Aims of the lab
We study vision in the primate brain. We focus on the cortex, specifically the area that allows object recognition: inferotemporal cortex or IT. IT contains neurons that give strong responses (a high number of action potentials) to images of particular object categories like faces, body parts or places. Many of these category-preferring neurons cluster into large groups called "domains." One of our goals is to define the function and development of IT neurons and these category-preferring domains. Because IT neurons exist in both humans and non-human primates, by studying macaque monkeys we can discover general principles of high-level vision that we share with other primates. One key question is whether these cortical domains are innate (i.e. largely encoded by a genetic program) or learned (i.e. largely created by common early experience).
How do we go about it?
We analyze IT neurons using functional imaging (fMRI), electrophysiology (single- and multi-electrode setups) and behavioral measures (looking behavior). To measure the relative contributions of genetic programs vs. intensive experience, we raise juvenile macaques under different conditions: for example, some are learn letters, numbers and other sets of human-made symbols in order to gain juice rewards; others are never shown certain visual categories, like faces, until they pass critical developmental windows. These early exposure manipulations dramatically change the response properties of IT neurons.
What insights have we gained?
We found that intensive early experience learning human symbols in young macaques can cause the development in monkeys of novel, entirely unnatural, domains, selectively responsive to human symbols. Conversely, monkeys raised without seeing faces do not develop face domains, which are present in normally raised humans and macaques. This double dissociation means that early experience is critical for the development of specialized domains. So if something as ubiquitous as face domains is not innate, what is the proto-organization that causes these domains to arise in stereotyped locations across monkeys and humans? We think it is maps: maps of the body, of the visual world, and of the auditory world, because we found that at birth, the cortex is already extensively covered by maps.
Summary of our research over 50 years:
I have been a neuroscientist for nearly 50 years. I have dedicated my life’s work to unraveling the mysteries of our brain, the ultimate frontier in science and medicine. My research has recently been attacked by claims that miscast my work, twist facts, and spread inaccurate and false information wrapped in emotionally charged, inflammatory language. As a consequence, I have been inundated with hateful, obscene, violent threats, and I am fearful for my safety and for the safety of my family. I therefore want to set the record straight by explaining what I do and why.
I have been studying the primate visual system for 40 years, but have been studying development in infant and young monkeys only for the last 10 years, and have NOT repeatedly performed eye closure procedures, as has been incorrectly suggested. For the first 30 years of my career I studied only adult macaques. Many vision labs use macaques because their visual systems are remarkably similar to humans, much more so than for any other research animal. With David Hubel I studied the functional organization of the early stages of the cortical visual pathway, making fundamental discoveries about how the first stage visual cortex (V1) is organized, that color selective regions are localized and show distinct patterns of connectivity, and that both V1 and V2 (second stage visual cortex) are mosaics of form, motion, and color regions that are interconnected according to this functional organization. Without these findings, we would have no idea how we are able to perceive and ultimately distinguish the basic building blocks of the visual world. it would be difficult to find any modern psychology or neurobiology textbook that does not describe our work.
About 20 years ago my lab started using awake animals for studying the function of individual neurons in the visual pathway. We shifted because techniques had been developed, largely at NIH, for recording using electrode arrays from alert animals while they fixated on a screen. These techniques are standard in pretty much all monkey vision labs. Indeed these arrays, and electrode arrays used in human epilepsy patients and for deep brain stimulation in human patients were all developed in monkeys. You may have seen or heard about these electrode arrays that are similar to those used in human brain-machine interfaces, in humans who are paralyzed or locked-in.
Usually the day after the procedure, the monkey is already turning flips and devouring fruit. The animals are trained, using copious rewards to look at a screen that presents visual stimuli. Once trained, our animals jump into the recording chairs with the prospect of snacking while sitting quietly looking at the screen while we record neurons
After the advent of the non-invasive technique of MRI, we started using it to get a broader picture of the functional organization of the primate visual system. Our studies complement similar studies in humans, because we could also use MRI to target our neuronal recordings to specific regions activated by particular kinds of visual stimuli. Again, convincing a monkey to sit quietly in an MRI scanner requires a lot of training with copious positive reinforcement. Our work showing convergence of single neuron selectivity with functional MRI activations has been key in validating the technique of functional MRI in humans. Combining fMRI with single neuronal recording has allowed us to explore information processing at higher levels in the visual system, in particular in regions of the temporal lobe involved in complex object recognition, such as faces, bodies and scenes. Our work has been pioneering in understanding high-level visual information processing, and is widely cited in human and computational research, and it fundamental and important enough that this work is also already widely cited in psychology and neurobiology textbooks.
I started looking at the development of higher-level visual areas about 10 years ago because there was the wide-spread belief in this field that domains specialized for processing faces, bodies, or scenes must be innately pre-determined to encode these particular object categories. I was surprised by this idea, because it had been well established that early visual areas, and early sensory areas in general, are wired up according to simple genetic rules that interact with spontaneous neuronal activity prenatally and with early experience postnatally to yield the adult functional organization. It seemed odd to me that early stages of a hierarchy should wire up by rules, but higher areas, that get all their input from early areas, should instead have some kind of pre-programmed genetic template. So we did longitudinal functional MRI on several infant monkeys, reared by their mothers, through their first year. We discovered that specialized domains, including face domains, are not present right after birth, but appear only at a few months of age. This meant either than the domains are innate and just need to mature, or they require experience to develop. The only thing that was present at birth was maps of the retina, in other words, maps of the visual world.
In order to address this major question, whether specialized visual domains are innately specified to process things like faces and social information, or whether the brain wires itself up according to early experience, including early social experience, we planned to raise infants without them seeing faces for the first year. To ensure that the animals would feel safe and with their welfare in mind, we decided to adopt an approach that has been used in primate centers for many years. Decades of studies had shown that infant monkeys require soft touch and soft materials to thrive. Gertrude van Wagenen had observed that infant macaques, separated from their mothers and fed from tiny nursing bottles, would not feed properly unless they could cling to a soft towel. In order to reduce the disease prevalence in his monkey colony, Harry Harlow adopted the towel technique for raising infant macaques and found that they developed strong attachments to the towels and were very distressed when the cloths were removed for cleaning. These laboratory-reared monkeys were larger and healthier and had a higher survival rate than infants left to the care of their monkey mothers, as long as they had a soft cloth to cuddle; without the cloth, survival was lower. The parallels between the abnormal behaviors of macaque infants reared without any cloths or soft surrogates and the psychological problems often found in children who as infants had been reared in sterile cubicles were instrumental in changing child-rearing practices and hospital visiting rules. Beyond its social importance, Harlow’s work showed that infant monkey attachment is based on surprisingly limited sensory features, i.e. primarily tactile, and may be established within only a limited time during development, as in imprinting. Ironically, Harlow was subsequently vilified by animal rights groups for his studies, even though his own work was instrumental in showing that isolating rearing conditions (common at the time in orphanages and institutions) were psychologically harmful.
Thus we set up to use Harlow’s soft surrogate approach to ensure that they felt comfortable and developed into healthy adults. The New England primate center contacted us that they had an infant monkey who had been rejected by its mother. We reared this animal while we wore masks, and separated him visually from the other monkeys in the room with a curtain. We gave him soft toys and cloths to cuddle, light-up musical toys to play with, and we handled him extensively; at the end of the deprivation, we socially housed him with peers. When we scanned him by MRI we found that he did not develop the typical face domains, but the other domains (body parts, scenes) were normal. He did develop particularly strong hand domains, which suggests that the brain indeed wires itself up according to the environment it experiences. This is an important result because it indicates that early experience is critical in wiring up the brain, even for higher functions that might seem innate, like social recognition. We subsequently non-invasively face deprived 4 more animals during their early development and strongly confirmed this initial result. We continue to study these animals, who are now healthy, behaviorally normal adults, with both fMRI and neuronal recordings. The presence of maps at birth, and the profound effects of experience on complex object recognition, suggests that maps provide an initial scaffolding on which experience sculpts the ability to recognize and discriminate things experienced in the environment.
The reason I had expected to find dramatic effects of early experience on higher-brain development was because of the pioneering experiments of David Hubel and Torsten Wiesel on lower-level visual areas when they were at Harvard. In conjunction with ophthalmological surgeons, they developed techniques for quickly healing, reversible, translucent occlusion of vision, as a model for congenital or acquired cataracts, a common malady in humans. At the time, children born with cataracts or misaligned eyes (crossed or divergent gaze) were usually surgically treated only after they were 5-10 years old, because surgery on infants was deemed difficult and risky. These children usually developed amblyopia, or ‘lazy eye’--even though nothing seemed to be wrong with the optics of their eyes, the ‘lazy’ eye could not see properly or at all. Hubel and Wiesel found that if one eye had been closed (the ‘deprived’ eye) early in development, the connections of that eye to the brain withered away, irreversibly. There was a critical time during development for the formation of these connections, so if the eye closure was done in older animals, or adults, there were no consequences. Indeed, if a baby has a cataract that is untreated for the first few months of life, the child becomes permanently blind in that eye, but an adult can have a cataract for 10 years, and as soon as it is removed, the person can see fine. Thus, ophthalmologists altered their approach to treating congenital cataracts and eye misalignment: now they fix them in newborns, not waiting until the surgery is easier, and one of the most common causes of childhood blindness is now completely preventable. Many opthalmological research laboratories still use reversible eye closure in their studies.
Hubel and Wiesel were surprised to find that amblyopia did not occur in binocular eye-closed animals. The connections of both eyes to visual cortex remained intact, indicating that the loss of connections of the deprived eye in monocular lid closures occurred because of some kind of competition between the two eyes. This is why children who are developing a lazy eye are now successfully treated with eye patching. But binocularly deprived animals, after the lids were re-opened, did not behave as if they could see normally, even though both eyes were optically normal, and the connections of both eyes to early visual cortex were intact. This is also true of humans who have had binocular congenital cataracts that are removed well after infancy. Indeed many of these people find the sudden onset of vision to be disruptive and disturbing. Because we had found that deprivation of a single category of visual objects, faces, had a profound effect on the functional organization of higher level visual areas, we suspected that the loss of visual abilities after binocular deprivation might also be due to a similar kind of critical period for wiring up these higher level visual areas. Most of the previous studies on binocular deprivation were done in the 1960s and 1970s, prior to the invention of MRI, so the only available tools for studying the effects were anatomical tracing and neuronal physiology. We decided to revisit this question in 2016, to use MRI to explore brain-wide effects of binocular deprivation, and to link our findings of experience-dependent effects on high-level vision with the observed deficits in visual behavior after binocular deprivation. We used the same reversible eye closure techniques as Hubel and Wiesel on two infant monkeys. Under supervision and scrutiny of federal and institutional oversight, the lids were fused under anesthesia, and powerful analgesics and local anesthetics were used to prevent pain post procedure. The lids were re-opened after a year. Like humans with early visual deprivation, these two animals could see, if given a touch-screen test of visual discrimination, yet they behaved as if they preferred to use sound and touch rather than vision for daily interacting with the environment. Using functional MRI we found that their visual system exhibited only a map-based organization, indicating that maps of the sensory periphery are indeed the fundamental, innate, organizing principle of the brain. This is a major insight. It is new enough that it has not yet been widely accepted, but I suspect it will also end up in psychology and neurobiology textbooks. The insight that our brains get wired up, starting with a map-based proto-organization, sculpted and refined by what we experience, and that there are critical periods for these experiences, should be important for how we deal with early deprivation in children, with their education, and potential interventions for children with autism spectrum disorder who might choose not to look at other people or their faces.
We have NOT performed eye closures since the two isolated cases in 2016, but we have studied and reported on these two cases in multiple papers because they yielded many insights. Indeed, it is a guiding principle in laboratory animal research that investigators REUSE the data or the experimental subject to minimize the numbers of animals needed in research, which is why we repeatedly report on the same subjects. Our methods to further study the importance of early visual experiences rely currently on entirely non-invasive techniques such as having our caregivers wearing face masks and having the animals wear removable goggles. Notably, eye closure was and is a routine tool across institutions that conduct this vision research, particularly ophthalmological institutes, and it helped lead to the non-invasive techniques that we use today to study vision.
Another line of research in my lab involves adult macaques for testing and developing an ultrasound technique for use in human patients for non-invasive surgical ablation of small regions of the brain and to permeabilize the blood-brain barrier so that therapeutic agents that usually cannot pass into the brain can access targets such as cancer. This non-invasive technique works at many centimeters distance and needs to pass through the intact skull without heating the skull, so testing it in a large-brain, thick-skulled animal has been essential for its development. Monkeys are the only appropriate model for addressing these problems. They are anesthetized throughout the procedure and wake up without any harm. Because of our research, this technique is now in use clinically to treat tremor by lesioning (non-invasively) a small target in the thalamus. Last year there was an article in the Boston Globe about this amazing new way of doing neurosurgery, but the article never mentioned the years, decades even, of animal research that led to this approach. It was as if the neurosurgeon had just thought it up out of the blue and started using it on human patients, which would be illegal. Using focused ultrasound to permeabilize the blood-brain barrier transiently to allow chemotherapeutics to penetrate into the brain is now in clinical trials in humans to treat brain cancers (glioblastoma and breast cancer metastases). It also shows enough promise to be in clinical trials to treat Alzheimer’s disease. None of this would have been possible without our monkey studies. We are currently attempting to enlarge the potential target areas that this technique can ablate, so that it can be used to non-invasively target epilepsy foci in patients with intractable epilepsy.
Thus, my lab’s work over these many years has contributed directly to multiple human health benefits and indirectly to human health by increasing our understanding of how the brain processes information. This is all peer-reviewed, federally funded research that for three decades has garnered sustained support from the National Institutes of Health, which underscores the value and promise of this work for our understanding of the human brain in health and disease. Our research has direct and indirect implications for human health, whether it leads to therapies for vision disorders, for treatment of neurologic diseases and cancer, or helps alleviate the sense of loss experienced by women who suffer miscarriage.
All of these research procedures are done in a manner that aims to ensure comfort, minimize distress, and reduce or completely eliminate pain. All of my research is subject to numerous federal, state, and institutional policies, regulations, and oversight groups charged with ensuring the proper care and treatment of research animals and ascertaining that the use of the animals is justified and cannot be achieved through alternative means.
Do I wish we lived in a world where generating this important knowledge were possible without the use of lab animals? Yes, but alas, we are not there yet. We continue to work toward this future through our ongoing efforts to refine, reduce, and replace animal models — the three critical Rs of animal research. To make any true insight in an experiment that involves animals requires that an animal be pain-free and not in distress. And so beyond my natural inclinations to care for these aninals that I truly adore, it would be counterproductive to me if they felt pain or were stressed.
If you or a loved one has ever had a vaccine, taken a pill for high blood pressure, been treated for diabetes, cancer, infection, or heart disease, you have benefited from animal research. Indeed the supply of research macaques is currently negligible because they are needed for developing COVID vaccines. Whether you support animal research or not, you have benefited from therapies derived from work done in animals. And so have your pets. Veterinary medicine too relies on studies in animals. Pets who receive antibiotics, pain killers, cancer treatments, vaccines or have surgery are the beneficiaries of research done in animals. Modern medicine would not be where it is without the proper use of animals in research.