Keep your finger on the pulse: Better rate perception and gap detection with vibrotactile compared to visual stimuli.

Important characteristics of the environment can be represented in the temporal pattern of sensory stimulation. In two experiments, we compared accuracy of temporal processing by different modalities. Experiment 1 examined binary categorization of rate for visual (V) or vibrotactile (T) stimulus pulses presented at either 4 or 6 Hz. Inter-pulse intervals were either constant or variable, perturbed by random Gaussian variates. Subjects categorized the rate of T pulse sequences more accurately than V sequences. In V conditions only, subjects disproportionately tended to mis-categorize 4-Hz pulse rates, for all but the most variable sequences. In Experiment 2, we compared gap detection thresholds across modalities, using the same V and T pulses from Experiment 1, as well as with bimodal (VT) pulses. Visual gap detection thresholds were larger (3[Formula: see text]) than tactile thresholds. Additionally, performance with VT stimuli seemed to be nearly completely dominated by their T components. Together, these results suggest (i) that vibrotactile temporal acuity surpasses visual temporal acuity, and (ii) that vibrotactile stimulation has considerable, untapped potential to convey temporal information like that needed for eyes-free alerting signals.

Perceptual timing precision with vibrotactile, auditory, and multisensory stimuli.

The growing use of vibrotactile signaling devices makes it important to understand the perceptual limits on vibrotactile information processing. To promote that understanding, we carried out a pair of experiments on vibrotactile, auditory, and bimodal (synchronous vibrotactile and auditory) temporal acuity. On each trial, subjects experienced a set of isochronous, standard intervals (400 ms each), followed by one interval of variable duration (400 ± 1-80 ms). Intervals were demarcated by short vibrotactile, auditory, or bimodal pulses. Subjects categorized the timing of the last interval by describing the final pulse as either "early" or "late" relative to its predecessors. In Experiment 1, each trial contained three isochronous standard intervals, followed by an interval of variable length. In Experiment 2, the number of isochronous standard intervals per trial varied, from one to four. Psychometric modeling revealed that vibrotactile stimulation produced poorer temporal discrimination than either auditory or bimodal stimulation. Moreover, auditory signals dominated bimodal sensitivity, and inter-individual differences in temporal discriminability were reduced with bimodal stimulation. Additionally, varying the number of isochronous intervals in a trial failed to improve temporal sensitivity in either modality, suggesting that memory played a key role in judgments of interval duration.

Feeling the Beat (and Seeing It, Too): Vibrotactile, Visual, and Bimodal Rate Discrimination.

Beats are among the basic units of perceptual experience. Produced by regular, intermittent stimulation, beats are most commonly associated with audition, but the experience of a beat can result from stimulation in other modalities as well. We studied the robustness of visual, vibrotactile, and bimodal signals as sources of beat perception. Subjects attempted to discriminate between pulse trains delivered at 3 Hz or at 6 Hz. To investigate signal robustness, we intentionally degraded signals on two-thirds of the trials using temporal-domain noise. On these trials, inter-pulse intervals (IPIs) were stochastic, perturbed independently from the nominal IPI by random samples from zero-mean Gaussian distributions with different variances. These perturbations produced directional changes in the IPIs, which either increased or decreased the likelihood of confusing the two pulse rates. In addition to affording an assay of signal robustness, this paradigm made it possible to gauge how subjects' judgments were influenced by successive IPIs. Logistic regression revealed a strong primacy effect: subjects' decisions were disproportionately influenced by a trial's initial IPIs. Response times and parameter estimates from drift-diffusion modeling showed that information accumulates more rapidly with bimodal stimulation than with either unimodal stimulus alone. Analysis of error rates within each condition suggested consistently optimal decision making, even with increased IPI variability. Finally, beat information delivered by vibrotactile signals proved just as robust as information conveyed by visual signals, confirming vibrotactile stimulation's potential as a communication channel.

Histopathological Insights Into Choroidal Vascular Loss in Clinically Documented Cases of Age-Related Macular Degeneration.

IMPORTANCE: Age-related macular degeneration (AMD) is a multifactorial disease with genetic and environmental factors contributing to risk. Histopathologic changes underlying AMD are not fully understood, particularly the relationship between choriocapillaris (CC) dysfunction and phenotypic variability of this disease. OBJECTIVE: To examine histopathologic changes in the CC of eyes with clinically documented AMD. DESIGN, SETTING, AND PARTICIPANTS: The study was designed in 2011. Tissues were collected post mortem (2012-2016), and histopathological images were obtained from participants enrolled in AMD studies since 1988. Clinical records and images were collected from participants as standard protocol. Eyes without AMD (n = 4) and eyes with early (n = 9), intermediate (n = 5), and advanced stages of AMD (geographic atrophy, n = 5; neovascular disease, n = 13) were evaluated. Choroidal vasculature was labeled using Ulex europaeus agglutinin lectin and examined using confocal microscopy. MAIN OUTCOMES AND MEASURES: A standardized classification system was applied to determine AMD stage. Ocular records and images were reviewed and histopathologic analyses performed. Viability of the choroidal vasculature was analyzed for each AMD stage. RESULTS: All participants were white. Fourteen were male, and 16 were female. The mean age was 90.5 years among AMD patients and 88.5 years among control participants. Submacular CC dropout without retinal pigment eipthelial (RPE) loss was observed in all cases with early stages of AMD. Higher vascular area loss for each AMD stage was observed compared with control participants: 20.5% in early AMD (95% CI, 11.2%-40.2%; P < .001), 12.5% in intermediate AMD (95% CI, 2.9%-21.4%; P = .01), 39.0% loss in GA (95% CI, 32.1%-45.4%; P < .001), and 38.2% loss in neovascular disease where RPE remained intact (95% CI, 27.7%-47.9%; P < .001). Hypercellular, apparent neovascular buds were adjacent to areas of CC loss in 22.2% of eyes with early AMD and 40% of eyes with intermediate AMD. CONCLUSIONS AND RELEVANCE: Retinal pigment epithelial atrophy preceded CC loss in geographic atrophy, but CC loss occurred in the absence of RPE atrophy in 2 of 9 eyes with early-stage AMD. Given the cross-sectional nature of this study and the small number of eyes evaluated, definitive conclusions regarding this progression cannot be determined with certainty. We speculate that neovascular buds may be a precursor to neovascular disease. Hypoxic RPE resulting from reduced blood supply might upregulate production of vascular endothelial growth factor, providing the stimulus for neovascular disease.

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD.

The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.

Idiopathic preretinal glia in aging and age-related macular degeneration.

During analysis of glia in wholemount aged human retinas, frequent projections onto the vitreal surface of the inner limiting membrane (ILM) were noted. The present study characterized these preretinal glial structures. The amount of glial cells on the vitreal side of the ILM was compared between eyes with age-related macular degeneration (AMD) and age-matched control eyes. Retinal wholemounts were stained for markers of retinal astrocytes and activated Müller cells (glial fibrillary acidic protein, GFAP), Müller cells (vimentin, glutamine synthetase) and microglia/hyalocytes (IBA-1). Retinal vessels were labeled with UEA lectin. Images were collected using a Zeiss LSM 710 confocal microscope. Retinas were then cryopreserved. Laminin labeling of cryosections determined the location of glial structures in relation to the ILM. All retinas investigated herein had varied amounts of preretinal glia. These glial structures were classified into three groups based on size: sprouts, blooms, and membranes. The simplest of the glial structures observed were focal sprouts of singular GFAP-positive cells or processes on the vitreal surface of the ILM. The intermediate structures observed, glial blooms, were created by multiple cells/processes exiting from a single point and extending along the vitreoretinal surface. The most extensive structures, glial membranes, consisted of compact networks of cells and processes. Preretinal glia were observed in all areas of the retina but they were most prominent over large vessels. While all glial blooms and membranes contained vimentin and GFAP-positive cells, these proteins did not always co-localize. Many areas had no preretinal GFAP but had numerous vimentin only glial sprouts. In double labeled glial sprouts, vimentin staining extended beyond that of GFAP. Hyalocytes and microglia were detected along with glial sprouts, blooms, and membranes. They did not, however, concentrate in the retina below these structures. Cross sectional analysis identified small breaks in the ILM above large retinal vessels through which glial cells exited the retina. Preretinal glial structures of varied sizes are a common occurrence in aged retinas and, in most cases, are subclinical. While all retinal glia are found in blooms, vimentin labeling suggests that Müller cells form the leading edge. All retinas investigated from eyes with active choroidal neovascularization (CNV) had extensive glial membranes on the vitreal surface of the ILM. Although these structures may be benign, they may exert traction on the retina as they spread along the vitreoretinal interface. In cases with CNV, glial cells in the vitreous could bind intravitreally injected anti-vascular endothelial growth factor. These preretinal glial structures indicate the remodeling of both astrocytes and Müller cells in aged retinas, in particular those with advanced AMD.