Week in Review: Number 40

Brain Implant Furthers Progress in Artificial Vision
The Moran|Cortivis Prosthesis is a visual prosthesis that combines a small brain implant with a specialized eyeglass-mounted video camera, which captures images to send to the implant. The implant itself, called the Utah Electrode Array (UEA), is a 4x4 mm microelectrode array composed of 96 microneedles, each 1.5 mm in length, which penetrate the surface of visual cortex to both record and stimulate the electrical activity of neurons. Eyeglasses equipped with a miniature video camera and specialized software encode the visual information collected by the camera and send it to the electrodes to produce a simple form of vision through phosphenes, or flashes of light. Depending on the strength of the stimulation, the phosphenes could be brighter or more faded, a white color or a sepia tone. Depending on the spatial arrangement (e.g., the distance between stimulated electrodes), the phosphenes could be perceived as rounded or elongated. Simultaneously stimulating multiple electrodes produced easier perception. This proof-of-concept has been tested for the first time in the visual cortex of Berna Gómez, a 60-year-old volunteer in Elche, Spain, who at the time of the study had been completely blind for 16 years due to an incidence of toxic optic neuropathy. With the prosthesis, Gómez was able to identify the edges of simple high-contrast shapes and perceive simple letters (specifically I, L, C, V, and O) evoked by different patterns of stimulation (up to 16 electrodes). At the end of the 6-month trial, the device was surgically removed, and the researchers report no complications following its removal, nor observed any impairment to the function of neurons in close proximity to the electrodes or to the function of the underlying cortex. The researchers estimate that between 7 and 10 UEAs (roughly 700 electrodes) could provide enough information to give a blind person a level of useful mobility, though further studies are needed to determine how long the implants are effective and can safely remain in the brain. A clinical trial of the device involving up to four other participants is scheduled to continue into 2024. In the next set of experiments, the researchers will use a more sophisticated image encoder system capable of stimulating more electrodes simultaneously to elicit more complex visual images.

This project furthers what the researchers say is a "long-held dream of scientists," to impart a rudimentary form of sight to blind people by sending information directly to the brain's visual cortex. In doing so, they hope to confer a greater degree of mobility, independence, and safety to people who are blind. One of the senior investigators states, “[A]lthough these preliminary results are very encouraging, we should be aware that there are still a number of important unanswered questions and that many problems have to be solved before a cortical visual prosthesis can be considered a viable clinical therapy.” For her clinically precise feedback and importance to the research, the subject and former science teacher is listed as a co-author of the study.

Fluoxetine as a Potential Treatment for Atrophic AMD
Related to research by Jayakrishna Ambati, M.D., at University of Virginia, colleagues at the same institution are exploring drug repurposing in the treatment of eye diseases such as atrophic age-related macular degeneration (AMD), also known as geographic atrophy. In this case, the research team is examining the therapeutic potential of fluoxetine (Prozac), an FDA-approved medication for clinical depression. The investigators explain, “Traditional approaches to drug development can be expensive and time-consuming: On average, a new FDA-approved drug takes 10-12 years and costs $2.8 billion (present-day dollars) to develop. Our identification of the unrecognized therapeutic activity of an existing FDA-approved drug using big data mining, coupled with demonstrating its efficacy in a disease-relevant model, could greatly accelerate and reduce the cost of drug development.” In particular, they tested fluoxetine and eight other antidepressant drugs in mouse models of Alu RNA-induced AMD, and note that fluoxetine, but not the other antidepressants, was effective at slowing the progression of the disease. They report that fluoxetine acts as a direct inhibitor of the inflammasome (components NLRP and ASC from assembling) in silico, in vitro, and in vivo to prevent the cytokine release that ultimately leads to retinal pigmented epithelium (RPE) and retinal degeneration. Next, the researchers applied big data mining to two large health insurance databases, together encompassing more than 100 million Americans, to determine any associations. The analysis showed "a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine." Senior author of the study remarks, “[W]e may have only begun to scratch the surface of finding new uses for old drugs. It is tempting to think about all the untapped therapeutic potential of medicines sitting on pharmacy shelves...Ultimately, the best way to test whether fluoxetine benefits macular degeneration is to run a prospective clinical trial.”

Pupils Reveal Strong Engagement with Metaphor
Eyes are the windows to the soul, capturing and relaying information about our inner thoughts and emotions. This subtle expression of engagement can nonetheless be seen through tell-tale reactions of our pupils. As an offshoot of previous work wherein functional magnetic resonance imaging (fMRI) of the amydala, considered the emotional center of our brains, was found to respond more to metaphors than to literal language, a group of scientists sought to further explore our response to metaphors through pupillometry. The latter method also allows for "tighter time controls," as pupils respond in a fraction of a second. Then undergraduate student and first author of the study explains, “We saw over and over again that when our subjects reached the metaphorical part of the sentence, that split second was when the pupils dilated.” Furthermore, the pupils remained dilated for a couple of seconds, suggesting heightened engagement. In the present study, the researchers wanted to tease apart the relationship beyond merely the difference between a common metaphor ("grasping an idea") and a literal paraphrase ("understanding an idea"), so they added a third category representing a concrete description ("grasp a rail"), which uses the same key words in a purely literal way. They then created a database of 180 sentences/phrases, 60 in each category, and placed them through a rigorous norming process for familiarity, complexity, intensity, plausibility and positivity. The database is made publicly available for other researchers. Survey data from the norming process indicated that when metaphorical and literal sentences were compared directly, participants judged metaphorical sentences to be significantly more emotional and convey richer meaning, but were not considered more informative. They report that initial intentions to disentangle the emotional and the cognitive aspects of response to metaphor have proven difficult. Senior author of the study comments that, similar to amygdala response, “Pupils likewise dilate in response to both emotional engagement or cognitive engagement. In fact, we’re hard pressed to come up with a dependent measure that doesn’t react to both.” They nonetheless conclude that conventional metaphors are more engaging than literal paraphrases or concrete sentences, which we should not shy away from.

Beacon Molecule Nephronectin Guides Optic Nerve Cells to the Superior Colliculus
The superior colliculi (SC) are a pair of eminences at the "roof" of the midbrain where visual, auditory, and somatosensory information are integrated to initiate and coordinate movement. This brain region plays a central role in visual processing, receiving binocular input from 85-90% of retinal ganglion cells (as studied in the mouse brain), and projecting output signals to a variety of motor control centers in the cerebrum. The SC's processing capability stems from the precise organization of its cellular layers to refine signaling patterns. Neuroscientists are studying how axons from the eyes migrate during early brain development to form the optic nerve, including extending to regions such as the superior colliculus, in the hopes of identifying new ways to regenerate injured optic nerve fibers. Senior investigator of the study states, “If our goal is to one day regenerate damaged brain circuits to restore vision, then first we need to know how to get the cell’s axons to grow into a precise destination in the brain.” In particular, his team looked at how a specific subtype of optic nerve cells, ipsilateral retinal ganglion cells (ipsiRGCs), find their way to the superior colliculus during brain development. Using a viral tag, they identified two chaperon proteins that guide the circuit formation. One protein, a beacon molecule called nephronectin emitted by a type of excitatory neuron in the superior colliculus, attracts the optic nerve cells. Once the migrating cell has moved to the right location, nephronectin docks with a receptor protein on the migrating cell's membrane, telling the cell that it has reach its destination. Absence of nephronectin in mouse models results in the superior colliculus's visual layer not forming properly. The superior colliculus in the human brain occupies less relative volume, though it is also thought to play a role in "stabilizing our image of a moving world by controlling head, neck, and eye movements." Nonetheless, because the superior colliculus is present in all mammals, study of the signaling mechanisms that guide axons of different types of retinal neurons into segregated layers of brain regions provides a better understanding of the organizing principles of the visual system's segregated, parallel pathways.

Diverse Genome-Wide Study of IRD Lineages
Inherited retinal diseases (IRD) are a diverse group of pathologies resulting from genetic mutations. Examples include retinal dystrophies such as retinitis pigmentosa, Leber congenital amaurosis, choroideremia, and ocular albinism. It is estimated that at least 260 different gene variants contribute to IRD etiologies. Although rare, IRDs affect people of all ages, with few, if any, treatment options. An international team of scientists led by researchers at UCSD are studying how inherited retinal dystrophies affect different populations of people and, in doing so, have also identified new causative gene variants. The researchers conducted whole-genome sequences (WGS) of 409 individuals from 108 unrelated family lineages (pedigrees), each with a previously diagnosed IRD. Genetic analysis, at a minimum of 30X depth, included linkage analysis and exome sequencing, which had not been performed in earlier gene sequencing of these 108 pedigrees. The study participants were recruited from three ethnic and geographic backgrounds, two of which from understudied populations: Mexico, Pakistan, and European American living in the U.S. Genomic analysis from blood samples revealed causative variants in 61 of the 108 pedigrees (57%), with a total of 93 causative variants in those 61 families. Among the 93 causative variants, 39 were newly reported. The authors note that more than half of the new variants were not listed in the Genome Aggregation Database (gnomAD), an international compilation of genomic data. Clinical diagnosis was consistent with 57 of the pedigrees, and 4 of the pedigrees were reclassified by the researchers. The whole-genome sequencing also identified "unexpected" genotypes specific to the study population, including 4 pedigrees carrying more than one IRD gene among all affected family members, one pedigree wherein different family members carried causal variants in different IRD genes, and one de-novo mutation. Taken together, the study revealed a variety of IRD variants and "shed light on the genetic architecture of IRD in these diverse global populations."

In Other News
(1) Judge David Tatel's experience with blindness
(2) NEI Audacious Goals Initiative to regenerate neurons in the visual system
(3) UCLA team awarded $1 million grant to treat rare melanomas (Related)