Researcher: Robert Desimone

Neuroscientists create a comprehensive map of the cerebral cortex

Anne Trafton |

By analyzing brain scans taken as people watched movie clips, MIT researchers have created the most comprehensive map yet of the functions of the brain’s cerebral cortex.

Using functional magnetic resonance imaging (fMRI) data, the research team identified 24 networks with different functions, which include processing language, social interactions, visual features, and other types of sensory input.

Many of these networks have been seen before but haven’t been precisely characterized using naturalistic conditions. While the new study mapped networks in subjects watching engaging movies, previous works have used a small number of specific tasks or examined correlations across the brain in subjects who were simply resting.

“There’s an emerging approach in neuroscience to look at brain networks under more naturalistic conditions. This is a new approach that reveals something different from conventional approaches in neuroimaging,” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research. “It’s not going to give us all the answers, but it generates a lot of interesting ideas based on what we see going on in the movies that’s related to these network maps that emerge.”

The researchers hope that their new map will serve as a starting point for further study of what each of these networks is doing in the brain.

Desimone and John Duncan, a program leader in the MRC Cognition and Brain Sciences Unit at Cambridge University, are the senior authors of the study, which appears today in Neuron. Reza Rajimehr, a research scientist in the McGovern Institute and a former graduate student at Cambridge University, is the lead author of the paper.

Precise mapping

The cerebral cortex of the brain contains regions devoted to processing different types of sensory information, including visual and auditory input. Over the past few decades, scientists have identified many networks that are involved in this kind of processing, often using fMRI to measure brain activity as subjects perform a single task such as looking at faces.

In other studies, researchers have scanned people’s brains as they do nothing, or let their minds wander. From those studies, researchers have identified networks such as the default mode network, a network of areas that is active during internally focused activities such as daydreaming.

“Up to now, most studies of networks were based on doing functional MRI in the resting-state condition. Based on those studies, we know some main networks in the cortex. Each of them is responsible for a specific cognitive function, and they have been highly influential in the neuroimaging field,” Rajimehr says.

However, during the resting state, many parts of the cortex may not be active at all. To gain a more comprehensive picture of what all these regions are doing, the MIT team analyzed data recorded while subjects performed a more natural task: watching a movie.

“By using a rich stimulus like a movie, we can drive many regions of the cortex very efficiently. For example, sensory regions will be active to process different features of the movie, and high-level areas will be active to extract semantic information and contextual information,” Rajimehr says. “By activating the brain in this way, now we can distinguish different areas or different networks based on their activation patterns.”

The data for this study was generated as part of the Human Connectome Project. Using a 7-Tesla MRI scanner, which offers higher resolution than a typical MRI scanner, brain activity was imaged in 176 people as they watched one hour of movie clips showing a variety of scenes.

The MIT team used a machine-learning algorithm to analyze the activity patterns of each brain region, allowing them to identify 24 networks with different activity patterns and functions.

Some of these networks are located in sensory areas such as the visual cortex or auditory cortex, as expected for regions with specific sensory functions. Other areas respond to features such as actions, language, or social interactions. Many of these networks have been seen before, but this technique offers more precise definition of where the networks are located, the researchers say.

“Different regions are competing with each other for processing specific features, so when you map each function in isolation, you may get a slightly larger network because it is not getting constrained by other processes,” Rajimehr says. “But here, because all the areas are considered together, we are able to define more precise boundaries between different networks.”

The researchers also identified networks that hadn’t been seen before, including one in the prefrontal cortex, which appears to be highly responsive to visual scenes. This network was most active in response to pictures of scenes within the movie frames.

Executive control networks

Three of the networks found in this study are involved in “executive control,” and were most active during transitions between different clips. The researchers also observed that these control networks appear to have a “push-pull” relationship with networks that process specific features such as faces or actions. When networks specific to a particular feature were very active, the executive control networks were mostly quiet, and vice versa.

“Whenever the activations in domain-specific areas are high, it looks like there is no need for the engagement of these high-level networks,” Rajimehr says. “But in situations where perhaps there is some ambiguity and complexity in the stimulus, and there is a need for the involvement of the executive control networks, then we see that these networks become highly active.”

Using a movie-watching paradigm, the researchers are now studying some of the networks they identified in more detail, to identify subregions involved in particular tasks. For example, within the social processing network, they have found regions that are specific to processing social information about faces and bodies. In a new network that analyzes visual scenes, they have identified regions involved in processing memory of places.

“This kind of experiment is really about generating hypotheses for how the cerebral cortex is functionally organized. Networks that emerge during movie watching now need to be followed up with more specific experiments to test the hypotheses. It’s giving us a new view into the operation of the entire cortex during a more naturalistic task than just sitting at rest,” Desimone says.

The research was funded by the McGovern Institute, the Cognitive Science and Technology Council of Iran, the MRC Cognition and Brain Sciences Unit at the University of Cambridge, and a Cambridge Trust scholarship.

Simons Center’s collaborative approach propels autism research, at MIT and beyond

by David Orenstein |

The secret to the success of MIT’s Simons Center for the Social Brain is in the name. With a founding philosophy of “collaboration and community” that has supported scores of scientists across more than a dozen Boston-area research institutions, the SCSB advances research by being inherently social.

SCSB’s mission is “to understand the neural mechanisms underlying social cognition and behavior and to translate this knowledge into better diagnosis and treatment of autism spectrum disorders.” When Director Mriganka Sur founded the center in 2012 in partnership with the Simons Foundation Autism Research Initiative (SFARI) of Jim and Marilyn Simons, he envisioned a different way to achieve urgently needed research progress than the traditional approach of funding isolated projects in individual labs. Sur wanted SCSB’s contribution to go beyond papers, though it has generated about 350 and counting. He sought the creation of a sustained, engaged autism research community at MIT and beyond.

“When you have a really big problem that spans so many issues — a clinical presentation, a gene, and everything in between — you have to grapple with multiple scales of inquiry,” says Sur, the Newton Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences (BCS) and The Picower Institute for Learning and Memory. “This cannot be solved by one person or one lab. We need to span multiple labs and multiple ways of thinking. That was our vision.”

In parallel with a rich calendar of public colloquia, lunches, and special events, SCSB catalyzes multiperspective, multiscale research collaborations in two programmatic ways. Targeted projects fund multidisciplinary teams of scientists with complementary expertise to collectively tackle a pressing scientific question. Meanwhile, the center supports postdoctoral Simons Fellows with not one, but two mentors, ensuring a further cross-pollination of ideas and methods.

Complementary collaboration

In 11 years, SCSB has funded nine targeted projects. Each one, by design, involves a deep and multifaceted exploration of a major question with both fundamental importance and clinical relevance. The first project, back in 2013, for example, marshaled three labs spanning BCS, the Department of Biology, and The Whitehead Institute for Biomedical Research to advance understanding of how mutation of the Shank3 gene leads to the pathophysiology of Phelan-McDermid Syndrome by working across scales ranging from individual neural connections to whole neurons to circuits and behavior.

Other past projects have applied similarly integrated, multiscale approaches to topics ranging from how 16p11.2 gene deletion alters the development of brain circuits and cognition to the critical role of the thalamic reticular nucleus in information flow during sleep and wakefulness. Two others produced deep examinations of cognitive functions: how we go from hearing a string of words to understanding a sentence’s intended meaning, and the neural and behavioral correlates of deficits in making predictions about social and sensory stimuli. Yet another project laid the groundwork for developing a new animal model for autism research.

SFARI is especially excited by SCSB’s team science approach, says Kelsey Martin, executive vice president of autism and neuroscience at the Simons Foundation. “I’m delighted by the collaborative spirit of the SCSB,” Martin says. “It’s wonderful to see and learn about the multidisciplinary team-centered collaborations sponsored by the center.”

New projects

In the last year, SCSB has launched three new targeted projects. One team is investigating why many people with autism experience sensory overload and is testing potential interventions to help. The scientists hypothesize that patients experience a deficit in filtering out the mundane stimuli that neurotypical people predict are safe to ignore. Studies suggest the predictive filter relies on relatively low-frequency “alpha/beta” brain rhythms from deep layers of the cortex moderating the higher frequency “gamma” rhythms in superficial layers that process sensory information.

Together, the labs of Charles Nelson, professor of pediatrics at Boston Children’s Hospital (BCH), and BCS faculty members Bob Desimone, the Doris and Don Berkey Professor of Neuroscience at MIT and director of the McGovern Institute, and Earl K. Miller, the Picower Professor, are testing the hypothesis in two different animal models at MIT and in human volunteers at BCH. In the animals they’ll also try out a new real-time feedback system invented in Miller’s lab that can potentially correct the balance of these rhythms in the brain. And in an animal model engineered with a Shank3 mutation, Desimone’s lab will test a gene therapy, too.

“None of us could do all aspects of this project on our own,” says Miller, an investigator in the Picower Institute. “It could only come about because the three of us are working together, using different approaches.”

Right from the start, Desimone says, close collaboration with Nelson’s group at BCH has been essential. To ensure his and Miller’s measurements in the animals and Nelson’s measurements in the humans are as comparable as possible, they have tightly coordinated their research protocols.

“If we hadn’t had this joint grant we would have chosen a completely different, random set of parameters than Chuck, and the results therefore wouldn’t have been comparable. It would be hard to relate them,” says Desimone, who also directs MIT’s McGovern Institute for Brain Research. “This is a project that could not be accomplished by one lab operating in isolation.”

Another targeted project brings together a coalition of seven labs — six based in BCS (professors Evelina Fedorenko, Edward Gibson, Nancy Kanwisher, Roger Levy, Rebecca Saxe, and Joshua Tenenbaum) and one at Dartmouth College (Caroline Robertson) — for a synergistic study of the cognitive, neural, and computational underpinnings of conversational exchanges. The study will integrate the linguistic and non-linguistic aspects of conversational ability in neurotypical adults and children and those with autism.

Fedorenko said the project builds on advances and collaborations from the earlier language Targeted Project she led with Kanwisher.

“Many directions that we started to pursue continue to be active directions in our labs. But most importantly, it was really fun and allowed the PIs [principal investigators] to interact much more than we normally would and to explore exciting interdisciplinary questions,” Fedorenko says. “When Mriganka approached me a few years after the project’s completion asking about a possible new targeted project, I jumped at the opportunity.”

Gibson and Robertson are studying how people align their dialogue, not only in the content and form of their utterances, but using eye contact. Fedorenko and Kanwisher will employ fMRI to discover key components of a conversation network in the cortex. Saxe will examine the development of conversational ability in toddlers using novel MRI techniques. Levy and Tenenbaum will complement these efforts to improve computational models of language processing and conversation.

The newest Targeted Project posits that the immune system can be harnessed to help treat behavioral symptoms of autism. Four labs — three in BCS and one at Harvard Medical School (HMS) — will study mechanisms by which peripheral immune cells can deliver a potentially therapeutic cytokine to the brain. A study by two of the collaborators, MIT associate professor Gloria Choi and HMS associate professor Jun Huh, showed that when IL-17a reaches excitatory neurons in a region of the mouse cortex, it can calm hyperactivity in circuits associated with social and repetitive behavior symptoms. Huh, an immunologist, will examine how IL-17a can get from the periphery to the brain, while Choi will examine how it has its neurological effects. Sur and MIT associate professor Myriam Heiman will conduct studies of cell types that bridge neural circuits with brain circulatory systems.

“It is quite amazing that we have a core of scientists working on very different things coming together to tackle this one common goal,” Choi says. “I really value that.”

Multiple mentors

While SCSB Targeted Projects unify labs around research, the center’s Simons Fellowships unify labs around young researchers, providing not only funding, but a pair of mentors and free-flowing interactions between their labs. Fellows also gain opportunities to inform and inspire their fundamental research by visiting with patients with autism, Sur says.

“The SCSB postdoctoral program serves a critical role in ensuring that a diversity of outstanding scientists are exposed to autism research during their training, providing a pipeline of new talent and creativity for the field,” adds Martin, of the Simons Foundation.

Simons Fellows praise the extra opportunities afforded by additional mentoring. Postdoc Alex Major was a Simons Fellow in Miller’s lab and that of Nancy Kopell, a mathematics professor at Boston University renowned for her modeling of the brain wave phenomena that the Miller lab studies experimentally.

“The dual mentorship structure is a very useful aspect of the fellowship” Major says. “It is both a chance to network with another PI and provides experience in a different neuroscience sub-field.”

Miller says co-mentoring expands the horizons and capabilities of not only the mentees but also the mentors and their labs. “Collaboration is 21st century neuroscience,” Miller says. “Some our studies of the brain have gotten too big and comprehensive to be encapsulated in just one laboratory. Some of these big questions require multiple approaches and multiple techniques.”

Desimone, who recently co-mentored Seng Bum (Michael Yoo) along with BCS and McGovern colleague Mehrdad Jazayeri in a project studying how animals learn from observing others, agrees.

“We hear from postdocs all the time that they wish they had two mentors, just in general to get another point of view,” Desimone says. “This is a really good thing and it’s a way for faculty members to learn about what other faculty members and their postdocs are doing.”

Indeed, the Simons Center model suggests that research can be very successful when it’s collaborative and social.

Study reveals a universal pattern of brain wave frequencies

Anne Trafton |

Throughout the brain’s cortex, neurons are arranged in six distinctive layers, which can be readily seen with a microscope. A team of MIT and Vanderbilt University neuroscientists has now found that these layers also show distinct patterns of electrical activity, which are consistent over many brain regions and across several animal species, including humans.

The researchers found that in the topmost layers, neuron activity is dominated by rapid oscillations known as gamma waves. In the deeper layers, slower oscillations called alpha and beta waves predominate. The universality of these patterns suggests that these oscillations are likely playing an important role across the brain, the researchers say.

“When you see something that consistent and ubiquitous across cortex, it’s playing a very fundamental role in what the cortex does,” says Earl Miller, the Picower Professor of Neuroscience, a member of MIT’s Picower Institute for Learning and Memory, and one of the senior authors of the new study.

Imbalances in how these oscillations interact with each other may be involved in brain disorders such as attention deficit hyperactivity disorder, the researchers say.

“Overly synchronous neural activity is known to play a role in epilepsy, and now we suspect that different pathologies of synchrony may contribute to many brain disorders, including disorders of perception, attention, memory, and motor control. In an orchestra, one instrument played out of synchrony with the rest can disrupt the coherence of the entire piece of music,” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research and one of the senior authors of the study.

André Bastos, an assistant professor of psychology at Vanderbilt University, is also a senior author of the open-access paper, which appears today in Nature Neuroscience. The lead authors of the paper are MIT research scientist Diego Mendoza-Halliday and MIT postdoc Alex Major.

Layers of activity

The human brain contains billions of neurons, each of which has its own electrical firing patterns. Together, groups of neurons with similar patterns generate oscillations of electrical activity, or brain waves, which can have different frequencies. Miller’s lab has previously shown that high-frequency gamma rhythms are associated with encoding and retrieving sensory information, while low-frequency beta rhythms act as a control mechanism that determines which information is read out from working memory.

His lab has also found that in certain parts of the prefrontal cortex, different brain layers show distinctive patterns of oscillation: faster oscillation at the surface and slower oscillation in the deep layers. One study, led by Bastos when he was a postdoc in Miller’s lab, showed that as animals performed working memory tasks, lower-frequency rhythms generated in deeper layers regulated the higher-frequency gamma rhythms generated in the superficial layers.

In addition to working memory, the brain’s cortex also is the seat of thought, planning, and high-level processing of emotion and sensory information. Throughout the regions involved in these functions, neurons are arranged in six layers, and each layer has its own distinctive combination of cell types and connections with other brain areas.

“The cortex is organized anatomically into six layers, no matter whether you look at mice or humans or any mammalian species, and this pattern is present in all cortical areas within each species,” Mendoza-Halliday says. “Unfortunately, a lot of studies of brain activity have been ignoring those layers because when you record the activity of neurons, it’s been difficult to understand where they are in the context of those layers.”

In the new paper, the researchers wanted to explore whether the layered oscillation pattern they had seen in the prefrontal cortex is more widespread, occurring across different parts of the cortex and across species.

Using a combination of data acquired in Miller’s lab, Desimone’s lab, and labs from collaborators at Vanderbilt, the Netherlands Institute for Neuroscience, and the University of Western Ontario, the researchers were able to analyze 14 different areas of the cortex, from four mammalian species. This data included recordings of electrical activity from three human patients who had electrodes inserted in the brain as part of a surgical procedure they were undergoing.

Recording from individual cortical layers has been difficult in the past, because each layer is less than a millimeter thick, so it’s hard to know which layer an electrode is recording from. For this study, electrical activity was recorded using special electrodes that record from all of the layers at once, then feed the data into a new computational algorithm the authors designed, termed FLIP (frequency-based layer identification procedure). This algorithm can determine which layer each signal came from.

“More recent technology allows recording of all layers of cortex simultaneously. This paints a broader perspective of microcircuitry and allowed us to observe this layered pattern,” Major says. “This work is exciting because it is both informative of a fundamental microcircuit pattern and provides a robust new technique for studying the brain. It doesn’t matter if the brain is performing a task or at rest and can be observed in as little as five to 10 seconds.”

Across all species, in each region studied, the researchers found the same layered activity pattern.

“We did a mass analysis of all the data to see if we could find the same pattern in all areas of the cortex, and voilà, it was everywhere. That was a real indication that what had previously been seen in a couple of areas was representing a fundamental mechanism across the cortex,” Mendoza-Halliday says.

Maintaining balance

The findings support a model that Miller’s lab has previously put forth, which proposes that the brain’s spatial organization helps it to incorporate new information, which carried by high-frequency oscillations, into existing memories and brain processes, which are maintained by low-frequency oscillations. As information passes from layer to layer, input can be incorporated as needed to help the brain perform particular tasks such as baking a new cookie recipe or remembering a phone number.

“The consequence of a laminar separation of these frequencies, as we observed, may be to allow superficial layers to represent external sensory information with faster frequencies, and for deep layers to represent internal cognitive states with slower frequencies,” Bastos says. “The high-level implication is that the cortex has multiple mechanisms involving both anatomy and oscillations to separate ‘external’ from ‘internal’ information.”

Under this theory, imbalances between high- and low-frequency oscillations can lead to either attention deficits such as ADHD, when the higher frequencies dominate and too much sensory information gets in, or delusional disorders such as schizophrenia, when the low frequency oscillations are too strong and not enough sensory information gets in.

“The proper balance between the top-down control signals and the bottom-up sensory signals is important for everything the cortex does,” Miller says. “When the balance goes awry, you get a wide variety of neuropsychiatric disorders.”

The researchers are now exploring whether measuring these oscillations could help to diagnose these types of disorders. They are also investigating whether rebalancing the oscillations could alter behavior — an approach that could one day be used to treat attention deficits or other neurological disorders, the researchers say.

The researchers also hope to work with other labs to characterize the layered oscillation patterns in more detail across different brain regions.

“Our hope is that with enough of that standardized reporting, we will start to see common patterns of activity across different areas or functions that might reveal a common mechanism for computation that can be used for motor outputs, for vision, for memory and attention, et cetera,” Mendoza-Halliday says.

The research was funded by the U.S. Office of Naval Research, the U.S. National Institutes of Health, the U.S. National Eye Institute, the U.S. National Institute of Mental Health, the Picower Institute, a Simons Center for the Social Brain Postdoctoral Fellowship, and a Canadian Institutes of Health Postdoctoral Fellowship.

Calling neurons to attention

by Jennifer Michalowski |

The world assaults our senses, exposing us to more noise and color and scents and sensations than we can fully comprehend. Our brains keep us tuned in to what’s important, letting less relevant sights and sounds fade into the background while we focus on the most salient features of our surroundings. Now, scientists at MIT’s McGovern Institute have a better understanding of how the brain manages this critical task of directing our attention.

In the January 15, 2023, issue of the journal Neuron, a team led by Diego Mendoza-Halliday, a research scientist in McGovern Institute Director Robert Desimone’s lab, reports on a group of neurons in the brain’s prefrontal cortex that are critical for directing an animal’s visual attention. Their findings not only demonstrate this brain region’s important role in guiding attention, but also help establish attention as a function that is distinct from other cognitive functions, such as short-term memory, in the brain.

Attention and working memory

Mendoza-Halliday, who is now an assistant professor at the University of Pittsburgh, explains that attention has a close relationship to working memory, which the brain uses to temporarily store information after our senses take it in. The two brain functions strongly influence one another: We’re more likely to remember something if we pay attention to it, and paying attention to certain features of our environment may involve representing those features in our working memory. For example, he explains, both attention and working memory are called on when searching for a triangular red keychain on a cluttered desk: “What my brain does is it remembers that my keyholder is red and it’s a triangle, and then builds a working memory representation and uses it as a search template. So now everything that is red and everything that is a triangle receives preferential processing, or is attended to.”

Working memory and attention are so closely associated that some neuroscientists have proposed that the brain calls on the same neural mechanisms to create them. “This has led to the belief that maybe attention and working memory are just two sides of the same coin—that they’re basically the same function in different modes,” Mendoza-Halliday says. His team’s findings, however, say otherwise.

Circuit manipulation

To study the origins of attention in the brain, Mendoza-Halliday and colleagues trained monkeys to focus their attention on a visual feature that matches a cue they have seen before. After seeing a set of dots move across the screen, they must call on their working memory to remember the direction of that movement for a few seconds while the screen goes blank. Then the experimenters present the animals with more moving dots, this time traveling in multiple directions. By focusing on the dots moving in the same direction as the first set they saw, the monkeys are able to recognize when those dots briefly accelerate. Reporting on the speed change earns the animals a reward.

While the monkeys performed this task, the researchers monitored cells in several brain regions, including the prefrontal cortex, which Desimone’s team has proposed plays a role in directing attention. The activity patterns they recorded suggested that distinct groups of cells participated in the attention and working memory aspects of the task.

To better understand those cells’ roles, the researchers manipulated their activity. They used optogenetics, an approach in which a light-sensitive protein is introduced into neurons so that they can be switched on or off with a pulse of light. Desimone’s lab, in collaboration with Edward Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT and a member of the McGovern Institute, pioneered the use of optogenetics in primates. “Optogenetics allows us to distinguish between correlation and causality in neural circuits,” says Desimone, the Doris and Don Berkey Professor of Neuroscience at MIT.  “If we turn off a circuit using optogenetics, and the animal can no longer perform the task, that is good evidence for a causal role of the circuit,” says Desimone, who is also a professor of brain and cognitive sciences at MIT.

Using this optogenetic method, they switched off neurons in a specific portion of the brain’s lateral prefrontal cortex for a few hundred milliseconds at a time as the monkeys performed their dot-tracking task. The researchers found that they could switch off signaling from the lateral prefrontal cortex early, when the monkeys needed their working memory but had no dots to attend to, without interfering with the animals’ ability to complete the task. But when they blocked signaling when the monkeys needed to focus their attention, the animals performed poorly.

The team also monitored activity in the brain visual’s cortex during the moving-dot task. When the lateral prefrontal cortex was shut off, neurons in connected visual areas showed less heightened reactivity to movement in the direction the monkey was attending to. Mendoza-Halliday says this suggests that cells in the lateral prefrontal cortex are important for telling sensory-processing circuits what visual features to pay attention to.

The discovery that at least part of the brain’s lateral prefrontal cortex is critical for attention but not for working memory offers a new view of the relationship between the two. “It is a physiological demonstration that working memory and attention cannot be the same function, since they rely on partially separate neuronal populations and neural mechanisms,” Mendoza-Halliday says.

McGovern Institute Director receives highest honor from the Society for Neuroscience

by Julie Pryor |

The Society for Neuroscience will present its highest honor, the Ralph W. Gerard Prize in Neuroscience, to McGovern Institute Director Robert Desimone at its annual meeting today.

The Gerard Prize is named for neuroscientist Ralph W. Gerard who helped establish the Society for Neuroscience, and honors “outstanding scientists who have made significant contributions to neuroscience throughout their careers.” Desimone will share the $30,000 prize with Vanderbilt University neuroscientist Jon Kaas.

Desimone is being recognized for his career contributions to understanding cortical function in the visual system. His seminal work on attention spans decades, including the discovery of a neural basis for covert attention in the temporal cortex and the creation of the biased competition model, suggesting that attention is biased towards material relevant to the task. More recent work revealed how synchronized brain rhythms help enhance visual processing. Desimone also helped discover both face cells and neural populations that identify objects even when the size or location of the object changes. His long list of contributions includes mapping the extrastriate visual cortex, publishing the first report of columns for motion processing outside the primary visual cortex, and discovering how the temporal cortex retains memories. Desimone’s work has moved the field from broad strokes of input and output to a more nuanced understanding of cortical function that allows the brain to make sense of the environment.

At its annual meeting, beginning today, the Society will honor Desimone and other leading researchers who have made significant contributions to neuroscience — including the understanding of cognitive processes, drug addiction, neuropharmacology, and theoretical models — with this year’s Outstanding Achievement Awards.

“The Society is honored to recognize this year’s awardees, whose groundbreaking research has revolutionized our understanding of the brain, from the level of the synapse to the structure and function of the cortex, shedding light on how vision, memory, perception of touch and pain, and drug
addiction are organized in the brain,” SfN President Barry Everitt, said. “This exceptional group of neuroscientists has made fundamental discoveries, paved the way for new therapeutic approaches, and introduced new tools that will lay the foundation for decades of research to come.”

A connectome for cognition

by Jennifer Michalowski |

The lateral prefrontal cortex is a particularly well-connected part of the brain. Neurons there communicate with processing centers throughout the rest of the brain, gathering information and sending commands to implement executive control over behavior. Now, scientists at MIT’s McGovern Institute have mapped these connections and revealed an unexpected order within them: The lateral prefrontal cortex, they’ve found, contains maps of other major parts of the brain’s cortex.

The researchers, led by postdoctoral researcher Rui Xu and McGovern Institute Director Robert Desimone, report that the lateral prefrontal cortex contains a set of maps that represent the major processing centers in the other parts of the cortex, including the temporal and parietal lobes. Their organization likely supports the lateral prefrontal cortex’s roles managing complex functions such as attention and working memory, which require integrating information from multiple sources and coordinating activity elsewhere in the brain. The findings are published November 4, 2021, in the journal Neuron.

Topographic maps

The layout of the maps, which allows certain regions of the lateral prefrontal cortex to directly interact with multiple areas across the brain, indicates that this part of the brain is particularly well positioned for its role. “This function of integrating and then sending back control signals to appropriate levels in the processing hierarchies of the brain is clearly one of the reasons that prefrontal cortex is so important for cognition and executive control,” says Desimone.

In many parts of the brain, neurons’ physical organization has been found to reflect the information represented there. For example, individual neurons’ positions within the visual cortex mirror the layout of the cells in the retina from which they receive input, such that the spatial pattern of neuronal activity in this part of the brain provides an approximate view of the image seen by the eyes. For example, if you fixate on the first letter of a word, the next letters in the word will map to sequential locations in the visual cortex. Likewise, the arm and hand are mapped to adjacent locations in the somatic cortex, where the brain receives sensory information from the skin.

Topographic maps such as these, which have been found primarily in brain regions involved in sensory and motor processing, offer clues about how information is stored and processed in the brain. Neuroscientists have hoped that topographic maps within the lateral prefrontal cortex will provide insight into the complex cognitive processes that are carried out there—but such maps have been elusive.

Previous anatomical studies had given little indication how different parts of the brain communicate preferentially to specific locations within the prefrontal cortex to give rise to regional specialization of cognitive functions. Recently, however, the Desimone lab identified two areas within the lateral prefrontal cortex of monkeys with specific roles in focusing an animal’s visual attention. Knowing that some spots within the lateral prefrontal cortex were wired for specific functions, they wondered if others were, too. They decided they needed a detailed map of the connections emanating from this part of the brain, and devised a plan to plot connectivity from hundreds of points within the lateral prefrontal cortex.

Cortical connectome

To generate a wiring diagram, or connectome, Xu used functional MRI to monitor activity throughout a monkey’s brain as he stimulated specific points within its lateral prefrontal cortex. He moved systematically through the brain region, stimulating points spaced as close as one millimeter apart, and noting which parts of the brain lit up in response. Ultimately, the team collected data from about 100 sites for each of two monkeys.

As the data accumulated, clear patterns emerged. Different regions within the lateral prefrontal cortex formed orderly connections with each of five processing centers throughout the brain. Points within each of these maps connected to sites with the same relative positions in the distant processing centers. Because some parts of the lateral prefrontal cortex are wired to interact with more than one processing centers, these maps overlap, positioning the prefrontal cortex to integrate information from different sources.

The team found significant overlap, for example, between the maps of the temporal cortex, a part of the brain that uses visual information to recognize objects, and the parietal cortex, which computes the spatial relationships between objects. “It is mapping objects and space together in a way that would integrate the two systems,” explains Desimone. “And then on top of that, it has other maps of other brain systems that are partially overlapping with that—so they’re all sort of coming together.”

Desimone and Xu say the new connectome will help guide further investigations of how the prefrontal cortex orchestrates complex cognitive processes. “I think this really gives us a direction for the future, because we now need to understand the cognitive concepts that are mapped there,” Desimone says.

Already, they say, the connectome offers encouragement that a deeper understanding of complex cognition is within reach. “This topographic connectivity gives the lateral prefrontal some specific advantage to serve its function,” says Xu. “This suggests that lateral prefrontal cortex has a fine organization, just like the more studied parts of the brain, so the approaches that have been used to study these other regions may also benefit the studies of high-level cognition.”

Robert Desimone to receive the Fred Kavli Distinguished Career Contributions Award

by Julie Pryor |

Robert Desimone, the Doris and Don Berkey Professor in Brain and Cognitive Sciences at MIT, has been recognized by the Cognitive Neuroscience Society as this year’s winner of the Fred Kavli Distinguished Career Contributions (DCC) award. Supported annually by the Kavli Foundation, the award honors senior cognitive neuroscientists for their distinguished career, leadership and mentoring in the field of cognitive neuroscience.

Desimone, who is also the director of the McGovern Institute for Brain Research, studies the brain mechanisms underlying attention, and most recently, has been studying animal models for brain disorders.

Desimone will deliver his prize lecture at the annual meeting of the Cognitive Neuroscience Society in March 2021.

20 Years of Discovery

by Robert Desimone |

 

McGovern Institute Director Robert Desimone.

Pat and Lore McGovern founded the McGovern Institute 20 years ago with a dual mission – to understand the brain, and to apply that knowledge to help the many people affected by brain disorders. Some of the amazing developments of the past 20 years, such as CRISPR, may seem entirely unexpected and “out of the blue.” But they were all built on a foundation of basic research spanning many years. With the incredible foundation we are building right now, I feel we are poised for many more “unexpected” discoveries in the years ahead.

I predict that in 20 years, we will have quantitative models of brain function that will not only explain how the brain gives rise to at least some aspects of our mind, but will also give us a new mechanistic understanding of brain disorders. This, in turn, will lead to new types of therapies, in what I imagine to be a post-pharmaceutical era of the future. I have no doubt that these same brain models will inspire new educational approaches for our children, and will be incorporated into whatever replaces my automobile, and iPhone, in 2040. I encourage you to read some other predictions from our faculty.

Our cutting-edge work depends not only on our stellar line up of faculty, but the more than 400 postdocs, graduate students, undergraduates, summer students, and staff who make up our community.

For this reason, I am particularly delighted to share with you McGovern’s rising stars — 20 young scientists from each of our labs — who represent the next generation of neuroscience.

And finally, we remain deeply indebted to our supporters for funding our research, including ongoing support from the Patrick J. McGovern Foundation. In recent years, more than 40% of our annual research funding has come from private individuals and foundations. This support enables critical seed funding for new research projects, the development of new technologies, our new research into autism and psychiatric disorders, and fellowships for young scientists just starting their careers. Our annual fund supporters have made possible more than 42 graduate fellowships, and you can read about some of these fellows on our website.

I hope that as you visit our website and read the pages of our special anniversary issue of Brain Scan, you will feel as optimistic as I do about our future.

Robert Desimone
Director, McGovern Institute
Doris and Don Berkey Professor of Neuroscience

Robert Desimone to receive Goldman-Rakic Prize

by Julie Pryor |

Robert Desimone, the Doris and Don Berkey Professor in Brain and Cognitive Sciences at MIT, has been named a winner of this year’s Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience Research. The award, given annually by the Brain and Behavior Research Foundation, is named in recognition of former Yale University neuroscientist Patricia Goldman-Rakic.

Desimone, who is also the director of the McGovern Institute for Brain Research, studies the brain mechanisms underlying attention, and most recently he has been studying animal models for brain disorders.

Desimone will deliver his prize lecture at the 2020 Annual International Mental Health Research Virtual Symposium on October 30, 2020.

Optogenetics with SOUL

by Sabbi Lall |

Optogenetics has revolutionized neurobiology, allowing researchers to use light to activate or deactivate neurons that are genetically modified to express a light-sensitive channel. This ability to manipulate neuron activity has allowed causal testing of the function of specific neurons, and also has therapeutic potential to reduce symptoms in brain disorders. However, activating neurons deep within a given brain, especially a large primate brain but even a small mouse brain, is challenging and currently requires implanting fibers that could cause damage or inflammation.

McGovern Investigator Guoping Feng and colleagues have now overcome this challenge, developing optogenetic tools that allow non-invasive stimulation of neurons in the deep brain.

“Neuroscientists have dreamed of methods to turn neurons on and off, to understand the function of different neurons, but also to repair brain malfunctions that lead to psychiatric disorders, and optogenetics made this possible” explained Feng, the James W. (1963) and Patricia T. Poitras Professor in Brain and Cognitive Sciences. “We were trying to improve the light sensitivity of optogenetic tools to broaden applications.”

Engineering with light

In order to stimulate neurons with minimal invasiveness, Feng and colleagues engineered a new type of opsin. The original breakthrough optogenetics protocol used channelrhodopsin, a light-sensitive channel discovered in algae. By expressing this channel in neurons, light of the right wavelength can be used to activate the neuron in a dish or in vivo. However, in vivo application requires the implantation of optical fibers to deliver the light close to the specific brain region being stimulated, especially if the target region is in the deep brain. In addition, if the neuron being targeted is in the deep brain, it is hard for light to reach the region in the absence of invasive tools that can damage tissue and impact the behavior of the animal.

Our study creates a method that can activate any mouse brain region, independent of its location, non-invasively.

“Prior to our study, a few studies have contributed in various ways to the development of optogenetic stimulation methods that would be minimally invasive to the brain. However, all of these studies had various limitations in the extent of brain regions they could activate,” said co-senior study author Robert Desimone, director of the McGovern Institute and the Doris and Don Berkey Professor of Neuroscience at MIT.

Probing the brain with SOUL

Feng and colleagues turned instead to new opsins, in particular SOUL, a new type of opsin that is very sensitive to even low-level light. The Feng group engineered this opsin, based on SSFO a second generation optogenetics tool, to have increased light sensitivity, and took advantage of a second property: that SOUL is activated in multiple steps, and once activated, it stays active for longer than other commonly used opsins. This means that a burst of a few seconds of low-level light can cause neurons to stay active for 10-30 minutes.

In order to put SOUL through its paces, the Feng lab expressed this channel in the lateral hypothalamus of the mouse brain. This is a deep region, challenging to reach with light, but with neurons that have clear functions that will lead to changes in behavior. Feng’s group was able to turn on this region non-invasively with light from outside the skull, and cause changes in feeding behavior.

“We were really surprised that SOUL was able to activate one of the deepest areas in the mouse brain, the lateral hypothalamus, which is 6 mm deep,” explains Feng.

But there were more surprises. When the authors activated a region of the primate brain using SOUL, they saw oscillations, waves of synchronized neuronal activity coming together like a choir. Such waves are believed to be important for many brain functions, and this result suggests that the new opsin can manipulate these brain waves, allowing scientists to study their role in the brain.

The authors are planning to move the study in several directions, studying models of brain disorders to identify circuits that may be suitable targets for therapy, as well as moving the methodology so that it can be used beyond the superficial cortex in larger animals. While it is too early to discuss applying the system to humans, the research brings us one step closer to future treatment of neurological disorders.