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)
