Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial.

OBJECTIVE: Hearing loss has been identified as a major modifiable risk factor for cognitive decline. The Early Age-Related Hearing Loss Investigation (EARHLI) study will assess the mechanisms linking early age-related hearing loss (ARHL) and cognitive impairment. STUDY DESIGN: Randomized, controlled, single-site, early phase II, superiority trial. SETTING: Tertiary academic medical center. PARTICIPANTS: One hundred fifty participants aged 55 to 75 years with early ARHL (severity defined as borderline to moderate) and amnestic mild cognitive impairment will be included. INTERVENTIONS: Participants will be randomized 1:1 to a best practice hearing intervention or a health education control. MAIN OUTCOME MEASURES: The primary study outcome is cognition measured by the Alzheimer Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite. Secondary outcomes include additional measures of cognition, social engagement, and brain organization/connectivity. RESULTS: Trial enrollment will begin in early 2024. CONCLUSIONS: After its completion in 2028, the EARHLI trial should offer evidence on the effect of hearing treatment versus a health education control on cognitive performance, social engagement, and brain organization/connectivity in 55- to 75-year-old community-dwelling adults with early ARHL and amnestic mild cognitive impairment.

A unified model for cross-modal plasticity and skill acquisition.

Historically, cross-modal plasticity following early blindness has been largely studied in the context of visual deprivation. However, more recently, there has been a shift in focus towards understanding cross-modal plasticity from the perspective of skill acquisition: the striking plasticity observed in early blind individuals reflects the extraordinary perceptual and cognitive challenges they solve. Here, inspired by two seminal papers on skill learning (the "cortical recycling" theory) and cross-modal plasticity (the "metamodal" hypothesis) respectively, we present a unified hypothesis of cortical specialization that describes how shared functional, algorithmic, and structural constraints might mediate both types of plasticity.

The perception of auditory motion in sighted and early blind individuals.

Motion perception is a fundamental sensory task that plays a critical evolutionary role. In vision, motion processing is classically described using a motion energy model with spatiotemporally nonseparable filters suited for capturing the smooth continuous changes in spatial position over time afforded by moving objects. However, it is still not clear whether the filters underlying auditory motion discrimination are also continuous motion detectors or infer motion from comparing discrete sound locations over time (spatiotemporally separable). We used a psychophysical reverse correlation paradigm, where participants discriminated the direction of a motion signal in the presence of spatiotemporal noise, to determine whether the filters underlying auditory motion discrimination were spatiotemporally separable or nonseparable. We then examined whether these auditory motion filters were altered as a result of early blindness. We found that both sighted and early blind individuals have separable filters. However, early blind individuals show increased sensitivity to auditory motion, with reduced susceptibility to noise and filters that were more accurate in detecting motion onsets/offsets. Model simulations suggest that this reliance on separable filters is optimal given the limited spatial resolution of auditory input.

Characterizing amblyopic perception under non-rivalrous viewing conditions.

Current assessments of interocular interactions in amblyopia often use rivalrous stimuli, with conflicting stimuli in each eye, which does not reflect vision under typical circumstances. Here we measure interocular interactions in observers with amblyopia, strabismus with equal vision, and controls using a non-rivalrous stimulus. Observers used a joystick to continuously report the perceived binocular contrast of dichoptic grating stimuli, identical except that the stimulus was contrast-modulated independently in each eye over time. Consistent with previous studies, a model predicting the time-course of perceived contrast found increased amblyopic eye attenuation, and reduced contrast normalization of the fellow eye by the amblyopic eye, in amblyopic participants compared to controls. However, these suppressive interocular effects were weaker than those found in previous studies, suggesting that rivalrous stimuli may overestimate the effects of amblyopia on interocular interactions during naturalistic viewing conditions.

Pulse trains to percepts: A virtual patient describing the perceptual effects of human visual cortical stimulation.

The field of cortical sight restoration prostheses is making rapid progress with three clinical trials of visual cortical prostheses underway. However, as yet, we have only limited insight into the perceptual experiences produced by these implants. Here we describe a computational model or 'virtual patient', based on the neurophysiological architecture of V1, which successfully predicts the perceptual experience of participants across a wide range of previously published cortical stimulation studies describing the location, size, brightness and spatiotemporal shape of electrically induced percepts in humans. Our simulations suggest that, in the foreseeable future the perceptual quality of cortical prosthetic devices is likely to be limited by the neurophysiological organization of visual cortex, rather than engineering constraints.

The impact of low vision on social function: The potential importance of lost visual social cues

Visual cues usually play a vital role in social interaction. As well as being the primary cue for identifying other people, visual cues also provide crucial non-verbal social information via both facial expressions and body language. One consequence of vision loss is the need to rely on non-visual cues during social interaction. Although verbal cues can carry a significant amount of information, this information is often not available to an untrained listener. Here, we review the current literature examining potential ways that the loss of social information due to vision loss might impact social functioning. A large number of studies suggest that low vision and blindness is a risk factor for anxiety and depression. This relationship has been attributed to multiple factors, including anxiety about disease progression, and impairments to quality of life that include difficulties reading, and a lack of access to work and social activities. However, our review suggests a potential additional contributing factor to reduced quality of life that has been hitherto overlooked: blindness may make it more difficult to effectively engage in social interactions, due to a loss of visual information. The current literature suggests it might be worth considering training in voice discrimination and/or recognition when carrying out rehabilitative training in late blind individuals. (AU)

Do you hear what I see? How do early blind individuals experience object motion?

One of the most important tasks for 3D vision is tracking the movement of objects in space. The ability of early blind individuals to understand motion in the environment from noisy and unreliable auditory information is an impressive example of cortical adaptation that is only just beginning to be understood. Here, we compare visual and auditory motion processing, and discuss the effect of early blindness on the perception of auditory motion. Blindness leads to cross-modal recruitment of the visual motion area hMT+ for auditory motion processing. Meanwhile, the planum temporale, associated with auditory motion in sighted individuals, shows reduced selectivity for auditory motion. We discuss how this dramatic shift in the cortical basis of motion processing might influence the perceptual experience of motion in early blind individuals. This article is part of a discussion meeting issue 'New approaches to 3D vision'.

The impact of low vision on social function: The potential importance of lost visual social cues.

Visual cues usually play a vital role in social interaction. As well as being the primary cue for identifying other people, visual cues also provide crucial non-verbal social information via both facial expressions and body language. One consequence of vision loss is the need to rely on non-visual cues during social interaction. Although verbal cues can carry a significant amount of information, this information is often not available to an untrained listener. Here, we review the current literature examining potential ways that the loss of social information due to vision loss might impact social functioning. A large number of studies suggest that low vision and blindness is a risk factor for anxiety and depression. This relationship has been attributed to multiple factors, including anxiety about disease progression, and impairments to quality of life that include difficulties reading, and a lack of access to work and social activities. However, our review suggests a potential additional contributing factor to reduced quality of life that has been hitherto overlooked: blindness may make it more difficult to effectively engage in social interactions, due to a loss of visual information. The current literature suggests it might be worth considering training in voice discrimination and/or recognition when carrying out rehabilitative training in late blind individuals.

Factors affecting two-point discrimination in Argus II patients.

Two of the main obstacles to the development of epiretinal prosthesis technology are electrodes that require current amplitudes above safety limits to reliably elicit percepts, and a failure to consistently elicit pattern vision. Here, we explored the causes of high current amplitude thresholds and poor spatial resolution within the Argus II epiretinal implant. We measured current amplitude thresholds and two-point discrimination (the ability to determine whether one or two electrodes had been stimulated) in 3 blind participants implanted with Argus II devices. Our data and simulations show that axonal stimulation, lift and retinal damage all play a role in reducing performance in the Argus 2, by either limiting sensitivity and/or reducing spatial resolution. Understanding the relative role of these various factors will be critical for developing and surgically implanting devices that can successfully subserve pattern vision.

Learning to see again: Perceptual learning of simulated abnormal on- off-cell population responses in sighted individuals.

Many forms of artificial sight recovery, such as electronic implants and optogenetic proteins, generally cause simultaneous, rather than complementary firing of on- and off-center retinal cells. Here, using virtual patients-sighted individuals viewing distorted input-we examine whether plasticity might compensate for abnormal neuronal population responses. Five participants were dichoptically presented with a combination of original and contrast-reversed images. Each image (I) and its contrast-reverse (I') was filtered using a radial checkerboard (F) in Fourier space and its inverse (F'). [I * F'] + [I' * F] was presented to one eye, and [I * F] + [I' * F'] was presented to the other, such that regions of the image that produced on-center responses in one eye produced off-center responses in the other eye, and vice versa. Participants continuously improved in a naturalistic object discrimination task over 20 one-hour sessions. Pre-training and post-training tests suggest that performance improvements were due to two learning processes: learning to recognize objects with reduced visual information and learning to suppress contrast-reversed image information in a non-eye-selective manner. These results suggest that, with training, it may be possible to adapt to the unnatural on- and off-cell population responses produced by electronic and optogenetic sight recovery technologies.

New insights into cortical development and plasticity: from molecules to behavior.

The human brain contains 100 billion neurons, and each neuron can have up to 200,000 connections to other neurons. Recent advancements in neuroscience-ranging from molecular studies in animal models to behavioral studies in humans-have given us deeper insights into the development of this extraordinarily intricate system. Studies show a complex interaction between biological predispositions and environment; while the gross neuroanatomy and low-level functions develop early prior to receiving environmental inputs, functional selectivity is shaped through experience, governed by the maturation of local excitatory and inhibitory circuits and synaptic plasticity during sensitive periods early in development. Plasticity does not end with the closing of the early sensitive period - the environment continues to play an important role in learning throughout the lifespan. Recent work delineating the cascade of events that initiates, controls and ends sensitive periods, offers new hope of eventually being able to remediate various clinical conditions by selectively reopening plasticity.

A model of ganglion axon pathways accounts for percepts elicited by retinal implants.

Degenerative retinal diseases such as retinitis pigmentosa and macular degeneration cause irreversible vision loss in more than 10 million people worldwide. Retinal prostheses, now implanted in over 250 patients worldwide, electrically stimulate surviving cells in order to evoke neuronal responses that are interpreted by the brain as visual percepts ('phosphenes'). However, instead of seeing focal spots of light, current implant users perceive highly distorted phosphenes that vary in shape both across subjects and electrodes. We characterized these distortions by asking users of the Argus retinal prosthesis system (Second Sight Medical Products Inc.) to draw electrically elicited percepts on a touchscreen. Using ophthalmic fundus imaging and computational modeling, we show that elicited percepts can be accurately predicted by the topographic organization of optic nerve fiber bundles in each subject's retina, successfully replicating visual percepts ranging from 'blobs' to oriented 'streaks' and 'wedges' depending on the retinal location of the stimulating electrode. This provides the first evidence that activation of passing axon fibers accounts for the rich repertoire of phosphene shape commonly reported in psychophysical experiments, which can severely distort the quality of the generated visual experience. Overall our findings argue for more detailed modeling of biological detail across neural engineering applications.

Responses in area hMT+ reflect tuning for both auditory frequency and motion after blindness early in life.

Previous studies report that human middle temporal complex (hMT+) is sensitive to auditory motion in early-blind individuals. Here, we show that hMT+ also develops selectivity for auditory frequency after early blindness, and that this selectivity is maintained after sight recovery in adulthood. Frequency selectivity was assessed using both moving band-pass and stationary pure-tone stimuli. As expected, within primary auditory cortex, both moving and stationary stimuli successfully elicited frequency-selective responses, organized in a tonotopic map, for all subjects. In early-blind and sight-recovery subjects, we saw evidence for frequency selectivity within hMT+ for the auditory stimulus that contained motion. We did not find frequency-tuned responses within hMT+ when using the stationary stimulus in either early-blind or sight-recovery subjects. We saw no evidence for auditory frequency selectivity in hMT+ in sighted subjects using either stimulus. Thus, after early blindness, hMT+ can exhibit selectivity for auditory frequency. Remarkably, this auditory frequency tuning persists in two adult sight-recovery subjects, showing that, in these subjects, auditory frequency-tuned responses can coexist with visually driven responses in hMT+.

Early Blindness Shapes Cortical Representations of Auditory Frequency within Auditory Cortex.

Early loss of vision is classically linked to large-scale cross-modal plasticity within occipital cortex. Much less is known about the effects of early blindness on auditory cortex. Here, we examine the effects of early blindness on the cortical representation of auditory frequency within human primary and secondary auditory areas using fMRI. We observe that 4 individuals with early blindness (2 females), and a group of 5 individuals with anophthalmia (1 female), a condition in which both eyes fail to develop, have lower response amplitudes and narrower voxelwise tuning bandwidths compared with a group of typically sighted individuals. These results provide some of the first evidence in human participants for compensatory plasticity within nondeprived sensory areas as a result of sensory loss.SIGNIFICANCE STATEMENT Early blindness has been linked to enhanced perception of the auditory world, including auditory localization and pitch perception. Here we used fMRI to compare neural responses with auditory stimuli within auditory cortex across sighted, early blind, and anophthalmic individuals, in whom both eyes fail to develop. We find more refined frequency tuning in blind subjects, providing some of the first evidence in human subjects for compensation within nondeprived primary sensory areas as a result of blindness early in life.

The Effect of Onset Age of Visual Deprivation on Visual Cortex Surface Area Across-Species.

Blindness early in life induces permanent alterations in brain anatomy, including reduced surface area of primary visual cortex (V1). Bilateral enucleation early in development causes greater reductions in primary visual cortex surface area than at later times. However, the time at which cortical surface area expansion is no longer sensitive to enucleation is not clearly established, despite being an important milestone for cortical development. Using histological and MRI techniques, we investigated how reductions in the surface area of V1 depends on the timing of blindness onset in rats, ferrets and humans. To compare data across species, we translated ages of all species to a common neuro-developmental event-time (ET) scale. Consistently, blindness during early cortical expansion induced large (~40%) reductions in V1 surface area, in rats and ferrets, while blindness occurring later had diminishing effects. Longitudinal measurements on ferrets confirmed that early enucleation disrupted cortical expansion, rather than inducing enhanced pruning. We modeled the ET associated with the conclusion of the effect of blindness on surface area at maturity (ETc), relative to the normal conclusion of visual cortex surface area expansion, (ETdev). A final analysis combining our data with extant published data confirmed that ETc occurred well before ETdev.

Model-Based Recommendations for Optimal Surgical Placement of Epiretinal Implants.

A major limitation of current electronic retinal implants is that in addition to stimulating the intended retinal ganglion cells, they also stimulate passing axon fibers, producing perceptual 'streaks' that limit the quality of the generated visual experience. Recent evidence suggests a dependence between the shape of the elicited visual percept and the retinal location of the stimulating electrode. However, this knowledge has yet to be incorporated into the surgical placement of retinal implants. Here we systematically explored the space of possible implant configurations to make recommendations for optimal intraocular positioning of the electrode array. Using a psychophysically validated computational model, we demonstrate that better implant placement has the potential to reduce the spatial extent of axonal activation in existing implant users by up to ~55%. Importantly, the best implant location, as inferred from a population of simulated virtual patients, is both surgically feasible and is relatively stable across individuals. This study is a first step towards the use of computer simulations in patient-specific planning of retinal implant surgery.

Blindness and Human Brain Plasticity.

Early blindness causes fundamental alterations of neural function across more than 25% of cortex-changes that span the gamut from metabolism to behavior and collectively represent one of the most dramatic examples of plasticity in the human brain. The goal of this review is to describe how the remarkable behavioral and neuroanatomical compensations demonstrated by blind individuals provide insights into the extent, mechanisms, and limits of human brain plasticity.