Research Area: Brain Imaging

brain mapping, functional connectivity, fMRI, EEG, MEG, predictive imaging, precision interventions, contrast agents, theory of mind, the developing brain, learning

A chemical approach to imaging cells from the inside

by Karen Zusi |

A team of researchers at the McGovern Institute and Broad Institute of MIT and Harvard have developed a new technique for mapping cells. The approach, called DNA microscopy, shows how biomolecules such as DNA and RNA are organized in cells and tissues, revealing spatial and molecular information that is not easily accessible through other microscopy methods. DNA microscopy also does not require specialized equipment, enabling large numbers of samples to be processed simultaneously.

“DNA microscopy is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen,” says first author Joshua Weinstein, a postdoctoral associate at the Broad Institute. “It will allow us to see how genetically unique cells — those comprising the immune system, cancer, or the gut, for instance — interact with one another and give rise to complex multicellular life.”

The new technique is described in Cell. Aviv Regev, core institute member and director of the Klarman Cell Observatory at the Broad Institute and professor of biology at MIT, and Feng Zhang, core institute member of the Broad Institute, investigator at the McGovern Institute for Brain Research at MIT, and the James and Patricia Poitras Professor of Neuroscience at MIT, are co-authors. Regev and Zhang are also Howard Hughes Medical Institute Investigators.

The evolution of biological imaging

In recent decades, researchers have developed tools to collect molecular information from tissue samples, data that cannot be captured by either light or electron microscopes. However, attempts to couple this molecular information with spatial data — to see how it is naturally arranged in a sample — are often machinery-intensive, with limited scalability.

DNA microscopy takes a new approach to combining molecular information with spatial data, using DNA itself as a tool.

To visualize a tissue sample, researchers first add small synthetic DNA tags, which latch on to molecules of genetic material inside cells. The tags are then replicated, diffusing in “clouds” across cells and chemically reacting with each other, further combining and creating more unique DNA labels. The labeled biomolecules are collected, sequenced, and computationally decoded to reconstruct their relative positions and a physical image of the sample.

The interactions between these DNA tags enable researchers to calculate the locations of the different molecules — somewhat analogous to cell phone towers triangulating the locations of different cell phones in their vicinity. Because the process only requires standard lab tools, it is efficient and scalable.

In this study, the authors demonstrate the ability to molecularly map the locations of individual human cancer cells in a sample by tagging RNA molecules. DNA microscopy could be used to map any group of molecules that will interact with the synthetic DNA tags, including cellular genomes, RNA, or proteins with DNA-labeled antibodies, according to the team.

“DNA microscopy gives us microscopic information without a microscope-defined coordinate system,” says Weinstein. “We’ve used DNA in a way that’s mathematically similar to photons in light microscopy. This allows us to visualize biology as cells see it and not as the human eye does. We’re excited to use this tool in expanding our understanding of genetic and molecular complexity.”

Funding for this study was provided by the Simons Foundation, Klarman Cell Observatory, NIH (R01HG009276, 1R01- HG009761, 1R01- MH110049, and 1DP1-HL141201), New York Stem Cell Foundation, Simons Foundation, Paul G. Allen Family Foundation, Vallee Foundation, the Poitras Center for Affective Disorders Research at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, J. and P. Poitras, and R. Metcalfe. 

The authors have applied for a patent on this technology.

McGovern Institute postcard collection

by Julie Pryor |

A collection of 13 postcards arranged in columns.
The McGovern Institute postcard collection, 2023.

The McGovern Institute may be best known for its scientific breakthroughs, but a captivating series of brain-themed postcards developed by McGovern researchers and staff now reveals the institute’s artistic side.

What began in 2017 with a series of brain anatomy postcards inspired by the U.S. Works Projects Administration’s iconic national parks posters, has grown into a collection of twelve different prints, each featuring a unique fusion of neuroscience and art.

More information about each series in the McGovern Institute postcard collection, including the color-your-own mindfulness postcards, can be found below.

Mindfulness Postcard Series, 2023

In winter 2023, the institute released its mindfulness postcard series, a collection of four different neuroscience-themed illustrations that can be colored in with pencils, markers, or paint. The postcard series was inspired by research conducted in John Gabrieli’s lab, which found that practicing mindfulness reduced children’s stress levels and negative emotions during the pandemic. These findings contribute to a growing body of evidence that practicing mindfulness — focusing awareness on the present, typically through meditation, but also through coloring — can change patterns of brain activity associated with emotions and mental health.

Download and color your own postcards.

Genes

The McGovern Institute is at the cutting edge of applications based on CRISPR, a genome editing tool pioneered by McGovern Investigator Feng Zhang. Hidden within this DNA-themed postcard is a clam, virus, bacteriophage, snail, and the word CRISPR. Click the links to learn how these hidden elements relate to genetic engineering research at the McGovern Institute.

 

Line art showing strands of DNA and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this DNA-themed illustration containing five hidden design elements related to McGovern research. Image: Joseph Laney

Neurons

McGovern researchers probe the nanoscale and cellular processes that are critical to brain function, including the complex computations conducted in neurons, to the synapses and neurotransmitters that facilitate messaging between cells. Find the mouse, worm, and microscope — three critical elements related to cellular and molecular neuroscience research at the McGovern Institute — in the postcard below.

 

Line art showing multiple neurons and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this neuron-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Human Brain

Cognitive neuroscientists at the McGovern Institute examine the brain processes that come together to inform our thoughts and understanding of the world.​ Find the musical note, speech bubbles, and human face in this postcard and click on the links to learn more about how these hidden elements relate to brain research at the McGovern Institute.

 

Line art of a human brain and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this brain-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Artificial Intelligence

McGovern researchers develop machine learning systems that mimic human processing of visual and auditory cues and construct algorithms to help us understand the complex computations made by the brain. Find the speech bubbles, DNA, and cochlea (spiral) in this postcard and click on the links to learn more about how these hidden elements relate to computational neuroscience research at the McGovern Institute.

Line art showing an artificial neural network in the shape of the human brain and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this AI-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Neuron Postcard Series, 2019

In 2019, the McGovern Institute released a second series of postcards based on the anatomy of a neuron. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown beloSynapse

Synapse

Snow melting off the branch of a bush at the water's edge creates a ripple effect in the pool of water below. Words at the bottom of the image say "It All Begins at the SYNAPSE"Signals flow through the nervous system from one neuron to the next across synapses.

Synapses are exquisitely organized molecular machines that control the transmission of information.

McGovern researchers are studying how disruptions in synapse function can lead to brain disorders like autism.

Image: Joseph Laney

Axon

Illustration of three bears hunting for fish in a flowing river with the words: "Axon: Where Action Finds Potential"The axon is the long, thin neural cable that carries electrical impulses called action potentials from the soma to synaptic terminals at downstream neurons.

Researchers at the McGovern Institute are developing and using tracers that label axons to reveal the elaborate circuit architecture of the brain.

Image: Joseph Laney

Soma

An elk stands on a rocky outcropping overlooking a large lake with an island in the center. Words at the top read: "Collect Your Thoughts at the Soma"The soma, or cell body, is the control center of the neuron, where the nucleus is located.

It connects the dendrites to the axon, which sends information to other neurons.

At the McGovern Institute, neuroscientists are targeting the soma with proteins that can activate single neurons and map connections in the brain.

Image: Joseph Laney

Dendrites

A mountain lake at sunset with colorful fish and snow from a distant mountaintop melting into the lake. Words say "DENDRITIC ARBOR"Long branching neuronal processes called dendrites receive synaptic inputs from thousands of other neurons and carry those signals to the cell body.

McGovern neuroscientists have discovered that human dendrites have different electrical properties from those of other species, which may contribute to the enhanced computing power of the human brain.

Image: Joseph Laney

Brain Anatomy Postcard Series, 2017

The original brain anatomy-themed postcard series, developed in 2017, was inspired by the U.S. Works Projects Administration’s iconic national parks posters created in the 1930s and 1940s. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown below.

Sylvian Fissure

Illustration of explorer in cave labeled with temporal and parietal letters
The Sylvian fissure is a prominent groove on the right side of the brain that separates the frontal and parietal lobes from the temporal lobe. McGovern researchers are studying a region near the right Sylvian fissure, called the rTPJ, which is involved in thinking about what another person is thinking.

Hippocampus

The hippocampus, named after its resemblance to the seahorse, plays an important role in memory. McGovern researchers are studying how changes in the strength of synapses (connections between neurons) in the hippocampus contribute to the formation and retention of memories.

Basal Ganglia

The basal ganglia are a group of deep brain structures best known for their control of movement. McGovern researchers are studying how the connections between the cerebral cortex and a part of the basal ganglia known as the striatum play a role in emotional decision making and motivation.

 

 

 

The arcuate fasciculus is a bundle of axons in the brain that connects Broca’s area, involved in speech production, and Wernicke’s area, involved in understanding language. McGovern researchers have found a correlation between the size of this structure and the risk of dyslexia in children.

 

 

Order and Share

To order your own McGovern brain postcards, contact our colleagues at the MIT Museum, where proceeds will support current and future exhibitions at the growing museum.

Please share a photo of yourself in your own lab (or natural habitat) with one of our cards on social media. Tell us what you’re studying and don’t forget to tag us @mcgovernmit using the hashtag #McGovernPostcards.

Alumnus gives MIT $4.5 million to study effects of cannabis on the brain

by MIT School of Science |

The following news is adapted from a press release issued in conjunction with Harvard Medical School.

Charles R. Broderick, an alumnus of MIT and Harvard University, has made gifts to both alma maters to support fundamental research into the effects of cannabis on the brain and behavior.

The gifts, totaling $9 million, represent the largest donation to date to support independent research on the science of cannabinoids. The donation will allow experts in the fields of neuroscience and biomedicine at MIT and Harvard Medical School to conduct research that may ultimately help unravel the biology of cannabinoids, illuminate their effects on the human brain, catalyze treatments, and inform evidence-based clinical guidelines, societal policies, and regulation of cannabis.

Lagging behind legislation

With the increasing use of cannabis both for medicinal and recreational purposes, there is a growing concern about critical gaps in knowledge.

In 2017, the National Academies of Sciences, Engineering, and Medicine issued a report calling upon philanthropic organizations, private companies, public agencies and others to develop a “comprehensive evidence base” on the short- and long-term health effects — both beneficial and harmful — of cannabis use.

“Our desire is to fill the research void that currently exists in the science of cannabis,” says Broderick, who was an early investor in Canada’s medical marijuana market.

Broderick is the founder of Uji Capital LLC, a family office focused on quantitative opportunities in global equity capital markets. Identifying the growth of the Canadian legal cannabis market as a strategic investment opportunity, Broderick took equity positions in Tweed Marijuana Inc. and Aphria Inc., which have since grown into two of North America’s most successful cannabis companies. Subsequently, Broderick made a private investment in and served as a board member for Tokyo Smoke, a cannabis brand portfolio, which merged in 2017 to create Hiku Brands, where he served as chairman. Hiku Brands was acquired by Canopy Growth Corp. in 2018.

Through the Broderick gifts to Harvard Medical School and MIT’s School of Science through the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research, the Broderick funds will support independent studies of the neurobiology of cannabis; its effects on brain development, various organ systems and overall health, including treatment and therapeutic contexts; and cognitive, behavioral and social ramifications.

“I want to destigmatize the conversation around cannabis — and, in part, that means providing facts to the medical community, as well as the general public,” says Broderick, who argues that independent research needs to form the basis for policy discussions, regardless of whether it is good for business. “Then we’re all working from the same information. We need to replace rhetoric with research.”

MIT: Focused on brain health and function

The gift to MIT from Broderick will provide $4.5 million over three years to support independent research for four scientists at the McGovern and Picower institutes.

Two of these researchers — John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research; and Myriam Heiman, the Latham Family Associate Professor of Neuroscience at the Picower Institute — will separately explore the relationship between cannabis and schizophrenia.

Gabrieli, who directs the Martinos Imaging Center at MIT, will monitor any potential therapeutic value of cannabis for adults with schizophrenia using fMRI scans and behavioral studies.

“The ultimate goal is to improve brain health and wellbeing,” says Gabrieli. “And we have to make informed decisions on the way to this goal, wherever the science leads us. We need more data.”

Heiman, who is a molecular neuroscientist, will study how chronic exposure to phytocannabinoid molecules THC and CBD may alter the developmental molecular trajectories of cell types implicated in schizophrenia.

“Our lab’s research may provide insight into why several emerging lines of evidence suggest that adolescent cannabis use can be associated with adverse outcomes not seen in adults,” says Heiman.

In addition to these studies, Gabrieli also hopes to investigate whether cannabis can have therapeutic value for autism spectrum disorders, and Heiman plans to look at whether cannabis can have therapeutic value for Huntington’s disease.

MIT Institute Professor Ann Graybiel has proposed to study the cannabinoid 1 (CB1) receptor, which mediates many of the effects of cannabinoids. Her team recently found that CB1 receptors are tightly linked to dopamine — a neurotransmitter that affects both mood and motivation. Graybiel, who is also a member of the McGovern Institute, will examine how CB1 receptors in the striatum, a deep brain structure implicated in learning and habit formation, may influence dopamine release in the brain. These findings will be important for understanding the effects of cannabis on casual users, as well as its relationship to addictive states and neuropsychiatric disorders.

Earl Miller, Picower Professor of Neuroscience at the Picower Institute, will study effects of cannabinoids on both attention and working memory. His lab has recently formulated a model of working memory and unlocked how anesthetics reduce consciousness, showing in both cases a key role in the brain’s frontal cortex for brain rhythms, or the synchronous firing of neurons. He will observe how these rhythms may be affected by cannabis use — findings that may be able to shed light on tasks like driving where maintenance of attention is especially crucial.

Harvard Medical School: Mobilizing basic scientists and clinicians to solve an acute biomedical challenge 

The Broderick gift provides $4.5 million to establish the Charles R. Broderick Phytocannabinoid Research Initiative at Harvard Medical School, funding basic, translational and clinical research across the HMS community to generate fundamental insights about the effects of cannabinoids on brain function, various organ systems, and overall health.

The research initiative will span basic science and clinical disciplines, ranging from neurobiology and immunology to psychiatry and neurology, taking advantage of the combined expertise of some 30 basic scientists and clinicians across the school and its affiliated hospitals.

The epicenter of these research efforts will be the Department of Neurobiology under the leadership of Bruce Bean and Wade Regehr.

“I am excited by Bob’s commitment to cannabinoid science,” says Regehr, professor of neurobiology in the Blavatnik Institute at Harvard Medical School. “The research efforts enabled by Bob’s vision set the stage for unraveling some of the most confounding mysteries of cannabinoids and their effects on the brain and various organ systems.”

Bean, Regehr, and fellow neurobiologists Rachel Wilson and Bernardo Sabatini, for example, focus on understanding the basic biology of the cannabinoid system, which includes hundreds of plant and synthetic compounds as well as naturally occurring cannabinoids made in the brain.

Cannabinoid compounds activate a variety of brain receptors, and the downstream biological effects of this activation are astoundingly complex, varying by age and sex, and complicated by a person’s physiologic condition and overall health. This complexity and high degree of variability in individual biology has hampered scientific understanding of the positive and negative effects of cannabis on the human body. Bean, Regehr, and colleagues have already made critical insights showing how cannabinoids influence cell-to-cell communication in the brain.

“Even though cannabis products are now widely available, and some used clinically, we still understand remarkably little about how they influence brain function and neuronal circuits in the brain,” says Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at HMS. “This gift will allow us to conduct critical research into the neurobiology of cannabinoids, which may ultimately inform new approaches for the treatment of pain, epilepsy, sleep and mood disorders, and more.”

To propel research findings from lab to clinic, basic scientists from HMS will partner with clinicians from Harvard-affiliated hospitals, bringing together clinicians and scientists from disciplines including cardiology, vascular medicine, neurology, and immunology in an effort to glean a deeper and more nuanced understanding of cannabinoids’ effects on various organ systems and the body as a whole, rather than just on isolated organs.

For example, Bean and colleague Gary Yellen, who are studying the mechanisms of action of antiepileptic drugs, have become interested in the effects of cannabinoids on epilepsy, an interest they share with Elizabeth Thiele, director of the pediatric epilepsy program at Massachusetts General Hospital. Thiele is a pioneer in the use of cannabidiol for the treatment of drug-resistant forms of epilepsy. Despite proven clinical efficacy and recent FDA approval for rare childhood epilepsies, researchers still do not know exactly how cannabidiol quiets the misfiring brain cells of patients with the seizure disorder. Understanding its mechanism of action could help in developing new agents for treating other forms of epilepsy and other neurologic disorders.

Why is the brain shaped like it is?

by Sabbi Lall |

The human brain has a very striking shape, and one feature stands out large and clear: the cerebral cortex with its stereotyped pattern of gyri (folds and convolutions) and sulci (fissures and depressions). This characteristic folded shape of the cortex is a major innovation in evolution that allowed an increase in the size and complexity of the human brain.

How the brain adopts these complex folds is surprisingly unclear, but probably involves both shape changes and movement of cells. Mechanical constraints within the overall tissue, and imposed by surrounding tissues also contribute to the ultimate shape: the brain has to fit into the skull after all. McGovern postdoc Jonathan Wilde has a long-term interest in studying how the brain develops, and explained to us how the shape of the brain initially arises.

In the case of humans, our historical reliance upon intelligence has driven a massive expansion of the cerebral cortex.

“Believe it or not, all vertebrate brains begin as a flat sheet of epithelial cells that folds upon itself to form a tube,” explains Wilde. “This neural tube is made up of a single layer of neural stem cells that go through a rapid and highly orchestrated process of expansion and differentiation, giving rise to all of the neurons in the brain. Throughout the first steps of development, the brains of most vertebrates are indistinguishable from one another, but the final shape of the brain is highly dependent upon the organism and primarily reflects that organism’s lifestyle, environment, and cognitive demands.”

So essentially, the brain starts off as a similar shape for creatures with spinal cords. But why is the human brain such a distinct shape?

“In the case of humans,” explains Wilde, “our historical reliance upon intelligence has driven a massive expansion of the cerebral cortex, which is the primary brain structure responsible for critical thinking and higher cognitive abilities. Accordingly, the human cortex is strikingly large and covered in a labyrinth of folds that serve to increase its surface area and computational power.”

The anatomical shape of the human brain is striking, but it also helps researchers to map a hidden functional atlas: specific brain regions that selectively activate in fMRI when you see a face, scene, hear music and a variety of other tasks. I asked former McGovern graduate student, and current postdoc at Boston Children’s Hospital, Hilary Richardson, for her perspective on this more hidden structure in the brain and how it relates to brain shape.

Illustration of person rappelling into the brain's sylvian fissure.
The Sylvian fissure is a prominent groove on each side of the brain that separates the frontal and parietal lobes from the temporaal lobe. McGovern researchers are studying a region near the right Sylvian fissure, called the rTPJ, which is involved in thinking about what another person is thinking. Image: Joe Laney

“One of the most fascinating aspects of brain shape is how similar it is across individuals, even very young infants and children,” explains Richardson. “Despite the dramatic cognitive changes that happen across childhood, the shape of the brain is remarkably consistent. Given this, one open question is what kinds of neural changes support cognitive development. For example, while the anatomical shape and size of the rTPJ seems to stay the same across childhood, its response becomes more specialized to information about mental states – beliefs, desires, and emotions – as children get older. One intriguing hypothesis is that this specialization helps support social development in childhood.”

We’ll end with an ode to a prominent feature of brain shape: the “Sylvian fissure,” a prominent groove on each side of the brain that separates the frontal and parietal lobes from the temporal lobe. Such landmarks in brain shape help orient researchers, and the Sylvian fissure was recently immortalized in this image, from a postcard by illustrator Joe Laney.

______

Do you have a question for The Brain? Ask it here.

 

How our gray matter tackles gray areas

by Gina Vitale | MIT News correspondent |

When Katie O’Nell’s high school biology teacher showed a NOVA video on epigenetics after the AP exam, he was mostly trying to fill time. But for O’Nell, the video sparked a whole new area of curiosity.

She was fascinated by the idea that certain genes could be turned on and off, controlling what traits or processes were expressed without actually editing the genetic code itself. She was further excited about what this process could mean for the human mind.

But upon starting at MIT, she realized that she was less interested in the cellular level of neuroscience and more fascinated by bigger questions, such as, what makes certain people generous toward certain others? What’s the neuroscience behind morality?

“College is a time you can learn about anything you want, and what I want to know is why humans are really, really wacky,” she says. “We’re dumb, we make super irrational decisions, it makes no sense. Sometimes it’s beautiful, sometimes it’s awful.”

O’Nell, a senior majoring in brain and cognitive sciences, is one of five MIT students to have received a Marshall Scholarship this year. Her quest to understand the intricacies of the wacky human brain will not be limited to any one continent. She will be using the funding to earn her master’s in experimental psychology at Oxford University.

Chocolate milk and the mouse brain

O’Nell’s first neuroscience-related research experience at MIT took place during her sophomore and junior year, in the lab of Institute Professor Ann Graybiel at the McGovern Institute.

The research studied the neurological components of risk-vs-reward decision making, using a key ingredient: chocolate milk. In the experiments, mice were given two options — they could go toward the richer, sweeter chocolate milk, but they would also have to endure a brighter light. Or, they could go toward a more watered-down chocolate milk, with the benefit of a softer light. All the while, a fluorescence microscope tracked when certain cell types were being activated.

“I think that’s probably the closest thing I’ve ever had to a spiritual experience … watching this mouse in this maze deciding what to do, and watching the cells light up on the screen. You can see single-cell evidence of cognition going on. That’s just the coolest thing.”

In her junior spring, O’Nell delved even deeper into questions of morality in the lab of Professor Rebecca Saxe. Her research there centers on how the human brain parses people’s identities and emotional states from their faces alone, and how those computations are related to each other. Part of what interests O’Nell is the fact that we are constantly making decisions, about ourselves and others, with limited information.

“We’re always solving under uncertainty,” she says. “And our brain does it so well, in so many ways.”

International intrigue

Outside of class, O’Nell has no shortage of things to do. For starters, she has been serving as an associate advisor for a first-year seminar since the fall of her sophomore year.

“Basically it’s my job to sit in on a seminar and bully them into not taking seven classes at a time, and reminding them that yes, your first 8.01 exam is tomorrow,” she says with a laugh.

She has also continued an activity she was passionate about in high school — Model United Nations. One of the most fun parts for her is serving on the Historical Crisis Committee, in which delegates must try to figure out a way to solve a real historical problem, like the Cuban Missile Crisis or the French and Indian War.

“This year they failed and the world was a nuclear wasteland,” she says. “Last year, I don’t entirely know how this happened, but France decided that they wanted to abandon the North American theater entirely and just took over all of Britain’s holdings in India.”

She’s also part of an MIT program called the Addir Interfaith Fellowship, in which a small group of people meet each week and discuss a topic related to religion and spirituality. Before joining, she didn’t think it was something she’d be interested in — but after being placed in a first-year class about science and spirituality, she has found discussing religion to be really stimulating. She’s been a part of the group ever since.

O’Nell has also been heavily involved in writing and producing a Mystery Dinner Theater for Campus Preview Weekend, on behalf of her living group J Entry, in MacGregor House. The plot, generally, is MIT-themed — a physics professor might get killed by a swarm of CRISPR nanobots, for instance. When she’s not cooking up murder mysteries, she might be running SAT classes for high school students, playing piano, reading, or spending time with friends. Or, when she needs to go grocery shopping, she’ll be stopping by the Trader Joe’s on Boylston Avenue, as an excuse to visit the Boston Public Library across the street.

Quite excited for the future

O’Nell is excited that the Marshall Scholarship will enable her to live in the country that produced so many of the books she cherished as a kid, like “The Hobbit.” She’s also thrilled to further her research there. However, she jokes that she still needs to get some of the lingo down.

“I need to learn how to use the word ‘quite’ correctly. Because I overuse it in the American way,” she says.

Her master’s research will largely expand on the principles she’s been examining in the Saxe lab. Questions of morality, processing, and social interaction are where she aims to focus her attention.

“My master’s project is going to be basically taking a look at whether how difficult it is for you to determine someone else’s facial expression changes how generous you are with people,” she explains.

After that, she hopes to follow the standard research track of earning a PhD, doing postdoctoral research, and then entering academia as a professor and researcher. Teaching and researching, she says, are two of her favorite things — she’s excited to have the chance to do both at the same time. But that’s a few years ahead. Right now, she hopes to use her time in England to learn all she can about the deeper functions of the brain, with or without chocolate milk.

How the brain decodes familiar faces

by Sabbi Lall |

Our brains are incredibly good at processing faces, and even have specific regions specialized for this function. But what face dimensions are we observing? Do we observe general properties first, then look at the details? Or are dimensions such as gender or other identity details decoded interdependently? In a study published today in Nature Communications, the Kanwisher lab measured the response of the brain to faces in real time, and found that the brain first decodes properties such as gender and age before drilling down to the specific identity of the face itself.

While functional magnetic resonance imaging (fMRI) has revealed an incredible level of detail about which regions of the brain respond to faces, the technology is less effective at telling us when these brain regions become activated. This is because fMRI measures brain activity by detecting changes in blood flow; when neurons become active, local blood flow to those brain regions increases. However, fMRI works too slowly to keep up with the brain’s millisecond-by-millisecond dynamics. Enter magnetoencephalography (MEG), a technique developed by MIT physicist David Cohen that detects the minuscule fluctuations in magnetic field that occur with the electrical activity of neurons. This allows better temporal resolution of neural activity.

McGovern Investigator Nancy Kanwisher and postdoc Katharina Dobs, along with their co-authors Leyla Isik and Dimitrios Pantazis, selected this temporally precise approach to measure the time it takes for the brain to respond to different dimensional features of faces.

“From a brief glimpse of a face, we quickly extract all this rich multidimensional information about a person, such as their sex, age, and identity,” explains Dobs. “I wanted to understand how the brain accomplishes this impressive feat, and what the neural mechanisms are that underlie this effect, but no one had measured the time scales of responses to these features in the same study.”

Previous studies have shown that people with prosopagnosia, a condition characterized by the inability to identify familiar faces, have no trouble determining gender, suggesting these features may be independent. “But examining when the brain recognizes gender and identity, and whether these are interdependent features is less clear,” explains Dobs.

By recording the brain activity of subjects in the MEG, Dobs and her co-authors found that the brain responds to coarse features, such as the gender of a face, much faster than the identity of the face itself. Their data showed that, in as little as 60-70 milliseconds, the brain begins to decode the age and gender of a person. Roughly 30 milliseconds later — at around 90 milliseconds — the brain begins processing the identity of the face.

After establishing a paradigm for measuring responses to these face dimensions, the authors then decided to test the effect of familiarity. It’s generally understood that the brain processes information about “familiar faces” more robustly than unfamiliar faces. For example, our brains are adept at recognizing actress Scarlett Johansson across multiple photographs, even if her hairstyle is different in each picture. Our brains have a much harder time, however, recognizing two images of the same person if the face is unfamiliar.

“Actually, for unfamiliar faces the brain is easily fooled,” Dobs explains, “variations in images, shadows, changes in hair color or style, quickly lead us to think we are looking at a different person. Conversely, we have no problem if a familiar face is in shadow, or a friend changes their hair style. But we didn’t know why familiar face perception is much more robust, whether this is due to better feed forward processing, or based on later memory retrieval.”

Familiar and unfamiliar celebrity faces side by side
Perception of a familiar face, Scarlett Johansson, is more robust than for unfamiliar faces, in this study German celebrity Karoline Herfurth (images: Wikimedia commons).

To test the effect of familiarity, the authors measured brain responses while the subjects viewed familiar faces (American celebrities) and unfamiliar faces (German celebrities) in the MEG. Surprisingly, they found that subjects recognize gender more quickly in familiar faces than unfamiliar faces. For example our brains decode that actor Scarlett Johansson is female, before we even realize she is Scarlett Johansson. And for the less familiar German actor, Karoline Herfurth, our brains unpack the same information less well.

Dobs and co-authors argue that better gender and identity recognition is not “top-down” for familiar faces, meaning that improved responses to familiar faces is not about retrieval of information from memory, but rather, a feed-forward mechanism. They found that the brain responds to facial familiarity at a much slower time scale (400 milliseconds) than it responds to gender, suggesting that the brain may be remembering associations related to the face (Johansson = Lost in Translation movie) in that longer timeframe.

This is good news for artificial intelligence. “We are interested in whether feed-forward deep learning systems can learn faces using similar mechanisms,” explains Dobs, “and help us to understand how the brain can process faces it has seen before in the absence of pulling on memory.”

When it comes to immediate next steps, Dobs would like to explore where in the brain these facial dimensions are extracted, how prior experience affects the general processing of objects, and whether computational models of face processing can capture these complex human characteristics.

 

How motion conveys emotion in the face

by Sabbi Lall |

While a static emoji can stand in for emotion, in real life we are constantly reading into the feelings of others through subtle facial movements. The lift of an eyebrow, the flicker around the lips as a smile emerges, a subtle change around the eyes (or the sudden rolling of the eyes), are all changes that feed into our ability to understand the emotional state, and the attitude, of others towards us. Ben Deen and Rebecca Saxe have now monitored changes in brain activity as subjects followed face movements in movies of avatars. Their findings argue that we can generalize across individual face part movements in other people, but that a particular cortical region, the face-responsive superior temporal sulcus (fSTS), is also responding to isolated movements of individual face parts. Indeed, the fSTS seems to be tied to kinematics, individual face part movement, more than the implied emotional cause of that movement.

We know that the brain responds to dynamic changes in facial expression, and that these are associated with activity in the fSTS, but how do calculations of these movements play out in the brain?

Do we understand emotional changes by adding up individual features (lifting of eyebrows + rounding of mouth= surprise), or are we assessing the entire face in a more holistic way that results in more generalized representations? McGovern Investigator Rebecca Saxe and her graduate student Ben Deen set out to answer this question using behavioral analysis and brain imaging, specifically fMRI.

“We had a good sense of what stimuli the fSTS responds strongly to,” explains Ben Deen, “but didn’t really have any sense of how those inputs are processed in the region – what sorts of features are represented, whether the representation is more abstract or more tied to visual features, etc. The hope was to use multivoxel pattern analysis, which has proven to be a remarkably useful method for characterizing representational content, to address these questions and get a better sense of what the region is actually doing.”

Facial movements were conveyed to subjects using animated “avatars.” By presenting avatars that made isolated eye and eyebrow movements (brow raise, eye closing, eye roll, scowl) or mouth movements (smile, frown, mouth opening, snarl), as well as composites of these movements, the researchers were able to assess whether our interpretation of the latter is distinct from the sum of its parts. To do this, Deen and Saxe first took a behavioral approach where people reported on what combinations of eye and mouth movements in a whole avatar face, or one where the top and bottom parts of the face were misaligned. What they found was that movement in the mouth region can influence perception of movement in the eye region, arguably due to some level of holistic processing. The authors then asked whether there were cortical differences upon viewing isolated vs. combined face part movements. They found that changes in fSTS, but not other brain regions, had patterns of activity that seemed to discriminate between different facial movements. Indeed, they could decode which part of the avatar’s face is being perceived as moving from fSTS activity. The researchers could even model the fSTS response to combined features linearly based on the response to individual face parts. In short, though the behavorial data indicate that there is holistic processing of complex facial movement, it is also clear that isolated parts-based representations are also present, a sort of intermediate state.

As part of this work, Deen and Saxe took the important step of pre-registering their experimental parameters, before collecting any data, at the Open Science Framework. This step allows others to more easily reproduce the analysis they conducted, since all parameters (the task that subjects are carrying out, the number of subjects needed, the rationale for this number, and the scripts used to analyze data) are openly available.

“Preregistration had a big impact on our workflow for the study,” explained Deen. “More of the work was done up front, in coming up with all of the analysis details and agonizing over whether we were choosing the right strategy, before seeing any of the data. When you tie your hands by making these decisions up front, you start thinking much more carefully about them.”

Pre-registration does remove post-hoc researcher subjectivity from the analysis. As an example, because Deen and Saxe predicted that the people would be accurately able to discriminate between faces per se, they decided ahead of the experiment to focus on analyzing reaction time, rather than looking at the collected data and deciding to focus on this number after the fact. This adds to the overall objectivity of the experiment and is increasingly seen as a robust way to conduct such experiments.

MRI sensor images deep brain activity

by Anne Trafton |

Calcium is a critical signaling molecule for most cells, and it is especially important in neurons. Imaging calcium in brain cells can reveal how neurons communicate with each other; however, current imaging techniques can only penetrate a few millimeters into the brain.

MIT researchers have now devised a new way to image calcium activity that is based on magnetic resonance imaging (MRI) and allows them to peer much deeper into the brain. Using this technique, they can track signaling processes inside the neurons of living animals, enabling them to link neural activity with specific behaviors.

“This paper describes the first MRI-based detection of intracellular calcium signaling, which is directly analogous to powerful optical approaches used widely in neuroscience but now enables such measurements to be performed in vivo in deep tissue,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering, and an associate member of MIT’s McGovern Institute for Brain Research.

Jasanoff is the senior author of the paper, which appears in the Feb. 22 issue of Nature Communications. MIT postdocs Ali Barandov and Benjamin Bartelle are the paper’s lead authors. MIT senior Catherine Williamson, recent MIT graduate Emily Loucks, and Arthur Amos Noyes Professor Emeritus of Chemistry Stephen Lippard are also authors of the study.

Getting into cells

In their resting state, neurons have very low calcium levels. However, when they fire an electrical impulse, calcium floods into the cell. Over the past several decades, scientists have devised ways to image this activity by labeling calcium with fluorescent molecules. This can be done in cells grown in a lab dish, or in the brains of living animals, but this kind of microscopy imaging can only penetrate a few tenths of a millimeter into the tissue, limiting most studies to the surface of the brain.

“There are amazing things being done with these tools, but we wanted something that would allow ourselves and others to look deeper at cellular-level signaling,” Jasanoff says.

To achieve that, the MIT team turned to MRI, a noninvasive technique that works by detecting magnetic interactions between an injected contrast agent and water molecules inside cells.

Many scientists have been working on MRI-based calcium sensors, but the major obstacle has been developing a contrast agent that can get inside brain cells. Last year, Jasanoff’s lab developed an MRI sensor that can measure extracellular calcium concentrations, but these were based on nanoparticles that are too large to enter cells.

To create their new intracellular calcium sensors, the researchers used building blocks that can pass through the cell membrane. The contrast agent contains manganese, a metal that interacts weakly with magnetic fields, bound to an organic compound that can penetrate cell membranes. This complex also contains a calcium-binding arm called a chelator.

Once inside the cell, if calcium levels are low, the calcium chelator binds weakly to the manganese atom, shielding the manganese from MRI detection. When calcium flows into the cell, the chelator binds to the calcium and releases the manganese, which makes the contrast agent appear brighter in an MRI image.

“When neurons, or other brain cells called glia, become stimulated, they often experience more than tenfold increases in calcium concentration. Our sensor can detect those changes,” Jasanoff says.

Precise measurements

The researchers tested their sensor in rats by injecting it into the striatum, a region deep within the brain that is involved in planning movement and learning new behaviors. They then used potassium ions to stimulate electrical activity in neurons of the striatum, and were able to measure the calcium response in those cells.

Jasanoff hopes to use this technique to identify small clusters of neurons that are involved in specific behaviors or actions. Because this method directly measures signaling within cells, it can offer much more precise information about the location and timing of neuron activity than traditional functional MRI (fMRI), which measures blood flow in the brain.

“This could be useful for figuring out how different structures in the brain work together to process stimuli or coordinate behavior,” he says.

In addition, this technique could be used to image calcium as it performs many other roles, such as facilitating the activation of immune cells. With further modification, it could also one day be used to perform diagnostic imaging of the brain or other organs whose functions rely on calcium, such as the heart.

The research was funded by the National Institutes of Health and the MIT Simons Center for the Social Brain.

Mapping the brain at high resolution

Anne Trafton |

Researchers have developed a new way to image the brain with unprecedented resolution and speed. Using this approach, they can locate individual neurons, trace connections between them, and visualize organelles inside neurons, over large volumes of brain tissue.

The new technology combines a method for expanding brain tissue, making it possible to image at higher resolution, with a rapid 3-D microscopy technique known as lattice light-sheet microscopy. In a paper appearing in Science Jan. 17, the researchers showed that they could use these techniques to image the entire fruit fly brain, as well as large sections of the mouse brain, much faster than has previously been possible. The team includes researchers from MIT, the University of California at Berkeley, the Howard Hughes Medical Institute, and Harvard Medical School/Boston Children’s Hospital.

This technique allows researchers to map large-scale circuits within the brain while also offering unique insight into individual neurons’ functions, says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, an associate professor of biological engineering and of brain and cognitive sciences at MIT, and a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research.

“A lot of problems in biology are multiscale,” Boyden says. “Using lattice light-sheet microscopy, along with the expansion microscopy process, we can now image at large scale without losing sight of the nanoscale configuration of biomolecules.”

Boyden is one of the study’s senior authors, along with Eric Betzig, a senior fellow at the Janelia Research Campus and a professor of physics and molecular and cell biology at UC Berkeley. The paper’s lead authors are MIT postdoc Ruixuan Gao, former MIT postdoc Shoh Asano, and Harvard Medical School Assistant Professor Srigokul Upadhyayula.

Large-scale imaging

In 2015, Boyden’s lab developed a way to generate very high-resolution images of brain tissue using an ordinary light microscope. Their technique relies on expanding tissue before imaging it, allowing them to image the tissue at a resolution of about 60 nanometers. Previously, this kind of imaging could be achieved only with very expensive high-resolution microscopes, known as super-resolution microscopes.

In the new study, Boyden teamed up with Betzig and his colleagues at HHMI’s Janelia Research Campus to combine expansion microscopy with lattice light-sheet microscopy. This technology, which Betzig developed several years ago, has some key traits that make it ideal to pair with expansion microscopy: It can image large samples rapidly, and it induces much less photodamage than other fluorescent microscopy techniques.

“The marrying of the lattice light-sheet microscope with expansion microscopy is essential to achieve the sensitivity, resolution, and scalability of the imaging that we’re doing,” Gao says.

Imaging expanded tissue samples generates huge amounts of data — up to tens of terabytes per sample — so the researchers also had to devise highly parallelized computational image-processing techniques that could break down the data into smaller chunks, analyze it, and stitch it back together into a coherent whole.

In the Science paper, the researchers demonstrated the power of their new technique by imaging layers of neurons in the somatosensory cortex of mice, after expanding the tissue volume fourfold. They focused on a type of neuron known as pyramidal cells, one of the most common excitatory neurons found in the nervous system. To locate synapses, or connections, between these neurons, they labeled proteins found in the presynaptic and postsynaptic regions of the cells. This also allowed them to compare the density of synapses in different parts of the cortex.

Using this technique, it is possible to analyze millions of synapses in just a few days.

“We counted clusters of postsynaptic markers across the cortex, and we saw differences in synaptic density in different layers of the cortex,” Gao says. “Using electron microscopy, this would have taken years to complete.”

The researchers also studied patterns of axon myelination in different neurons. Myelin is a fatty substance that insulates axons and whose disruption is a hallmark of multiple sclerosis. The researchers were able to compute the thickness of the myelin coating in different segments of axons, and they measured the gaps between stretches of myelin, which are important because they help conduct electrical signals. Previously, this kind of myelin tracing would have required months to years for human annotators to perform.

This technology can also be used to image tiny organelles inside neurons. In the new paper, the researchers identified mitochondria and lysosomes, and they also measured variations in the shapes of these organelles.

Circuit analysis

The researchers demonstrated that this technique could be used to analyze brain tissue from other organisms as well; they used it to image the entire brain of the fruit fly, which is the size of a poppy seed and contains about 100,000 neurons. In one set of experiments, they traced an olfactory circuit that extends across several brain regions, imaged all dopaminergic neurons, and counted all synapses across the brain. By comparing multiple animals, they also found differences in the numbers and arrangements of synaptic boutons within each animal’s olfactory circuit.

In future work, Boyden envisions that this technique could be used to trace circuits that control memory formation and recall, to study how sensory input leads to a specific behavior, or to analyze how emotions are coupled to decision-making.

“These are all questions at a scale that you can’t answer with classical technologies,” he says.

The system could also have applications beyond neuroscience, Boyden says. His lab is planning to work with other researchers to study how HIV evades the immune system, and the technology could also be adapted to study how cancer cells interact with surrounding cells, including immune cells.

The research was funded by John Doerr, K. Lisa Yang and Y. Eva Tan, the Open Philanthropy Project, the National Institutes of Health, the Howard Hughes Medical Institute, the HHMI-Simons Faculty Scholars Program, the U.S. Army Research Laboratory and Army Research Office, the US-Israel Binational Science Foundation, Biogen, and Ionis Pharmaceuticals.

Rebecca Saxe

Mind Reading

How do we think about the thoughts of other people? How are some thoughts universal and others specific to a culture or an individual?

Rebecca Saxe is tackling these and other thorny questions surrounding human thought in adults, children, and infants. Leveraging behavioral testing, brain imaging, and computational modeling, her lab is focusing on a diverse set of research questions including what people learn from punishment, the role of generosity in social relationships, and the navigation and language abilities in toddlers. The team is also using computational models to deconstruct complex thought processes, such as how humans predict the emotions of others. This research not only expands the junction of sociology and neuroscience, but also unravels—and gives clarity to—the social threads that form the fabric of society.

Virtual Tour of Saxe Lab