Interview: From Neurons to Artificial Visual Systems, with a Dash of Inspired Science Outreach
The brain's visual system is central to our perception and
interpretation of the world we see. Yet, how it gathers and integrates
visual information into a cohesive whole still remains largely a
mystery. Harvard Medicine News interviewed Carlos Ponce, M.D.,
Ph.D., assistant professor of neurobiology at HMS, about his interest in
the visual system and how he uses this information to build better
computational models. Ponce explains that his research is focused on the
brain's ventral stream, or parts of the visual system that analyze and
categorize shapes, whether they be faces, objects, scenes, etc. He uses
macaque monkeys as animal models, since they are an experimental model
with brains most similar to humans. Using images as stimuli and electrophysiology recordings, Ponce studies how the responses of neurons approximate our visual perception. As he explains, "The pictures represent a hypothesis, and the neural response is an evaluation of that." However,
images that are selected by human minds cannot fully capture the range
of variability and nuance in visual stimuli that the brain encounters in
the world; the images we select as input are limited by our
imaginations and biases. This is where advances in computational
modeling come in handy. The models not only learn from the input of
millions of pictures, but can also generate entirely new images.
In an earlier paper from 2019, Ponce presents how applying this "cooperation
between neurons and machine intelligence" to neurons in part of the
macaque brain that responds to faces produced, from initial noise, a
computational model that contained features of a face. "Our discovery was that
you can couple computational models to neurons in the macaque brain that
are visually responsive, and have the neurons guide the model to create
pictures that activate them best," the assistant professor explains, "However, we were puzzled
by some of the pictures that were created. Some made a lot of sense,
like parts of faces or bodies, but others didn’t look like any one
object. Instead, they were patterns that cut across semantic
categories...We realized that the neurons in the macaque
brain are learning specific motifs that don’t necessarily fit our
language. The neurons have a language of their own that is about
describing the statistics of the natural world." In a sequel of the research,
published this year, Ponce applied computational models to both the
posterior (upstream) parts of the macaque brain that process simple
objects and the more anterior (downstream) parts that process complex
shapes. In doing so, he was able to quantify the information coming from
the neurons as having an intermediate level of complexity, somewhere
between the simplicity of a line and the complexity of a photograph. In
other experiments, he found that macaques prefer to look at parts of
pictures that were similar to the features encoded by their neurons. "That gives us a clue
that during development, the brain extracts important patterns from the
world and stores those patterns in neurons," he says.
When asked
what he wants to do next, Ponce answers that he is intrigued by many
questions, such as extending his individual-neuron recordings to
characterize full populations of neurons, or reconstructing images of
what the brain sees based on the pattern of activity of neurons. He is
also interested in how clusters of neurons that share a function develop
where they do in the brain, and hopes that his approach will help to
map that topography. Once we are able to characterize the patterns and
networks of the brain, he states, we can then develop computational
models to improve artificial visual systems. Ponce recalls his own
medical training to connect his research to clinical applications, for
example, to save lives through improved screening that "doesn't miss
anything." Finally, he references his own childhood and inspiration from
scientists to motivate his work in science outreach to youth, to
inspire young students every year toward careers in science.
Large Association Study Finds Cataract Surgery Linked with Lower Risk of Dementia
Cataracts are an opacification or clouding of the eye's crystalline
lens, most commonly as a result of aging and decades of filtering
ultraviolet radiation. Although connections between poor vision and
cognitive decline have been explored in many studies, ophthalmologists
at University of Washington were interested in the effect of surgical
intervention in the form of cataract extraction on dementia risk.
Specifically, they looked at data from the Adult Changes in Thought
(ACT) study, an ongoing longitudinal cohort study started in 1994 by
Kaiser Permanente Washington and designed to study the development of
dementia. Electronic medical records data was collected from 3,038
participants 65 years of age or older who had either cataract or
glaucoma diagnosis before enrollment or during follow-up care. Among
those included in the analysis, there were 853 cases of dementia (all
cause) and 709 cases of Alzheimer's disease. Approximately half of the
participants (1,382 individuals) had cataract surgery. Based on 23,554
person-years of follow-up, and after controlling for a variety of
potentially confounding factors, participants who underwent cataract
extraction in either eye had a 29% reduced risk of developing dementia
compared to participants without surgery; moreover, the reduced
risk applied for at least 10 years after surgery. Similar findings
were seen in
dementia specific to Alzheimer's disease. Importantly, no association
was observed between glaucoma surgery and dementia risk. The authors
point out that evaluation of glaucoma surgery, which, unlike cataract
surgery, does not restore vision, was to address potential healthy
patient bias. Although the mechanisms by which cataract extraction is
associated with decreased dementia risk were not explored in this
observational study, the researchers hypothesize that patients were
getting higher quality sensory input after cataract extraction,
highlighting neurological, circadian, and social improvements. Lead
researcher of the study states, "This kind of evidence is as good
as it gets in epidemiology. This is really exciting because no other
medical intervention has
shown such a strong association with lessening dementia risk in older
individuals." Given the risk of cognitive decline in older age,
interventions such as cataract surgery have major clinical relevance not
only in enhancing quality of vision but also in improvement of mental
health.
Large Single-Cell Gene Atlas of Human Eye Disorders
An international team led by researchers from several universities in
Singapore, with colleagues in the U.S. and other countries, have
produced the first single-cell atlas of human and porcine eyes. They
report applying single-cell RNA sequencing to catalogue more than 50,000
cells in human and porcine eyes, as well as developing a cell atlas
that distinguishes these cells by the activity of their genes. The use
of porcine eyes (and other animal species, such as zebrafish) in this
study allowed for comparison of interspecies differences as well as
conserved regulating factors in the eye, which the authors state is
lacking in integrative research of the eye. The study produced a wide
range of findings, some of which are simple, such as evidence of adult
stems cells in iris tissue. Others have clinical implications regarding
ocular routes of infection and disease transmission. For example, the
team found that ACE2 and TMPRSS2, the primary cell surface proteins
responsible for entry of SARS-CoV-2 into human, are expressed in the
eye's conjunctival cells. Some of the researchers also worked on lab
techniques in regenerative medicine, such as using embryonic stem cells
to generate retinal ganglion cell (RGC) progenitors in culture; they
discovered that a switch called KLF7 could accelerate RGC generation,
with results that could inform potential therapies for eye diseases like
glaucoma that results from progressive damage to the RGCs that make up
the optic nerve. They are working to further validate the KLF7-derived
RGCs for preclinical studies, with broad aims of understanding key
molecular switches to better engineer lab-grown cells as a means of
therapy.
i27-Breg: Discovery of a New Anti-inflammatory B Cell
Scientists at the National Eye Institute have discovered a new type of B cell that tempers the immune system, thereby reducing chronic
inflammation in autoimmune diseases. Termed regulatory B cells (Bregs), these cells represent a small population of B cells that are derived from plasma
blasts or plasma cells; although similar to other Bregs, the newly
discovered cells express a distinct genetic profile of innate B-1a cell lineage. Bregs patrol the blood and function in
modulating the immune system through expression of anti-inflammatory
cytokines (e.g., IL-10 and IL-35) that counterbalance the physiological
effects of pro-inflammatory cytokines (e.g., IFN-gamma
and IL-17). A balance between pro- and anti-inflammatory cytokines is
essential to a healthy immune system, one that can mount a robust
response against pathogens while not reacting excessively to self-cells,
as in autoimmune disease. In lab tests in mice, purified infusion of i27-Breg suppressed autoimmune uveitis (and encephalomyelitis) through "up-regulation of inhibitory receptors (Lag3, PD-1),
suppression of T-cell (Th17/Th1) responses, and propagation of
inhibitory signals that converted conventional B cells to regulatory
lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, and spinal
cord." Unlike i35-Breg, a similar Breg also discovered by these researchers, i27-Breg
demonstrated a quicker response to suppress
autoimmune uveitis and MS-like disease. i27-Breg also has an advantage
of being able to proliferate to sustain IL-27 secretion in vivo,
suggesting that
it may have greater therapeutic potential over biologics (IL-10 or IL-35), which are rapidly cleared by the body. Notably, IL-27
receptor is necessary for any therapeutic effect, as i27-Breg infusions into mice lacking the IL-27 receptor failed to attenuate disease symptoms. Finally, because i27-Breg is neither antigen-specific nor disease-specific, the researchers point out that it could be effective immunotherapy for a wide range of autoimmune diseases. They are currently working on the
use of exosomes (extracellular vesicles) as a vector to deliver
lab-grown IL-27 into the body, which they acknowledge is less
technically challenging than producing Breg cells in the lab.
Suprachoroidal Bionic Eye Implant Trialled in Sheep
Researchers in Australia are investigating a new type of bionic eye
implant for the treatment of degenerative retinal diseases. The result
of "decades of experience and technological breakthroughs in the field
of implantable electronics," the Phoenix99 Bionic Eye is a
98-channel visual prosthesis comprising two components: a stimulator
implanted in the eye in the suprachoroidal space and a communication
module positioned under the skin behind the ear. This system is attached
to an external glasses-mounted miniature camera that captures images to send instructions wirelessly to the
communication module behind the ear, which decodes and transfers the
signals to the stimulation module behind the retina. The research team
has tested implantation of 9 devices in an ovine (sheep)
model, reporting positive results up to 3 months in this study. One of
the engineers on the project remarks, "Importantly, we found the device
has a very low impact on the neurons
required to ‘trick’ the brain. There were no unexpected reactions from
the tissue around the device and we expect it could safely remain in
place for many years." Implant stability and safety profile were assessed with indirect ophthalmoscopy, infrared imaging, and optical coherence tomography. Biocompatibility
was evaluated with histological analysis with an emphasis on the health
of the retinal cells; only mild fibrosis and inflammation of the
surrounding tissue were observed. Although assessments of
visual function were not conducted, the researchers state being
confident with the results in terms of safety to submit ethics approval
for human
clinical trials. They
continue to make refinements in more advanced stimulation and surgical
techniques in the meantime.
In Other News
(1) New contrast sensitivity test created by NECO faculty
(2) The human visual system's awesome complexity: Are we ready for self-driving cars?
(3) Dark adaptometry device for screening of Plaquenil retinal toxicity
