Research Area: Neurotechnology

​optogenetics, expansion microscopy, robotic technologies, protein engineering, nanoparticles, probes, apps, sensors, nanomagnetics, drug delivery

New sensor uses MRI to detect light deep in the brain

Anne Trafton |

Using a specialized MRI sensor, MIT researchers have shown that they can detect light deep within tissues such as the brain.

Imaging light in deep tissues is extremely difficult because as light travels into tissue, much of it is either absorbed or scattered. The MIT team overcame that obstacle by designing a sensor that converts light into a magnetic signal that can be detected by MRI (magnetic resonance imaging).

This type of sensor could be used to map light emitted by optical fibers implanted in the brain, such as the fibers used to stimulate neurons during optogenetic experiments. With further development, it could also prove useful for monitoring patients who receive light-based therapies for cancer, the researchers say.

“We can image the distribution of light in tissue, and that’s important because people who use light to stimulate tissue or to measure from tissue often don’t quite know where the light is going, where they’re stimulating, or where the light is coming from. Our tool can be used to address those unknowns,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.

Jasanoff, who is also an associate investigator at MIT’s McGovern Institute for Brain Research, is the senior author of the study, which appears today in Nature Biomedical Engineering. Jacob Simon PhD ’21 and MIT postdoc Miriam Schwalm are the paper’s lead authors, and Johannes Morstein and Dirk Trauner of New York University are also authors of the paper.

A light-sensitive probe

Scientists have been using light to study living cells for hundreds of years, dating back to the late 1500s, when the light microscope was invented. This kind of microscopy allows researchers to peer inside cells and thin slices of tissue, but not deep inside an organism.

“One of the persistent problems in using light, especially in the life sciences, is that it doesn’t do a very good job penetrating many materials,” Jasanoff says. “Biological materials absorb light and scatter light, and the combination of those things prevents us from using most types of optical imaging for anything that involves focusing in deep tissue.”

To overcome that limitation, Jasanoff and his students decided to design a sensor that could transform light into a magnetic signal.

“We wanted to create a magnetic sensor that responds to light locally, and therefore is not subject to absorbance or scattering. Then this light detector can be imaged using MRI,” he says.

Jasanoff’s lab has previously developed MRI probes that can interact with a variety of molecules in the brain, including dopamine and calcium. When these probes bind to their targets, it affects the sensors’ magnetic interactions with the surrounding tissue, dimming or brightening the MRI signal.

To make a light-sensitive MRI probe, the researchers decided to encase magnetic particles in a nanoparticle called a liposome. The liposomes used in this study are made from specialized light-sensitive lipids that Trauner had previously developed. When these lipids are exposed to a certain wavelength of light, the liposomes become more permeable to water, or “leaky.” This allows the magnetic particles inside to interact with water and generate a signal detectable by MRI.

The particles, which the researchers called liposomal nanoparticle reporters (LisNR), can switch from permeable to impermeable depending on the type of light they’re exposed to. In this study, the researchers created particles that become leaky when exposed to ultraviolet light, and then become impermeable again when exposed to blue light. The researchers also showed that the particles could respond to other wavelengths of light.

“This paper shows a novel sensor to enable photon detection with MRI through the brain. This illuminating work introduces a new avenue to bridge photon and proton-driven neuroimaging studies,” says Xin Yu, an assistant professor radiology at Harvard Medical School, who was not involved in the study.

Mapping light

The researchers tested the sensors in the brains of rats — specifically, in a part of the brain called the striatum, which is involved in planning movement and responding to reward. After injecting the particles throughout the striatum, the researchers were able to map the distribution of light from an optical fiber implanted nearby.

The fiber they used is similar to those used for optogenetic stimulation, so this kind of sensing could be useful to researchers who perform optogenetic experiments in the brain, Jasanoff says.

“We don’t expect that everybody doing optogenetics will use this for every experiment — it’s more something that you would do once in a while, to see whether a paradigm that you’re using is really producing the profile of light that you think it should be,” Jasanoff says.

In the future, this type of sensor could also be useful for monitoring patients receiving treatments that involve light, such as photodynamic therapy, which uses light from a laser or LED to kill cancer cells.

The researchers are now working on similar probes that could be used to detect light emitted by luciferases, a family of glowing proteins that are often used in biological experiments. These proteins can be used to reveal whether a particular gene is activated or not, but currently they can only be imaged in superficial tissue or cells grown in a lab dish.

Jasanoff also hopes to use the strategy used for the LisNR sensor to design MRI probes that can detect stimuli other than light, such as neurochemicals or other molecules found in the brain.

“We think that the principle that we use to construct these sensors is quite broad and can be used for other purposes too,” he says.

The research was funded by the National Institutes of Health, the G. Harold and Leila Y. Mathers Foundation, a Friends of the McGovern Fellowship from the McGovern Institute for Brain Research, the MIT Neurobiological Engineering Training Program, and a Marie Curie Individual Fellowship from the European Commission.

Season’s Greetings from the McGovern Institute

by McGovern Institute |

This year’s holiday video (shown above) was inspired by Ev Fedorenko’s July 2022 Nature Neuroscience paper, which found similar patterns of brain activation and language selectivity across speakers of 45 different languages.

Universal language network

Ev Fedorenko uses the widely translated book “Alice in Wonderland” to test brain responses to different languages. Photo: Caitlin Cunningham

Over several decades, neuroscientists have created a well-defined map of the brain’s “language network,” or the regions of the brain that are specialized for processing language. Found primarily in the left hemisphere, this network includes regions within Broca’s area, as well as in other parts of the frontal and temporal lobes. Although roughly 7,000 languages are currently spoken and signed across the globe, the vast majority of those mapping studies have been done in English speakers as they listened to or read English texts.

To truly understand the cognitive and neural mechanisms that allow us to learn and process such diverse languages, Fedorenko and her team scanned the brains of speakers of 45 different languages while they listened to Alice in Wonderland in their native language. The results show that the speakers’ language networks appear to be essentially the same as those of native English speakers — which suggests that the location and key properties of the language network appear to be universal.

The many languages of McGovern

English may be the primary language used by McGovern researchers, but more than 35 other languages are spoken by scientists and engineers at the McGovern Institute. Our holiday video features 30 of these researchers saying Happy New Year in their native (or learned) language. Below is the complete list of languages included in our video. Expand each accordion to learn more about the speaker of that particular language and the meaning behind their new year’s greeting.

The ways we move

by Jennifer Michalowski |

This story originally appeared in the Winter 2023 issue of BrainScan.
__

Many people barely consider how their bodies move — at least not until movement becomes more difficult due to injury or disease. But the McGovern scientists who are working to understand human movement and restore it after it has been lost know that the way we move is an engineering marvel.
Muscles, bones, brain, and nerves work together to navigate and interact with an ever-changing environment, making constant but often imperceptible adjustments to carry out our goals. It’s an efficient and highly adaptable system, and the way it’s put together is not at all intuitive, says Hugh Herr, a new associate investigator at the Institute.

That’s why Herr, who also co-directs MIT’s new K. Lisa Yang Center for Bionics, looks to biology to guide the development of artificial limbs that aim to give people the same agency, control, and comfort of natural limbs. McGovern Associate Investigator Nidhi Seethapathi, who like Herr joined the Institute in September, is also interested in understanding human movement in all its complexity. She is coming at the problem from a different direction, using computational modeling to predict how and why we move the way we do.

Moving through change

The computational models that Seethapathi builds in her lab aim to predict how humans will move under different conditions. If a person is placed in an unfamiliar environment and asked to navigate a course under time pressure, what path will they take? How will they move their limbs, and what forces will they exert? How will their movements change as they become more comfortable on the terrain?

McGovern Associate Investigator Nidhi Seethapathi with lab members (from left to right) Inseung Kang, Nikasha Patel, Antoine De Comite, Eric Wang, and Crista Falk. Photo: Steph Stevens

Seethapathi uses the principles of robotics to build models that answer these questions, then tests them by placing real people in the same scenarios and monitoring their movements. So far, that has mostly meant inviting study subjects to her lab, but as she expands her models to predict more complex movements, she will begin monitoring people’s activity in the real world, over longer time periods than laboratory experiments typically allow.

Seethapathi’s hope is that her findings will inform the way doctors, therapists, and engineers help patients regain control over their movements after an injury or stroke, or learn to live with movement disorders like Parkinson’s disease. To make a real difference, she stresses, it’s important to bring studies of human movement out of the lab, where subjects are often limited to simple tasks like walking on a treadmill, into more natural settings. “When we’re talking about doing physical therapy, neuromotor rehabilitation, robotic exoskeletons — any way of helping people move better — we want to do it in the real world, for everyday, complex tasks,” she says.

When we’re talking about helping people move better — we want to do it in the real world, for everyday, complex tasks,” says Seethapathi.

Seethapathi’s work is already revealing how the brain directs movement in the face of competing priorities. For example, she has found that when people are given a time constraint for traveling a particular distance, they walk faster than their usual, comfortable pace — so much so that they often expend more energy than necessary and arrive at their destination a bit early. Her models suggest that people pick up their pace more than they need to because humans’ internal estimations of time are imprecise.

Her team is also learning how movements change as a person becomes familiar with an environment or task. She says people find an efficient way to move through a lot of practice. “If you’re walking in a straight line for a very long time, then you seem to pick the movement that is optimal for that long-distance walk,” she explains. But in the real world, things are always changing — both in the body and in the environment. So Seethapathi models how people behave when they must move in a new way or navigate a new environment. “In these kinds of conditions, people eventually wind up on an energy-optimal solution,” she says. “But initially, they pick something that prevents them from falling down.”

To capture the complexity of human movement, Seethapathi and her team are devising new tools that will let them monitor people’s movements outside the lab. They are also drawing on data from other fields, from architecture to physical therapy, and even from studies of other animals. “If I have general principles, they should be able to tell me how modifications in the body or in how the brain is connected to the body would lead to different movements,” she says. “I’m really excited about generalizing these principles across timescales and species.”

Building new bodies

In Herr’s lab, a deepening understanding of human movement is helping drive the development of increasingly sophisticated artificial limbs and other wearable robots. The team designs devices that interface directly with a user’s nervous system, so they are not only guided by the brain’s motor control systems, but also send information back to the brain.

Herr, a double amputee with two artificial legs of his own, says prosthetic devices are getting better at replicating natural movements, guided by signals from the brain. Mimicking the design and neural signals found in biology can even give those devices much of the extraordinary adaptability of natural human movement. As an example, Herr notes that his legs effortlessly navigate varied terrain. “There’s adaptive, stabilizing features, and the machine doesn’t have to detect every pothole and pebble and banana peel on the ground, because the morphology and the nervous system control is so inherently adaptive,” he says.

McGovern Associate Investigator Hugh Herr at work in the K. Lisa Yang Center for Bionics at MIT. Photo: Jimmy Day/Media Lab

But, he notes, the field of bionics is in its infancy, and there’s lots of room for improvement. “It’s only a matter of time before a robotic knee, for example, can be as good as the biological knee or better,” he says. “But the problem is the human attached to that knee won’t feel it’s their knee until they can feel it, and until their central nervous system has complete agency over that knee,” he says. “So if you want to actually build new bodies and not just more and more powerful tools for humans, you have to link to the brain bidirectionally.”

Herr’s team has found that surgically restoring natural connections between pairs of muscles that normally work in opposition to move a limb, such as the arm’s biceps and triceps, gives the central nervous system signals about how that limb is moving, even when a natural limb is gone. The idea takes a cue from the work of McGovern Emeritus Investigator Emilio Bizzi, who found that the coordinated activation of groups of muscles by the nervous system, called muscle synergies, is important for motor control.

“It’s only a matter of time before a robotic knee can be as good as the biological knee or better,” says Herr.

“When a person thinks and moves their phantom limb, those muscle pairings move dynamically, so they feel, in a natural way, the limb moving — even though the limb is not there,” Herr explains. He adds that when those proprioceptive signals communicate instead how an artificial limb is moving, a person experiences “great agency and ownership” of that limb. Now, his group is working to develop sensors that detect and relay information usually processed by sensory neurons in the skin, so prosthetic devices can also perceive pressure and touch.

At the same time, they’re working to improve the mechanical interface between wearable robots and the body to optimize comfort and fit — whether that’s by using detailed anatomical imaging to guide the design of an individual’s device or by engineering devices that integrate directly with a person’s skeleton. There’s no “average” human, Herr says, and effective technologies must meet individual needs, not just for fit, but also for function. At that same time, he says it’s important to plan for cost-effective, mass production, because the need for these technologies is so great.

“The amount of human suffering caused by the lack of technology to address disability is really beyond comprehension,” he says. He expects tremendous progress in the growing field of bionics in the coming decades, but he’s impatient. “I think in 50 years, when scientists look back to this era, it’ll be laughable,” he says. “I’m always anxiously wanting to be in the future.”

Magnetic sensors track muscle length

Anne Trafton |

Using a simple set of magnets, MIT researchers have come up with a sophisticated way to monitor muscle movements, which they hope will make it easier for people with amputations to control their prosthetic limbs.

In a new pair of papers, the researchers demonstrated the accuracy and safety of their magnet-based system, which can track the length of muscles during movement. The studies, performed in animals, offer hope that this strategy could be used to help people with prosthetic devices control them in a way that more closely mimics natural limb movement.

“These recent results demonstrate that this tool can be used outside the lab to track muscle movement during natural activity, and they also suggest that the magnetic implants are stable and biocompatible and that they don’t cause discomfort,” says Cameron Taylor, an MIT research scientist and co-lead author of both papers.

McGovern Institute Associate Investigator Hugh Herr. Photo: Jimmy Day / MIT Media Lab

In one of the studies, the researchers showed that they could accurately measure the lengths of turkeys’ calf muscles as the birds ran, jumped, and performed other natural movements. In the other study, they showed that the small magnetic beads used for the measurements do not cause inflammation or other adverse effects when implanted in muscle.

“I am very excited for the clinical potential of this new technology to improve the control and efficacy of bionic limbs for persons with limb-loss,” says Hugh Herr, a professor of media arts and sciences, co-director of the K. Lisa Yang Center for Bionics at MIT, and an associate member of MIT’s McGovern Institute for Brain Research.

Herr is a senior author of both papers, which appear today in the journal Frontiers in Bioengineering and Biotechnology. Thomas Roberts, a professor of ecology, evolution, and organismal biology at Brown University, is a senior author of the measurement study.

Tracking movement

Currently, powered prosthetic limbs are usually controlled using an approach known as surface electromyography (EMG). Electrodes attached to the surface of the skin or surgically implanted in the residual muscle of the amputated limb measure electrical signals from a person’s muscles, which are fed into the prosthesis to help it move the way the person wearing the limb intends.

However, that approach does not take into account any information about the muscle length or velocity, which could help to make the prosthetic movements more accurate.

Several years ago, the MIT team began working on a novel way to perform those kinds of muscle measurements, using an approach that they call magnetomicrometry. This strategy takes advantage of the permanent magnetic fields surrounding small beads implanted in a muscle. Using a credit-card-sized, compass-like sensor attached to the outside of the body, their system can track the distances between the two magnets. When a muscle contracts, the magnets move closer together, and when it flexes, they move further apart.

The new muscle measuring approach takes advantage of the magnetic attraction between two small beads implanted in a muscle. Using a small sensor attached to the outside of the body, the system can track the distances between the two magnets as the muscle contracts and flexes. Image: Hugh Herr

In a study published last year, the researchers showed that this system could be used to accurately measure small ankle movements when the beads were implanted in the calf muscles of turkeys. In one of the new studies, the researchers set out to see if the system could make accurate measurements during more natural movements in a nonlaboratory setting.

To do that, they created an obstacle course of ramps for the turkeys to climb and boxes for them to jump on and off of. The researchers used their magnetic sensor to track muscle movements during these activities, and found that the system could calculate muscle lengths in less than a millisecond.

They also compared their data to measurements taken using a more traditional approach known as fluoromicrometry, a type of X-ray technology that requires much larger equipment than magnetomicrometry. The magnetomicrometry measurements varied from those generated by fluoromicrometry by less than a millimeter, on average.

“We’re able to provide the muscle-length tracking functionality of the room-sized X-ray equipment using a much smaller, portable package, and we’re able to collect the data continuously instead of being limited to the 10-second bursts that fluoromicrometry is limited to,” Taylor says.

Seong Ho Yeon, an MIT graduate student, is also a co-lead author of the measurement study. Other authors include MIT Research Support Associate Ellen Clarrissimeaux and former Brown University postdoc Mary Kate O’Donnell.

Biocompatibility

In the second paper, the researchers focused on the biocompatibility of the implants. They found that the magnets did not generate tissue scarring, inflammation, or other harmful effects. They also showed that the implanted magnets did not alter the turkeys’ gaits, suggesting they did not produce discomfort. William Clark, a postdoc at Brown, is the co-lead author of the biocompatibility study.

The researchers also showed that the implants remained stable for eight months, the length of the study, and did not migrate toward each other, as long as they were implanted at least 3 centimeters apart. The researchers envision that the beads, which consist of a magnetic core coated with gold and a polymer called Parylene, could remain in tissue indefinitely once implanted.

“Magnets don’t require an external power source, and after implanting them into the muscle, they can maintain the full strength of their magnetic field throughout the lifetime of the patient,” Taylor says.

The researchers are now planning to seek FDA approval to test the system in people with prosthetic limbs. They hope to use the sensor to control prostheses similar to the way surface EMG is used now: Measurements regarding the length of muscles will be fed into the control system of a prosthesis to help guide it to the position that the wearer intends.

“The place where this technology fills a need is in communicating those muscle lengths and velocities to a wearable robot, so that the robot can perform in a way that works in tandem with the human,” Taylor says. “We hope that magnetomicrometry will enable a person to control a wearable robot with the same comfort level and the same ease as someone would control their own limb.”

In addition to prosthetic limbs, those wearable robots could include robotic exoskeletons, which are worn outside the body to help people move their legs or arms more easily.

The research was funded by the Salah Foundation, the K. Lisa Yang Center for Bionics at MIT, the MIT Media Lab Consortia, the National Institutes of Health, and the National Science Foundation.

A “golden era” to study the brain

by Leah Campbell | School of Science |

As an undergraduate, Mitch Murdock was a rare science-humanities double major, specializing in both English and molecular, cellular, and developmental biology at Yale University. Today, as a doctoral student in the MIT Department of Brain and Cognitive Sciences, he sees obvious ways that his English education expanded his horizons as a neuroscientist.

“One of my favorite parts of English was trying to explore interiority, and how people have really complicated experiences inside their heads,” Murdock explains. “I was excited about trying to bridge that gap between internal experiences of the world and that actual biological substrate of the brain.”

Though he can see those connections now, it wasn’t until after Yale that Murdock became interested in brain sciences. As an undergraduate, he was in a traditional molecular biology lab. He even planned to stay there after graduation as a research technician; fortunately, though, he says his advisor Ron Breaker encouraged him to explore the field. That’s how Murdock ended up in a new lab run by Conor Liston, an associate professor at Weill Cornell Medicine, who studies how factors such as stress and sleep regulate the modeling of brain circuits.

It was in Liston’s lab that Murdock was first exposed to neuroscience and began to see the brain as the biological basis of the philosophical questions about experience and emotion that interested him. “It was really in his lab where I thought, ‘Wow, this is so cool. I have to do a PhD studying neuroscience,’” Murdock laughs.

During his time as a research technician, Murdock examined the impact of chronic stress on brain activity in mice. Specifically, he was interested in ketamine, a fast-acting antidepressant prone to being abused, with the hope that better understanding how ketamine works will help scientists find safer alternatives. He focused on dendritic spines, small organelles attached to neurons that help transmit electrical signals between neurons and provide the physical substrate for memory storage. His findings, Murdock explains, suggested that ketamine works by recovering dendritic spines that can be lost after periods of chronic stress.

After three years at Weill Cornell, Murdock decided to pursue doctoral studies in neuroscience, hoping to continue some of the work he started with Liston. He chose MIT because of the research being done on dendritic spines in the lab of Elly Nedivi, the William R. (1964) and Linda R. Young Professor of Neuroscience in The Picower Institute for Learning and Memory.

Once again, though, the opportunity to explore a wider set of interests fortuitously led Murdock to a new passion. During lab rotations at the beginning of his PhD program, Murdock spent time shadowing a physician at Massachusetts General Hospital who was working with Alzheimer’s disease patients.

“Everyone knows that Alzheimer’s doesn’t have a cure. But I realized that, really, if you have Alzheimer’s disease, there’s very little that can be done,” he says. “That was a big wake-up call for me.”

After that experience, Murdock strategically planned his remaining lab rotations, eventually settling into the lab of Li-Huei Tsai, the Picower Professor of Neuroscience and the director of the Picower Institute. For the past five years, Murdock has worked with Tsai on various strands of Alzheimer’s research.

In one project, for example, members of the Tsai lab have shown how certain kinds of non-invasive light and sound stimulation induce brain activity that can improve memory loss in mouse models of Alzheimer’s. Scientists think that, during sleep, small movements in blood vessels drive spinal fluid into the brain, which, in turn, flushes out toxic metabolic waste. Murdock’s research suggests that certain kinds of stimulation might drive a similar process, flushing out waste that can exacerbate memory loss.

Much of his work is focused on the activity of single cells in the brain. Are certain neurons or types of neurons genetically predisposed to degenerate, or do they break down randomly? Why do certain subtypes of cells appear to be dysfunctional earlier on in the course of Alzheimer’s disease? How do changes in blood flow in vascular cells affect degeneration? All of these questions, Murdock believes, will help scientists better understand the causes of Alzheimer’s, which will translate eventually into developing cures and therapies.

To answer these questions, Murdock relies on new single-cell sequencing techniques that he says have changed the way we think about the brain. “This has been a big advance for the field, because we know there are a lot of different cell types in the brain, and we think that they might contribute differentially to Alzheimer’s disease risk,” says Murdock. “We can’t think of the brain as only about neurons.”

Murdock says that that kind of “big-picture” approach — thinking about the brain as a compilation of many different cell types that are all interacting — is the central tenet of his research. To look at the brain in the kind of detail that approach requires, Murdock works with Ed Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research. Working with Boyden has allowed Murdock to use new technologies such as expansion microscopy and genetically encoded sensors to aid his research.

That kind of new technology, he adds, has helped blow the field wide open. “This is such a cool time to be a neuroscientist because the tools available now make this a golden era to study the brain.” That rapid intellectual expansion applies to the study of Alzheimer’s as well, including newly understood connections between the immune system and Alzheimer’s — an area in which Murdock says he hopes to continue after graduation.

Right now, though, Murdock is focused on a review paper synthesizing some of the latest research. Given the mountains of new Alzheimer’s work coming out each year, he admits that synthesizing all the data is a bit “crazy,” but he couldn’t be happier to be in the middle of it. “There’s just so much that we are learning about the brain from these new techniques, and it’s just so exciting.”

Hugh Herr

Revolutionizing Bionics

Hugh Herr creates bionic limbs that emulate the function of natural limbs. In 2011, TIME magazine named him the “Leader of the Bionic Age” for his revolutionary work in the emerging field of biomechatronics, an emerging field that marries human physiology with electromechanics.

Herr, who lost both of his legs below the knee to a climbing accident in 1982, has dedicated his career to the creation of technologies that push the possibilities of prosthetics. As co-director of the K. Lisa Yang Center for Bionics, Herr seeks to develop neural and mechanical interfaces for human-machine communications; integrate these interfaces into novel bionic platforms; perform clinical trials to accelerate the deployment of bionic products by the private sector; and leverage novel and durable, but affordable, materials and manufacturing processes to ensure equitable access of the latest bionic technology to all impacted individuals, especially to those in developing countries.

Herr’s story has been told in the National Geographic film, Ascent: The Story of Hugh Herr as well as the PBS documentary, Augmented.

Microscopy technique reveals hidden nanostructures in cells and tissues

Anne Trafton |

Press Mentions

Making the invisible visible

The Economist

Inside a living cell, proteins and other molecules are often tightly packed together. These dense clusters can be difficult to image because the fluorescent labels used to make them visible can’t wedge themselves in between the molecules.

MIT researchers have now developed a novel way to overcome this limitation and make those “invisible” molecules visible. Their technique allows them to “de-crowd” the molecules by expanding a cell or tissue sample before labeling the molecules, which makes the molecules more accessible to fluorescent tags.

This method, which builds on a widely used technique known as expansion microscopy previously developed at MIT, should allow scientists to visualize molecules and cellular structures that have never been seen before.

“It’s becoming clear that the expansion process will reveal many new biological discoveries. If biologists and clinicians have been studying a protein in the brain or another biological specimen, and they’re labeling it the regular way, they might be missing entire categories of phenomena,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research.

Using this technique, Boyden and his colleagues showed that they could image a nanostructure found in the synapses of neurons. They also imaged the structure of Alzheimer’s-linked amyloid beta plaques in greater detail than has been possible before.

“Our technology, which we named expansion revealing, enables visualization of these nanostructures, which previously remained hidden, using hardware easily available in academic labs,” says Deblina Sarkar, an assistant professor in the Media Lab and one of the lead authors of the study.

The senior authors of the study are Boyden; Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory; and Thomas Blanpied, a professor of physiology at the University of Maryland. Other lead authors include Jinyoung Kang, an MIT postdoc, and Asmamaw Wassie, a recent MIT PhD recipient. The study appears today in Nature Biomedical Engineering.

De-crowding

Imaging a specific protein or other molecule inside a cell requires labeling it with a fluorescent tag carried by an antibody that binds to the target. Antibodies are about 10 nanometers long, while typical cellular proteins are usually about 2 to 5 nanometers in diameter, so if the target proteins are too densely packed, the antibodies can’t get to them.

This has been an obstacle to traditional imaging and also to the original version of expansion microscopy, which Boyden first developed in 2015. In the original version of expansion microscopy, researchers attached fluorescent labels to molecules of interest before they expanded the tissue. The labeling was done first, in part because the researchers had to use an enzyme to chop up proteins in the sample so the tissue could be expanded. This meant that the proteins couldn’t be labeled after the tissue was expanded.

To overcome that obstacle, the researchers had to find a way to expand the tissue while leaving the proteins intact. They used heat instead of enzymes to soften the tissue, allowing the tissue to expand 20-fold without being destroyed. Then, the separated proteins could be labeled with fluorescent tags after expansion.

With so many more proteins accessible for labeling, the researchers were able to identify tiny cellular structures within synapses, the connections between neurons that are densely packed with proteins. They labeled and imaged seven different synaptic proteins, which allowed them to visualize, in detail, “nanocolumns” consisting of calcium channels aligned with other synaptic proteins. These nanocolumns, which are believed to help make synaptic communication more efficient, were first discovered by Blanpied’s lab in 2016.

“This technology can be used to answer a lot of biological questions about dysfunction in synaptic proteins, which are involved in neurodegenerative diseases,” Kang says. “Until now there has been no tool to visualize synapses very well.”

New patterns

The researchers also used their new technique to image beta amyloid, a peptide that forms plaques in the brains of Alzheimer’s patients. Using brain tissue from mice, the researchers found that amyloid beta forms periodic nanoclusters, which had not been seen before. These clusters of amyloid beta also include potassium channels. The researchers also found amyloid beta molecules that formed helical structures along axons.

“In this paper, we don’t speculate as to what that biology might mean, but we show that it exists. That is just one example of the new patterns that we can see,” says Margaret Schroeder, an MIT graduate student who is also an author of the paper.

Sarkar says that she is fascinated by the nanoscale biomolecular patterns that this technology unveils. “With a background in nanoelectronics, I have developed electronic chips that require extremely precise alignment, in the nanofab. But when I see that in our brain Mother Nature has arranged biomolecules with such nanoscale precision, that really blows my mind,” she says.

Boyden and his group members are now working with other labs to study cellular structures such as protein aggregates linked to Parkinson’s and other diseases. In other projects, they are studying pathogens that infect cells and molecules that are involved in aging in the brain. Preliminary results from these studies have also revealed novel structures, Boyden says.

“Time and time again, you see things that are truly shocking,” he says. “It shows us how much we are missing with classical unexpanded staining.”

The researchers are also working on modifying the technique so they can image up to 20 proteins at a time. They are also working on adapting their process so that it can be used on human tissue samples.

Sarkar and her team, on the other hand, are developing tiny wirelessly powered nanoelectronic devices which could be distributed in the brain. They plan to integrate these devices with expansion revealing. “This can combine the intelligence of nanoelectronics with the nanoscopy prowess of expansion technology, for an integrated functional and structural understanding of the brain,” Sarkar says.

The research was funded by the National Institutes of Health, the National Science Foundation, the Ludwig Family Foundation, the JPB Foundation, the Open Philanthropy Project, John Doerr, Lisa Yang and the Tan-Yang Center for Autism Research at MIT, the U.S. Army Research Office, Charles Hieken, Tom Stocky, Kathleen Octavio, Lore McGovern, Good Ventures, and HHMI.

New research center focused on brain-body relationship established at MIT

by Julie Pryor |

The inextricable link between our brains and our bodies has been gaining increasing recognition among researchers and clinicians over recent years. Studies have shown that the brain-body pathway is bidirectional — meaning that our mental state can influence our physical health and vice versa. But exactly how the two interact is less clear.

A new research center at MIT, funded by a $38 million gift to the McGovern Institute for Brain Research from philanthropist K. Lisa Yang, aims to unlock this mystery by creating and applying novel tools to explore the multidirectional, multilevel interplay between the brain and other body organ systems. This gift expands Yang’s exceptional philanthropic support of human health and basic science research at MIT over the past five years.

“Lisa Yang’s visionary gift enables MIT scientists and engineers to pioneer revolutionary technologies and undertake rigorous investigations into the brain’s complex relationship with other organ systems,” says MIT President L. Rafael Reif.  “Lisa’s tremendous generosity empowers MIT scientists to make pivotal breakthroughs in brain and biomedical research and, collectively, improve human health on a grand scale.”

The K. Lisa Yang Brain-Body Center will be directed by Polina Anikeeva, professor of materials science and engineering and brain and cognitive sciences at MIT and an associate investigator at the McGovern Institute. The center will harness the power of MIT’s collaborative, interdisciplinary life sciences research and engineering community to focus on complex conditions and diseases affecting both the body and brain, with a goal of unearthing knowledge of biological mechanisms that will lead to promising therapeutic options.

“Under Professor Anikeeva’s brilliant leadership, this wellspring of resources will encourage the very best work of MIT faculty, graduate fellows, and research — and ultimately make a real impact on the lives of many,” Reif adds.

microscope image of gut
Mouse small intestine stained to reveal cell nucleii (blue) and peripheral nerve fibers (red).
Image: Polina Anikeeva, Marie Manthey, Kareena Villalobos

Center goals  

Initial projects in the center will focus on four major lines of research:

  • Gut-Brain: Anikeeva’s group will expand a toolbox of new technologies and apply these tools to examine major neurobiological questions about gut-brain pathways and connections in the context of autism spectrum disorders, Parkinson’s disease, and affective disorders.
  • Aging: CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and investigator at the McGovern Institute, will lead a group in developing molecular tools for precision epigenomic editing and erasing accumulated “errors” of time, injury, or disease in various types of cells and tissues.
  • Pain: The lab of Fan Wang, investigator at the McGovern Institute and professor of brain and cognitive sciences, will design new tools and imaging methods to study autonomic responses, sympathetic-parasympathetic system balance, and brain-autonomic nervous system interactions, including how pain influences these interactions.
  • Acupuncture: Wang will also collaborate with Hilda (“Scooter”) Holcombe, a veterinarian in MIT’s Division of Comparative Medicine, to advance techniques for documenting changes in brain and peripheral tissues induced by acupuncture in mouse models. If successful, these techniques could lay the groundwork for deeper understandings of the mechanisms of acupuncture, specifically how the treatment stimulates the nervous system and restores function.

A key component of the K. Lisa Yang Brain-Body Center will be a focus on educating and training the brightest young minds who aspire to make true breakthroughs for individuals living with complex and often devastating diseases. A portion of center funding will endow the new K. Lisa Yang Brain-Body Fellows Program, which will support four annual fellowships for MIT graduate students and postdocs working to advance understanding of conditions that affect both the body and brain.

Mens sana in corpore sano

“A phrase I remember reading in secondary school has always stuck with me: ‘mens sana in corpore sano’ — ‘a healthy mind in a healthy body,’” says Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities. “When we look at how stress, nutrition, pain, immunity, and other complex factors impact our health, we truly see how inextricably linked our brains and bodies are. I am eager to help MIT scientists and engineers decode these links and make real headway in creating therapeutic strategies that result in longer, healthier lives.”

“This center marks a once-in-a-lifetime opportunity for labs like mine to conduct bold and risky studies into the complexities of brain-body connections,” says Anikeeva, who works at the intersection of materials science, electronics, and neurobiology. “The K. Lisa Yang Brain-Body Center will offer a pathbreaking, holistic approach that bridges multiple fields of study. I have no doubt that the center will result in revolutionary strides in our understanding of the inextricable bonds between the brain and the body’s peripheral organ systems, and a bold new way of thinking in how we approach human health overall.”

New MRI probe can reveal more of the brain’s inner workings

Anne Trafton |

Using a novel probe for functional magnetic resonance imaging (fMRI), MIT biological engineers have devised a way to monitor individual populations of neurons and reveal how they interact with each other.

Similar to how the gears of a clock interact in specific ways to turn the clock’s hands, different parts of the brain interact to perform a variety of tasks, such as generating behavior or interpreting the world around us. The new MRI probe could potentially allow scientists to map those networks of interactions.

“With regular fMRI, we see the action of all the gears at once. But with our new technique, we can pick up individual gears that are defined by their relationship to the other gears, and that’s critical for building up a picture of the mechanism of the brain,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.

Using this technique, which involves genetically targeting the MRI probe to specific populations of cells in animal models, the researchers were able to identify neural populations involved in a circuit that responds to rewarding stimuli. The new MRI probe could also enable studies of many other brain circuits, the researchers say.

Jasanoff, who is also an associate investigator at the McGovern Institute, is the senior author of the study, which appears today in Nature Neuroscience. The lead authors of the paper are recent MIT PhD recipient Souparno Ghosh and former MIT research scientist Nan Li.

Tracing connections

Traditional fMRI imaging measures changes to blood flow in the brain, as a proxy for neural activity. When neurons receive signals from other neurons, it triggers an influx of calcium, which causes a diffusible gas called nitric oxide to be released. Nitric oxide acts in part as a vasodilator that increases blood flow to the area.

Imaging calcium directly can offer a more precise picture of brain activity, but that type of imaging usually requires fluorescent chemicals and invasive procedures. The MIT team wanted to develop a method that could work across the brain without that type of invasiveness.

“If we want to figure out how brain-wide networks of cells and brain-wide mechanisms function, we need something that can be detected deep in tissue and preferably across the entire brain at once,” Jasanoff says. “The way that we chose to do that in this study was to essentially hijack the molecular basis of fMRI itself.”

The researchers created a genetic probe, delivered by viruses, that codes for a protein that sends out a signal whenever the neuron is active. This protein, which the researchers called NOSTIC (nitric oxide synthase for targeting image contrast), is an engineered form of an enzyme called nitric oxide synthase. The NOSTIC protein can detect elevated calcium levels that arise during neural activity; it then generates nitric oxide, leading to an artificial fMRI signal that arises only from cells that contain NOSTIC.

The probe is delivered by a virus that is injected into a particular site, after which it travels along axons of neurons that connect to that site. That way, the researchers can label every neural population that feeds into a particular location.

“When we use this virus to deliver our probe in this way, it causes the probe to be expressed in the cells that provide input to the location where we put the virus,” Jasanoff says. “Then, by performing functional imaging of those cells, we can start to measure what makes input to that region take place, or what types of input arrive at that region.”

Turning the gears

In the new study, the researchers used their probe to label populations of neurons that project to the striatum, a region that is involved in planning movement and responding to reward. In rats, they were able to determine which neural populations send input to the striatum during or immediately following a rewarding stimulus — in this case, deep brain stimulation of the lateral hypothalamus, a brain center that is involved in appetite and motivation, among other functions.

One question that researchers have had about deep brain stimulation of the lateral hypothalamus is how wide-ranging the effects are. In this study, the MIT team showed that several neural populations, located in regions including the motor cortex and the entorhinal cortex, which is involved in memory, send input into the striatum following deep brain stimulation.

“It’s not simply input from the site of the deep brain stimulation or from the cells that carry dopamine. There are these other components, both distally and locally, that shape the response, and we can put our finger on them because of the use of this probe,” Jasanoff says.

During these experiments, neurons also generate regular fMRI signals, so in order to distinguish the signals that are coming specifically from the genetically altered neurons, the researchers perform each experiment twice: once with the probe on, and once following treatment with a drug that inhibits the probe. By measuring the difference in fMRI activity between these two conditions, they can determine how much activity is present in probe-containing cells specifically.

The researchers now hope to use this approach, which they call hemogenetics, to study other networks in the brain, beginning with an effort to identify some of the regions that receive input from the striatum following deep brain stimulation.

“One of the things that’s exciting about the approach that we’re introducing is that you can imagine applying the same tool at many sites in the brain and piecing together a network of interlocking gears, which consist of these input and output relationships,” Jasanoff says. “This can lead to a broad perspective on how the brain works as an integrated whole, at the level of neural populations.”

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

Augmented: The journey of Hugh Herr

by Julie Pryor |

Augmented is a Nova PBS documentary that premiered in February 2022, featuring Hugh Herr, the co-director of the K. Lisa Yang Center for Bionics at MIT.

Follow the dramatic personal journey of Hugh Herr, a biophysicist working to create brain-controlled robotic limbs. At age 17, Herr’s legs were amputated after a climbing accident. Frustrated by the crude prosthetic limbs he was given, Herr set out to remedy their design, leading him to a career as an inventor of innovative prosthetic devices. Now, Herr is teaming up with an injured climber and a surgeon at a leading Boston hospital to test a new approach to surgical amputation that allows prosthetic limbs to move and feel like the real thing. Herr’s journey is a powerful tale of innovation and the inspiring story of a personal tragedy transformed into a life-long quest to help others.

Read more at PBS.org.