graminicola with a function in virulence. Similarities and differences with its presumed ortholog MgAtr4 are described, and the putative function of MfAtr4 are discussed. Analysis of MfAtr4 gene expression in field banana samples exhibiting visible symptoms of black Sigatoka disease indicated a higher expression of MfAtr4 during the first symptomatic stages in comparison to the late necrotrophic phases, suggesting a role for MfAtr4 in the early stages of pathogenic development of M. fijiensis . Key words : ABC transporters, virulence factors, MgAtr4 ortholog, Mycosphaerella fijiensis, black Sigatoka, Musa sp.

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.

The hemibiotrophic fungus Mycosphaerella fijiensis is the causal agent of black Sigatoka (BS), the most devastating foliar disease in banana (Musa spp.) worldwide. Little is known about genes that are important during M. fijiensis-Musa sp. interaction. The fungal cell wall is an attractive area of study because it is essential for maintenance of cellular homeostasis and it is the most external structure in the fungal cell and therefore mediates the interaction of the pathogen with the host. In this manuscript we describe the in silico identification of glycosyl phosphatidylinositol-protein (GPI) family in M. fijiensis, and the analysis of two β-1,3-glucanosyltrans-ferases (Gas), selected by homology with fungal pathogenicity factors. Potential roles in pathogenesis were evaluated through analyzing expression during different stages of black Sigatoka disease, comparing expression data with BS symptoms and fungal biomass inside leaves. Real-time quantitative RT-PCR showed nearly constant expression of MfGAS1 with slightly increases (about threefold) in conidia and at speck-necrotrophic stage during banana-pathogen interaction. Conversely, MfGAS2 expression was increased during biotrophy (about seven times) and reached a maximum at speck (about 23 times) followed by a progressive decrease in next stages, suggesting an active role in M. fijiensis pathogenesis.

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.

SUMMARY Idiomorphs mat1-1 and mat1-2 from Mycosphaerella fijiensis, the causal agent of black leaf streak disease of banana, were isolated. Degenerate oligos were used to amplify the HMG box of the mat1-2 idiomorph from M. fijiensis, showing homology with the HMG box of Mycosphaerella graminicola. Using a DNA walking strategy, anchored on the DNA lyase gene towards the HMG box, a 9-kb-long region of mat1-2 was obtained. A 5-kb fragment from the mat1-1 region was obtained by long-range PCR using primers on the flanking regions, which have close to 100% identity between both idiomorphs. High-identity (77‐ 89%), inverted regions within both idiomorphs were found, which suggest unique inversion events, which have not been found before, and that could have been significant in the evolution of this species. The predicted genes showed the conserved introns in both idiomorphs as well as an additional intron within the alpha box. The implications for the evolution of species in the Mycosphaerella complex on banana are discussed.

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.

The Craik-O'Brien Cornsweet effect (COCE) is a visual illusion where the luminance of image boundaries sets the apparent brightness of enclosed regions. The COCE may be produced by the cortex constructing the observed brightness through a lateral 'filling-in' process: propagating brightness information from the edges of the enclosed regions towards their centres. Any such filling-in process would imply a speed of propagation.Data on the propagation speed of brightness information in two different brightness induction effects are compared using a multivariate regression analysis.We demonstrate similar non-zero speeds for the COCE and for a brightness contrast effect.

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.

To determine the sensitivity and specificity of blue-on-yellow multifocal visual evoked potentials (mfVEPs) in early glaucoma.Cross-sectional study.Fifty patients with a confirmed diagnosis of early glaucoma and 60 normal participants.Black-and-white mfVEPs and blue-on-yellow mfVEPs were recorded using the Accumap version 2.0 (ObjectiVision Pty. Ltd., Sydney, Australia). All patients also underwent achromatic standard automated perimetry (SAP).Multifocal VEP amplitude and latency values in glaucoma patients were analyzed and compared with those of the normal controls.Based on the definition of visual field defect, in the group of glaucomatous eyes with SAP defects, amplitude of blue-on-yellow mfVEP was abnormal in all 64 cases (100% sensitivity), whereas black-and-white mfVEP missed 5 cases (92.2% sensitivity). Generally, larger scotomata were noted on blue-on-yellow mfVEP compared with black-and-white mfVEP for the same eyes. There was high topographic correspondence between SAP and amplitude of blue-on-yellow mfVEP and significant (P0.0001) correlation between them (correlation coefficient, 0.73). Abnormal amplitude was detected in 3 of 60 eyes of control subjects (95% specificity). There was, however, no correlation between visual field defect and latency delay in glaucoma patients. Although there was a significant difference between averaged latency of control and glaucoma eyes, values considerably overlapped.The blue-on-yellow mfVEP is a sensitive and specific tool for detecting early glaucoma based on amplitude analysis.

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.

Adult dragonflies augment their compound eyes with three simple eyes known as the dorsal ocelli. While the ocellar system is known to mediate stabilizing head reflexes during flight, the ability of the ocellar retina to dynamically resolve the environment is unknown. For the first time, we directly measured the angular sensitivities of the photoreceptors of the dragonfly median (middle) ocellus. We performed a second-order Wiener Kernel analysis of intracellular recordings of light-adapted photoreceptors. These were stimulated with one-dimensional horizontal or vertical patterns of concurrent UV and green light with different contrast levels and at different ambient temperatures. The photoreceptors were found to have anisotropic receptive fields with vertical and horizontal acceptance angles of 15° and 28°, respectively. The first-order (linear) temporal kernels contained significant undershoots whose amplitudes are invariant under changes in the contrast of the stimulus but significantly reduced at higher temperatures. The second-order kernels showed evidence of two distinct nonlinear components: a fast acting self-facilitation, which is dominant in the UV, followed by delayed self- and cross-inhibition of UV and green light responses. No facilitatory interactions between the UV and green light were found, indicating that facilitation of the green and UV responses occurs in isolated compartments. Inhibition between UV and green stimuli was present, indicating that inhibition occurs at a common point in the UV and green response pathways. We present a nonlinear cascade model (NLN) with initial stages consisting of separate UV and green pathways. Each pathway contains a fast facilitating nonlinearity coupled to a linear response. The linear response is described by an extended log-normal model, accounting for the phasic component. The final nonlinearity is composed of self-inhibition in the UV and green pathways and inhibition between these pathways. The model can largely predict the response of the photoreceptors to UV and green light.

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.