Research Area: Neurotechnology

expansion microscopy, bionic limbs, hydrogel fibers, magnetic nanodiscs, soft-bodied robots, protein engineering, molecular syringes, switchable fluorophores, stealthy probes, apps, MRI sensors, drug delivery systems

Ten years of bigger samples, better views

by Jennifer Michalowski |

Nearly 150 years ago, scientists began to imagine how information might flow through the brain based on the shapes of neurons they had seen under the microscopes of the time. With today’s imaging technologies, scientists can zoom in much further, seeing the tiny synapses through which neurons communicate with one another and even the molecules the cells use to relay their messages. These inside views can spark new ideas about how healthy brains work and reveal important changes that contribute to disease.

McGovern Institute Investigator Edward Boyden. Photo: Justin Knight

This sharper view of biology is not just about the advances that have made microscopes more powerful than ever before. Using methodology developed in the lab of McGovern investigator Edward Boyden, researchers around the world are imaging samples that have been swollen to as much as 20 times their original size so their finest features can be seen more clearly.

“It’s a very different way to do microscopy,” says Boyden, who is also a Howard Hughes Medical Institute investigator and a member of the Yang Tan Collective at MIT. “In contrast to the last 300 years of bioimaging, where you use a lens to magnify an image of light from an object, we physically magnify objects themselves.” Once a tissue is expanded, Boyden says, researchers can see more even with widely available, conventional microscopy hardware.

Boyden’s team introduced this approach, which they named expansion microscopy (ExM), in 2015. Since then, they have been refining the method and adding to its capabilities, while researchers at MIT and beyond deploy it to learn about life on the smallest of scales.

“It’s spreading very rapidly throughout biology and medicine,” Boyden says. “It’s being applied to kidney disease, the fruit fly brain, plant seeds, the microbiome, Alzheimer’s disease, viruses, and more.”

Origins of ExM 

To develop expansion microscopy, Boyden and his team turned to hydrogels: a material with remarkable water-absorbing properties that had already been put to practical use: it’s layered inside disposable diapers to keep babies dry. Boyden’s lab hypothesized that hydrogels could retain their structure while they absorbed hundreds of times their original weight in water, expanding the space between their chemical components as they swell.

After some experimentation, Boyden’s team settled on four key steps to enlarging tissue samples for better imaging. First, the tissue must be infused with a hydrogel. Components of the tissue, biomolecules, are anchored to the gel’s web-like matrix, linking them directly to the molecules that make up the gel. Then the tissue is chemically softened and water is added. As the hydrogel absorbs the water, it swells and the tissue expands, growing evenly so the relative positions of its components are preserved.

Boyden and graduate students Fei Chen and Paul Tillberg’s first report on expansion microscopy was published in the journal Science in 2015. In it, the team demonstrated that by spreading apart molecules that had been crowded inside cells, features that would have blurred together under a standard light microscope became separate and distinct. Light microscopes can discriminate between objects that are separated by about 300 nanometers—a limit imposed by the laws of physics. With expansion microscopy, Boyden’s group reported an effective resolution of about 70 nanometers, for a four-fold expansion.

Boyden says this is a level of clarity that biologists need. “Biology is fundamentally, in the end, a nanoscale science,” he says. “Biomolecules are nanoscale, and the interactions between biomolecules are over nanoscale distances. Many of the most important problems in biology and medicine involve nanoscale questions.” Several kinds of sophisticated microscopes, each with their own advantages and disadvantages, can bring this kind of detail to light. But those methods are costly and require specialized skills, making them inaccessible for most researchers. “Expansion microscopy democratizes nanoimaging,” Boyden says. “Now anybody can go look at the building blocks of life and how they relate to each other.”

Empowering scientists

Since Boyden’s team introduced expansion microscopy in 2015, research groups around the world have published hundreds of papers reporting on discoveries they have made using expansion microscopy. For neuroscientists, the technique has lit up the intricacies of elaborate neural circuits, exposed how particular proteins organize themselves at and across synapses to facilitate communication between neurons, and uncovered changes associated with aging and disease.

It has been equally empowering for studies beyond the brain. Sabrina Absalon uses expansion microscopy every week in her lab at Indiana University School of Medicine to study the malaria parasite, a single-celled organism packed with specialized structures that enable it to infect and live inside its hosts. The parasite is so small, most of those structures can’t be seen with ordinary light microscopy. “So as a cell biologist, I’m losing the biggest tool to infer protein function, organelle architecture, morphology, linked to function, and all those things–which is my eye,” she says. With expansion, she can not only see the organelles inside a malaria parasite, she can watch them assemble and follow what happens to them when the parasite divides. Understanding those processes, she says, could help drug developers find new ways to interfere with the parasite’s life cycle.

Longitudinally opened mosquito midguts prepared using MoTissU-ExM. Image: Sabrina Absalon

Absalon adds that the accessibility of expansion microscopy is particularly important in the field of parasitology, where a lot of research is happening in parts of the world where resources are limited. Workshops and training programs in Africa, South America, and Asia are ensuring the technology reaches scientists whose communities are directly impacted by malaria and other parasites. “Now they can get super-resolution imaging without very fancy equipment,” Absalon says.

Always Improving

Since 2015, Boyden’s interdisciplinary lab group has found a variety of creative ways to improve expansion microscopy and use it in new ways. Their standard technique today enables better labeling, bigger expansion factors, and higher resolution imaging. Cellular features less than 20 nanometers from one another can now be separated enough to appear distinct under a light microscope.

They’ve also adapted their protocols to work with a range of important sample types, from entire roundworms (popular among neuroscientists, developmental biologists, and other researchers) to clinical samples. In the latter regard, they’ve shown that expansion can help reveal subtle signs of disease, which could enable earlier or less costly diagnoses.

Originally, the group optimized its protocol for visualizing proteins inside cells, by labeling proteins of interest and anchoring them to the hydrogel prior to expansion. With a new way of processing samples, users can now restain their expanded samples with new labels for multiple rounds of imaging, so they can pinpoint the positions of dozens of different proteins in the same tissue. That means researchers can visualize how molecules are organized with respect to one another and how they might interact, or survey large sets of proteins to see, for example, what changes with disease.

Synaptic proteins and their associations to neuronal processes in the mouse primary somatosensory cortex imaged using expansion microscopy. Image: Boyden lab

But better views of proteins were just the beginning for expansion microscopy. “We want to see everything,” Boyden says. “We’d love to see every biomolecule there is, with precision down to atomic scale.” They’re not there yet—but with new probes and modified procedures, it’s now possible to see not just proteins, but also RNA and lipids in expanded tissue samples.

Labeling lipids, including those that form the membranes surrounding cells, means researchers can now see clear outlines of cells in expanded tissues. With the enhanced resolution afforded by expansion, even the slender projections of neurons can be traced through an image. Typically, researchers have relied on electron microscopy, which generates exquisitely detailed pictures but requires expensive equipment, to map the brain’s circuitry. “Now you can get images that look a lot like electron microscopy images, but on regular old light microscopes—the kind that everybody has access to,” Boyden says.

Boyden says expansion can be powerful in combination with other cutting-edge tools. When expanded samples are used with an ultra-fast imaging method developed by Eric Betzig, an HHMI investigator at the University of California, Berkeley, called lattice light-sheet microscopy, the entire brain of a fruit fly can be imaged at high resolution in just a few days. (See HHMI video below).

And when RNA molecules are anchored within a hydrogel network and then sequenced in place, scientists can see exactly where inside cells the instructions for building specific proteins are positioned, which Boyden’s team demonstrated in a collaboration with Harvard University geneticist George Church and then-MIT-professor Aviv Regev. “Expansion basically upgrades many other technologies’ resolutions,” Boyden says. “You’re doing mass-spec imaging, X-ray imaging, or Raman imaging? Expansion just improved your instrument.”

Expanding Possibilities

Ten years past the first demonstration of expansion microscopy’s power, Boyden and his team are committed to continuing to make expansion microscopy more powerful. “We want to optimize it for different kinds of problems, and making technologies faster, better, and cheaper is always important,” he says. But the future of expansion microscopy will be propelled by innovators outside the Boyden lab, too. “Expansion is not only easy to do, it’s easy to modify—so lots of other people are improving expansion in collaboration with us, or even on their own,” Boyden says.

Boyden points to a group led by Silvio Rizzoli at the University Medical Center Göttingen in Germany that, collaborating with Boyden, has adapted the expansion protocol to discern the physical shapes of proteins. At the Korea Advanced Institute of Science and Technology, researchers led by Jae-Byum Chang, a former postdoctoral researcher in Boyden’s group, have worked out how to expand entire bodies of mouse embryos and young zebrafish, collaborating with Boyden to set the stage for examining developmental processes and long-distance neural connections with a new level of detail. And mapping connections within the brain’s dense neural circuits could become easier with light-microscopy based connectomics, an approach developed by Johann Danzl and colleagues at the Institute of Science and Technology in Austria that takes advantage of both the high resolution and molecular information that expansion microscopy can reveal.

“The beauty of expansion is that it lets you see a biological system down to its smallest building blocks,” Boyden says.

His team is intent on pushing the method to its physical limits, and anticipates new opportunities for discovery as they do. “If you can map the brain or any biological system at the level of individual molecules, you might be able to see how they all work together as a network—how life really operates,” he says.

Seeing more in expansion microscopy

by Jennifer Michalowski |

In biology, seeing can lead to understanding, and researchers in Edward Boyden’s lab at MIT’s McGovern Institute are committed to bringing life into sharper focus. With a pair of new methods, they are expanding the capabilities of expansion microscopy—a high-resolution imaging technique the group introduced in 2015—so researchers everywhere can see more when they look at cells and tissues under a light microscope.

McGovern Institute Investigator Edward Boyden. Photo: Justin Knight

“We want to see everything, so we’re always trying to improve it,” says Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT.  “A snapshot of all life, down to its fundamental building blocks, is really the goal.” Boyden is also a Howard Hughes Medical Institute investigator and a member of the Yang Tan Collective at MIT.

With new ways of staining their samples and processing images, users of expansion microscopy can now see vivid outlines of the shapes of cells in their images and pinpoint the locations of many different proteins inside a single tissue sample with resolution that far exceeds that of conventional light microscopy. These advances, both reported in the journal Nature Communications, enable new ways of tracing the slender projections of neurons and visualizing spatial relationships between molecules that contribute to health and disease.

Expansion microscopy uses a water-absorbing hydrogel to physically expand biological tissues. After a tissue sample has been permeated by the hydrogel, it is hydrated. The hydrogel swells as it absorbs water, preserving the relative locations of molecules in the tissue as it gently pulls them away from one another. As a result, crowded cellular components appear separate and distinct when the expanded tissue is viewed under a light microscope. The approach, which can be performed using standard laboratory equipment, has made super-resolution imaging accessible to most research teams.

Since first developing expansion microscopy, Boyden and his team have continued to enhance the method—increasing its resolution, simplifying the procedure, devising new features, and integrating it with other tools.

Visualizing cell membranes

One of the team’s latest advances is a method called ultrastructural membrane expansion microscopy (umExM), which they described in the February 12 issue of Nature Communications. With it, biologists can use expansion microscopy to visualize the thin membranes that form the boundaries of cells and enclose the organelles inside them. These membranes, built mostly of molecules called lipids, have been notoriously difficult to densely label in intact tissues for imaging with light microscopy. Now, researchers can use umExM to study cellular ultrastructure and organization within tissues.

Tay Shin, a former graduate student in Boyden’s lab and a J. Douglas Tan Fellow in the Tan-Yang Center for Autism Research at MIT, led the development of umExM. “Our goal was very simple at first: Let’s label membranes in intact tissue, much like how an electron microscope uses osmium tetroxide to label membranes to visualize the membranes in tissue,” he says. “It turns out that it’s extremely hard to achieve this.”

The team first needed to design a label that would make the membranes in tissue samples visible under a light microscope. “We almost had to start from scratch,” Shin says. “We really had to think about the fundamental characteristics of the probe that is going to label the plasma membrane, and then think about how to incorporate them into expansion microscopy.” That meant engineering a molecule that would associate with the lipids that make up the membrane and link it to both the hydrogel used to expand the tissue sample and a fluorescent molecule for visibility.

After optimizing the expansion microscopy protocol for membrane visualization and extensively testing and improving potential probes, Shin found success one late night in the lab. He placed an expanded tissue sample on a microscope and saw sharp outlines of cells.

Traceability of umExM. 3D rendering of 20 manually traced and reconstructed myelinated axons in the corpus callosum. Image: Ed Boyden

Because of the high resolution enabled by expansion, the method allowed Boyden’s team to identify even the tiny dendrites that protrude from neurons and clearly see the long extensions of their slender axons. That kind of clarity could help researchers follow individual neurons’ paths within the densely interconnected networks of the brain, the researchers say.

Boyden calls tracing these neural processes “a top priority of our time in brain science.” Such tracing has traditionally relied heavily on electron microscopy, which requires specialized skills and expensive equipment. Shin says that because expansion microscopy uses a standard light microscope, it is far more accessible to laboratories worldwide.

Shin and Boyden point out that users of expansion microscopy can learn even more about their samples when they pair the new ability to reveal lipid membranes with fluorescent labels that show where specific proteins are located. “That’s important, because proteins do a lot of the work of the cell, but you want to know where they are with respect to the cell’s structure,” Boyden says.

One sample, many proteins

To that end, researchers no longer have to choose just a few proteins to see when they use expansion microscopy. With a new method called multiplexed expansion revealing (multiExR), users can now label and see more than 20 different proteins in a single sample. Biologists can use the method to visualize sets of proteins, see how they are organized with respect to one another, and generate new hypotheses about how they might interact.

A key to the new method, reported November 9, 2024, in Nature Communications, is the ability to repeatedly link fluorescently labeled antibodies to specific proteins in an expanded tissue sample, image them, then strip these away and use a new set of antibodies to reveal a new set of proteins. Postdoctoral fellow Jinyoung Kang fine-tuned each step of this process, assuring tissue samples stayed intact and the labeled proteins produced bright signals in each round of imaging.

After capturing many images of a single sample, Boyden’s team faced another challenge: how to ensure those images were in perfect alignment so they could be overlaid with one another, producing a final picture that showed the precise positions of all of the proteins that had been labeled and visualized one by one.

Expansion microscopy lets biologists visualize some of cells’ tiniest features—but to find the same features over and over again during multiple rounds of imaging, Boyden’s team first needed to home in on a larger structure. “These fields of view are really tiny, and you’re trying to find this really tiny field of view in a gel that’s actually become quite large once you’ve expanded it,” explains Margaret Schroeder, a graduate student in Boyden’s lab who, with Kang, led the development of multiExR.

“Here’s one of the most famous receptors in all of neuroscience, hiding out in one of the most famous molecular hallmarks of pathology in neuroscience.” – Ed Boyden

To navigate to the right spot every time, the team decided to label the blood vessels that pass through each tissue sample and use these as a guide. To enable precise alignment, certain fine details also needed to consistently appear in every image; for this, the team labeled several structural proteins. With these reference points and customized imaging processing software, the team was able to integrate all of their images of a sample into one, revealing how proteins that had been visualized separately were arranged relative to one another.

The team used multiExR to look at amyloid plaques—the aberrant protein clusters that notoriously develop in brains affected by Alzheimer’s disease. “We could look inside those amyloid plaques and ask, what’s inside of them? And because we can stain for many different proteins, we could do a high throughput exploration,” Boyden says. The team chose 23 different proteins to view in their images. The approach revealed some surprises, such as the presence of certain neurotransmitter receptors (AMPARs). “Here’s one of the most famous receptors in all of neuroscience, and there it is, hiding out in one of the most famous molecular hallmarks of pathology in neuroscience,” says Boyden. It’s unclear what role, if any, the receptors play in Alzheimer’s disease—but the finding illustrates how the ability to see more inside cells can expose unexpected aspects of biology and raise new questions for research.

Funding for this work came from MIT, Lisa Yang and Y. Eva Tan, John Doerr, the Open Philanthropy Project, the Howard Hughes Medical Institute, the US Army, Cancer Research UK, the New York Stem Cell Foundation, the National Institutes of Health, Lore McGovern, Good Ventures, Schmidt Futures. Samsung, MathWorks, the Collamore-Rogers Fellowship, the National Science Foundation, Alana Foundation USA, the Halis Family Foundation, Lester A. Gimpelson, Donald and Glenda Mattes, David B. Emmes, Thomas A. Stocky, Avni U. Shah, Kathleen Octavio, Good Ventures/Open Philanthropy, and the European Union’s Horizon 2020 program.

A new method makes high-resolution imaging more accessible

Anne Trafton |

A classical way to image nanoscale structures in cells is with high-powered, expensive super-resolution microscopes. As an alternative, MIT researchers have developed a way to expand tissue before imaging it — a technique that allows them to achieve nanoscale resolution with a conventional light microscope.

In the newest version of this technique, the researchers have made it possible to expand tissue 20-fold in a single step. This simple, inexpensive method could pave the way for nearly any biology lab to perform nanoscale imaging.

“This democratizes imaging,” says Laura Kiessling, the Novartis Professor of Chemistry at MIT and a member of the Broad Institute of MIT and Harvard and MIT’s Koch Institute for Integrative Cancer Research. “Without this method, if you want to see things with a high resolution, you have to use very expensive microscopes. What this new technique allows you to do is see things that you couldn’t normally see with standard microscopes. It drives down the cost of imaging because you can see nanoscale things without the need for a specialized facility.”

At the resolution achieved by this technique, which is around 20 nanometers, scientists can see organelles inside cells, as well as clusters of proteins.

“Twenty-fold expansion gets you into the realm that biological molecules operate in. The building blocks of life are nanoscale things: biomolecules, genes, and gene products,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT; a professor of biological engineering, media arts and sciences, and brain and cognitive sciences; a Howard Hughes Medical Institute investigator; and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research.

Boyden and Kiessling are the senior authors of the new study, which appears today in Nature Methods. MIT graduate student Shiwei Wang and Tay Won Shin PhD ’23 are the lead authors of the paper.

A single expansion

Boyden’s lab invented expansion microscopy in 2015. The technique requires embedding tissue into an absorbent polymer and breaking apart the proteins that normally hold tissue together. When water is added, the gel swells and pulls biomolecules apart from each other.

The original version of this technique, which expanded tissue about fourfold, allowed researchers to obtain images with a resolution of around 70 nanometers. In 2017, Boyden’s lab modified the process to include a second expansion step, achieving an overall 20-fold expansion. This enables even higher resolution, but the process is more complicated.

“We’ve developed several 20-fold expansion technologies in the past, but they require multiple expansion steps,” Boyden says. “If you could do that amount of expansion in a single step, that could simplify things quite a bit.”

With 20-fold expansion, researchers can get down to a resolution of about 20 nanometers, using a conventional light microscope. This allows them see cell structures like microtubules and mitochondria, as well as clusters of proteins.

In the new study, the researchers set out to perform 20-fold expansion with only a single step. This meant that they had to find a gel that was both extremely absorbent and mechanically stable, so that it wouldn’t fall apart when expanded 20-fold.

To achieve that, they used a gel assembled from N,N-dimethylacrylamide (DMAA) and sodium acrylate. Unlike previous expansion gels that rely on adding another molecule to form crosslinks between the polymer strands, this gel forms crosslinks spontaneously and exhibits strong mechanical properties. Such gel components previously had been used in expansion microscopy protocols, but the resulting gels could expand only about tenfold. The MIT team optimized the gel and the polymerization process to make the gel more robust, and to allow for 20-fold expansion.

To further stabilize the gel and enhance its reproducibility, the researchers removed oxygen from the polymer solution prior to gelation, which prevents side reactions that interfere with crosslinking. This step requires running nitrogen gas through the polymer solution, which replaces most of the oxygen in the system.

Once the gel is formed, select bonds in the proteins that hold the tissue together are broken and water is added to make the gel expand. After the expansion is performed, target proteins in tissue can be labeled and imaged.

“This approach may require more sample preparation compared to other super-resolution techniques, but it’s much simpler when it comes to the actual imaging process, especially for 3D imaging,” Shin says. “We document the step-by-step protocol in the manuscript so that readers can go through it easily.”

Imaging tiny structures

Using this technique, the researchers were able to image many tiny structures within brain cells, including structures called synaptic nanocolumns. These are clusters of proteins that are arranged in a specific way at neuronal synapses, allowing neurons to communicate with each other via secretion of neurotransmitters such as dopamine.

In studies of cancer cells, the researchers also imaged microtubules — hollow tubes that help give cells their structure and play important roles in cell division. They were also able to see mitochondria (organelles that generate energy) and even the organization of individual nuclear pore complexes (clusters of proteins that control access to the cell nucleus).

Wang is now using this technique to image carbohydrates known as glycans, which are found on cell surfaces and help control cells’ interactions with their environment. This method could also be used to image tumor cells, allowing scientists to glimpse how proteins are organized within those cells, much more easily than has previously been possible.

The researchers envision that any biology lab should be able to use this technique at a low cost since it relies on standard, off-the-shelf chemicals and common equipment such confocal microscopes and glove bags, which most labs already have or can easily access.

“Our hope is that with this new technology, any conventional biology lab can use this protocol with their existing microscopes, allowing them to approach resolution that can only be achieved with very specialized and costly state-of-the-art microscopes,” Wang says.

The research was funded, in part, by the U.S. National Institutes of Health, an MIT Presidential Graduate Fellowship, U.S. National Science Foundation Graduate Research Fellowship grants, Open Philanthropy, Good Ventures, the Howard Hughes Medical Institute, Lisa Yang, Ashar Aziz, and the European Research Council.

Tiny magnetic discs offer remote brain stimulation without transgenes

by David L. Chandler |

Novel magnetic nanodiscs could provide a much less invasive way of stimulating parts of the brain, paving the way for stimulation therapies without implants or genetic modification, MIT researchers report.

The scientists envision that the tiny discs, which are about 250 nanometers across (about 1/500 the width of a human hair), would be injected directly into the desired location in the brain. From there, they could be activated at any time simply by applying a magnetic field outside the body. The new particles could quickly find applications in biomedical research, and eventually, after sufficient testing, might be applied to clinical uses.

The development of these nanoparticles is described in the journal Nature Nanotechnology, in a paper by Polina Anikeeva, a professor in MIT’s departments of Materials Science and Engineering and Brain and Cognitive Sciences, graduate student Ye Ji Kim, and 17 others at MIT and in Germany.

Deep brain stimulation (DBS) is a common clinical procedure that uses electrodes implanted in the target brain regions to treat symptoms of neurological and psychiatric conditions such as Parkinson’s disease and obsessive-compulsive disorder. Despite its efficacy, the surgical difficulty and clinical complications associated with DBS limit the number of cases where such an invasive procedure is warranted. The new nanodiscs could provide a much more benign way of achieving the same results.

Over the past decade other implant-free methods of producing brain stimulation have been developed. However, these approaches were often limited by their spatial resolution or ability to target deep regions. For the past decade, Anikeeva’s Bioelectronics group as well as others in the field used magnetic nanomaterials to transduce remote magnetic signals into brain stimulation. However, these magnetic methods relied on genetic modifications and can’t be used in humans.

Since all nerve cells are sensitive to electrical signals, Kim, a graduate student in Anikeeva’s group, hypothesized that a magnetoelectric nanomaterial that can efficiently convert magnetization into electrical potential could offer a path toward remote magnetic brain stimulation. Creating a nanoscale magnetoelectric material was, however, a formidable challenge.

Kim synthesized novel magnetoelectric nanodiscs and collaborated with Noah Kent, a postdoc in Anikeeva’s lab with a background in physics who is a second author of the study, to understand the properties of these particles.

The structure of the new nanodiscs consists of a two-layer magnetic core and a piezoelectric shell. The magnetic core is magnetostrictive, which means it changes shape when magnetized. This deformation then induces strain in the piezoelectric shell which produces a varying electrical polarization. Through the combination of the two effects, these composite particles can deliver electrical pulses to neurons when exposed to magnetic fields.

One key to the discs’ effectiveness is their disc shape. Previous attempts to use magnetic nanoparticles had used spherical particles, but the magnetoelectric effect was very weak, says Kim. This anisotropy enhances magnetostriction by over a 1000-fold, adds Kent.

The team first added their nanodiscs to cultured neurons, which allowed then to activate these cells on demand with short pulses of magnetic field. This stimulation did not require any genetic modification.

They then injected small droplets of magnetoelectric nanodiscs solution into specific regions of the brains of mice. Then, simply turning on a relatively weak electromagnet nearby triggered the particles to release a tiny jolt of electricity in that brain region. The stimulation could be switched on and off remotely by the switching of the electromagnet. That electrical stimulation “had an impact on neuron activity and on behavior,” Kim says.

The team found that the magnetoelectric nanodiscs could stimulate a deep brain region, the ventral tegmental area, that is associated with feelings of reward.

The team also stimulated another brain area, the subthalamic nucleus, associated with motor control. “This is the region where electrodes typically get implanted to manage Parkinson’s disease,” Kim explains. The researchers were able to successfully demonstrate the modulation of motor control through the particles. Specifically, by injecting nanodiscs only in one hemisphere, the researchers could induce rotations in healthy mice by applying magnetic field.

The nanodiscs could trigger the neuronal activity comparable with conventional implanted electrodes delivering mild electrical stimulation. The authors achieved subsecond temporal precision for neural stimulation with their method yet observed significantly reduced foreign body responses as compared to the electrodes, potentially allowing for even safer deep brain stimulation.

The multilayered chemical composition and physical shape and size of the new multilayered nanodiscs is what made precise stimulation possible.

While the researchers successfully increased the magnetostrictive effect, the second part of the process, converting the magnetic effect into an electrical output, still needs more work, Anikeeva says. While the magnetic response was a thousand times greater, the conversion to an electric impulse was only four times greater than with conventional spherical particles.

“This massive enhancement of a thousand times didn’t completely translate into the magnetoelectric enhancement,” says Kim. “That’s where a lot of the future work will be focused, on making sure that the thousand times amplification in magnetostriction can be converted into a thousand times amplification in the magnetoelectric coupling.”

What the team found, in terms of the way the particles’ shapes affects their magnetostriction, was quite unexpected. “It’s kind of a new thing that just appeared when we tried to figure out why these particles worked so well,” says Kent.

Anikeeva adds: “Yes, it’s a record-breaking particle, but it’s not as record-breaking as it could be.” That remains a topic for further work, but the team has ideas about how to make further progress.

While these nanodiscs could in principle already be applied to basic research using animal models, to translate them to clinical use in humans would require several more steps, including large-scale safety studies, “which is something academic researchers are not necessarily most well-positioned to do,” Anikeeva says. “When we find that these particles are really useful in a particular clinical context, then we imagine that there will be a pathway for them to undergo more rigorous large animal safety studies.”

The team included researchers affiliated with MIT’s departments of Materials Science and Engineering, Electrical Engineering and Computer Science, Chemistry, and Brain and Cognitive Sciences; the Research Laboratory of Electronics; the McGovern Institute for Brain Research; and the Koch Institute for Integrative Cancer Research; and from the Friedrich-Alexander University of Erlangen, Germany. The work was supported, in part, by the National Institutes of Health, the National Center for Complementary and Integrative Health, the National Institute for Neurological Disorders and Stroke, the McGovern Institute for Brain Research, and the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience.

Polina Anikeeva named 2024 Blavatnik Award Finalist

by Julie Pryor |

The Blavatnik Family Foundation and New York Academy of Sciences has announced the honorees of the 2024 Blavatnik National Awards, and McGovern Investigator Polina Anikeeva is among five finalists in the category of physical sciences and engineering.

Anikeeva, the Matoula S. Salapatas Professor in Materials Science and Engineering at MIT, works at the intersection of materials science, electronics, and neurobiology to improve our understanding of brain-body communication. She is head of MIT’s Materials Science and Engineering Department, and is also a professor of brain and cognitive sciences, director of the K. Lisa Yang Brain-Body Center, and associate director of the Research Laboratory of Electronics. Anikeeva’s lab has developed ultrathin, flexible fibers that probe the flow of information between the brain and peripheral organs in the body. Her ultimate goal is to develop novel technologies to achieve healthy minds in healthy bodies.

The Blavatnik National Awards for Young Scientists is the largest unrestricted scientific prize offered to America’s most promising, faculty-level scientific researchers under 42. The 2024 Blavatnik National Awards received 331 nominations from 172 institutions in 43 US states and selected three women scientists as laureates (Cigall Kadoch, Dana Farber Cancer Institute; Markita del Carpio Landry, UC Berkeley; and Britney Schmidt, Cornell University). An additional 15 finalists, including two from MIT: Anikeeva and Yogesh Surendranath will also receive monetary prizes.

“On behalf of the Blavatnik Family Foundation, I congratulate this year’s outstanding laureates and finalists for their exceptional research. They are among the preeminent leaders of the next generation of scientific innovation and discovery,” said Len Blavatnik, founder of Access Industries and the Blavatnik Family Foundation and a member of the President’s Council of The New York Academy of Sciences.

The Blavatnik National Awards for Young Scientists will celebrate the 2024 laureates and finalists in a gala ceremony on October 1, 2024, at the American Museum of Natural History in New York.

Polina Anikeeva named head of the Department of Materials Science and Engineering

by Mary Beth Gallagher | School of Engineering |

Polina Anikeeva PhD ’09, the Matoula S. Salapatas Professor at MIT, has been named the new head of MIT’s Department of Materials Science and Engineering (DMSE), effective July 1.

“Professor Anikeeva’s passion and dedication as both a researcher and educator, as well as her impressive network of connections across the wider Institute, make her incredibly well suited to lead DMSE,” says Anantha Chandrakasan, chief innovation and strategy officer, dean of engineering, and Vannevar Bush Professor of Electrical Engineering and Computer Science.

In addition to serving as a professor in DMSE, Anikeeva is a professor of brain and cognitive sciences, director of the K. Lisa Yang Brain-Body Center, a member of the McGovern Institute for Brain Research, and associate director of MIT’s Research Laboratory of Electronics.

Anikeeva leads the MIT Bioelectronics Group, which focuses on developing magnetic and optoelectronic tools to study neural communication in health and disease. Her team applies magnetic nanomaterials and fiber-based devices to reveal physiological processes underlying brain-organ communication, with particular focus on gut-brain circuits. Their goal is to develop minimally invasive treatments for a range of neurological, psychiatric, and metabolic conditions.

Anikeeva’s research sits at the intersection of materials chemistry, electronics, and neurobiology. By bridging these disciplines, Anikeeva and her team are deepening our understanding and treatment of complex neurological disorders. Her approach has led to the creation of optoelectronic and magnetic devices that can record neural activity and stimulate neurons during behavioral studies.

Throughout her career, Anikeeva has been recognized with numerous awards for her groundbreaking research. Her honors include receiving an NSF CAREER Award, DARPA Young Faculty Award, and the Pioneer Award from the NIH’s High-Risk, High-Reward Research Program. MIT Technology Review named her one of the 35 Innovators Under 35 and the Vilcek Foundation awarded her the Prize for Creative Promise in Biomedical Science.

Her impact extends beyond the laboratory and into the classroom, where her dedication to education has earned her the Junior Bose Teaching Award, the MacVicar Faculty Fellowship, and an MITx Prize for Teaching and Learning in MOOCs. Her entrepreneurial spirit was acknowledged with a $100,000 prize in the inaugural MIT Faculty Founders Initiative Prize Competition, recognizing her pioneering work in neuroprosthetics.

In 2023, Anikeeva co-founded Neurobionics Inc., which develops flexible fibers that can interface with the brain — opening new opportunities for sensing and therapeutics. The team has presented their technologies at MIT delta v Demo Day and won $50,000 worth of lab space at the LabCentral Ignite Golden Ticket pitch competition. Anikeeva serves as the company’s scientific advisor.

Anikeeva earned her bachelor’s degree in physics at St. Petersburg State Polytechnic University in Russia. She continued her education at MIT, where she received her PhD in materials science and engineering. Vladimir Bulović, director of MIT.nano and the Fariborz Maseeh Chair in Emerging Technology, served as Anikeeva’s doctoral advisor. After completing a postdoctoral fellowship at Stanford University, working on devices for optical stimulation and recording of neural activity, Anikeeva returned to MIT as a faculty member in 2011.

Anikeeva succeeds Caroline Ross, the Ford Professor of Engineering, who has served as interim department head since August 2023.

“Thanks to Professor Ross’s steadfast leadership, DMSE has continued to thrive during this period of transition. I’m incredibly grateful for her many contributions and long-standing commitment to strengthening the DMSE community,” adds Chandrakasan.

A prosthesis driven by the nervous system helps people with amputation walk naturally

Anne Trafton |

State-of-the-art prosthetic limbs can help people with amputations achieve a natural walking gait, but they don’t give the user full neural control over the limb. Instead, they rely on robotic sensors and controllers that move the limb using predefined gait algorithms.

Using a new type of surgical intervention and neuroprosthetic interface, MIT researchers, in collaboration with colleagues from Brigham and Women’s Hospital, have shown that a natural walking gait is achievable using a prosthetic leg fully driven by the body’s own nervous system. The surgical amputation procedure reconnects muscles in the residual limb, which allows patients to receive “proprioceptive” feedback about where their prosthetic limb is in space.

In a study of seven patients who had this surgery, the MIT team found that they were able to walk faster, avoid obstacles, and climb stairs much more naturally than people with a traditional amputation.

“This is the first prosthetic study in history that shows a leg prosthesis under full neural modulation, where a biomimetic gait emerges. No one has been able to show this level of brain control that produces a natural gait, where the human’s nervous system is controlling the movement, not a robotic control algorithm,” says Hugh Herr, a professor of media arts and sciences, co-director of the K. Lisa Yang Center for Bionics at MIT, an associate member of MIT’s McGovern Institute for Brain Research, and the senior author of the new study.

Patients also experienced less pain and less muscle atrophy following this surgery, which is known as the agonist-antagonist myoneural interface (AMI). So far, about 60 patients around the world have received this type of surgery, which can also be done for people with arm amputations.

Hyungeun Song, a postdoc in MIT’s Media Lab, is the lead author of the paper, which appears today in Nature Medicine.

Sensory feedback

Most limb movement is controlled by pairs of muscles that take turns stretching and contracting. During a traditional below-the-knee amputation, the interactions of these paired muscles are disrupted. This makes it very difficult for the nervous system to sense the position of a muscle and how fast it’s contracting — sensory information that is critical for the brain to decide how to move the limb.

People with this kind of amputation may have trouble controlling their prosthetic limb because they can’t accurately sense where the limb is in space. Instead, they rely on robotic controllers built into the prosthetic limb. These limbs also include sensors that can detect and adjust to slopes and obstacles.

To try to help people achieve a natural gait under full nervous system control, Herr and his colleagues began developing the AMI surgery several years ago. Instead of severing natural agonist-antagonist muscle interactions, they connect the two ends of the muscles so that they still dynamically communicate with each other within the residual limb. This surgery can be done during a primary amputation, or the muscles can be reconnected after the initial amputation as part of a revision procedure.

“With the AMI amputation procedure, to the greatest extent possible, we attempt to connect native agonists to native antagonists in a physiological way so that after amputation, a person can move their full phantom limb with physiologic levels of proprioception and range of movement,” Herr says.

In a 2021 study, Herr’s lab found that patients who had this surgery were able to more precisely control the muscles of their amputated limb, and that those muscles produced electrical signals similar to those from their intact limb.

After those encouraging results, the researchers set out to explore whether those electrical signals could generate commands for a prosthetic limb and at the same time give the user feedback about the limb’s position in space. The person wearing the prosthetic limb could then use that proprioceptive feedback to volitionally adjust their gait as needed.

In the new Nature Medicine study, the MIT team found this sensory feedback did indeed translate into a smooth, near-natural ability to walk and navigate obstacles.

“Because of the AMI neuroprosthetic interface, we were able to boost that neural signaling, preserving as much as we could. This was able to restore a person’s neural capability to continuously and directly control the full gait, across different walking speeds, stairs, slopes, even going over obstacles,” Song says.

A natural gait

For this study, the researchers compared seven people who had the AMI surgery with seven who had traditional below-the-knee amputations. All of the subjects used the same type of bionic limb: a prosthesis with a powered ankle as well as electrodes that can sense electromyography (EMG) signals from the tibialis anterior the gastrocnemius muscles. These signals are fed into a robotic controller that helps the prosthesis calculate how much to bend the ankle, how much torque to apply, or how much power to deliver.

The researchers tested the subjects in several different situations: level-ground walking across a 10-meter pathway, walking up a slope, walking down a ramp, walking up and down stairs, and walking on a level surface while avoiding obstacles.

In all of these tasks, the people with the AMI neuroprosthetic interface were able to walk faster — at about the same rate as people without amputations — and navigate around obstacles more easily. They also showed more natural movements, such as pointing the toes of the prosthesis upward while going up stairs or stepping over an obstacle, and they were better able to coordinate the movements of their prosthetic limb and their intact limb. They were also able to push off the ground with the same amount of force as someone without an amputation.

“With the AMI cohort, we saw natural biomimetic behaviors emerge,” Herr says. “The cohort that didn’t have the AMI, they were able to walk, but the prosthetic movements weren’t natural, and their movements were generally slower.”

These natural behaviors emerged even though the amount of sensory feedback provided by the AMI was less than 20 percent of what would normally be received in people without an amputation.

“One of the main findings here is that a small increase in neural feedback from your amputated limb can restore significant bionic neural controllability, to a point where you allow people to directly neurally control the speed of walking, adapt to different terrain, and avoid obstacles,” Song says.

“This work represents yet another step in us demonstrating what is possible in terms of restoring function in patients who suffer from severe limb injury. It is through collaborative efforts such as this that we are able to make transformational progress in patient care,” says Matthew Carty, a surgeon at Brigham and Women’s Hospital and associate professor at Harvard Medical School, who is also an author of the paper.

Enabling neural control by the person using the limb is a step toward Herr’s lab’s goal of “rebuilding human bodies,” rather than having people rely on ever more sophisticated robotic controllers and sensors — tools that are powerful but do not feel like part of the user’s body.

“The problem with that long-term approach is that the user would never feel embodied with their prosthesis. They would never view the prosthesis as part of their body, part of self,” Herr says. “The approach we’re taking is trying to comprehensively connect the brain of the human to the electromechanics.”

The research was funded by the MIT K. Lisa Yang Center for Bionics and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

MIT scientists learn how to control muscles with light

Anne Trafton |

For people with paralysis or amputation, neuroprosthetic systems that artificially stimulate muscle contraction with electrical current can help them regain limb function. However, despite many years of research, this type of prosthesis is not widely used because it leads to rapid muscle fatigue and poor control.

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

MIT researchers have developed a new approach that they hope could someday offer better muscle control with less fatigue. Instead of using electricity to stimulate muscles, they used light. In a study in mice, the researchers showed that this optogenetic technique offers more precise muscle control, along with a dramatic decrease in fatigue.

“It turns out that by using light, through optogenetics, one can control muscle more naturally. In terms of clinical application, this type of interface could have very broad utility,” 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.

Optogenetics is a method based on genetically engineering cells to express light-sensitive proteins, which allows researchers to control activity of those cells by exposing them to light. This approach is currently not feasible in humans, but Herr, MIT graduate student Guillermo Herrera-Arcos, and their colleagues at the K. Lisa Yang Center for Bionics are now working on ways to deliver light-sensitive proteins safely and effectively into human tissue.

Herr is the senior author of the study, which appears today in Science Robotics. Herrera-Arcos is the lead author of the paper.

Optogenetic control

For decades, researchers have been exploring the use of functional electrical stimulation (FES) to control muscles in the body. This method involves implanting electrodes that stimulate nerve fibers, causing a muscle to contract. However, this stimulation tends to activate the entire muscle at once, which is not the way that the human body naturally controls muscle contraction.

“Humans have this incredible control fidelity that is achieved by a natural recruitment of the muscle, where small motor units, then moderate-sized, then large motor units are recruited, in that order, as signal strength is increased,” Herr says. “With FES, when you artificially blast the muscle with electricity, the largest units are recruited first. So, as you increase signal, you get no force at the beginning, and then suddenly you get too much force.”

This large force not only makes it harder to achieve fine muscle control, it also wears out the muscle quickly, within five or 10 minutes.

The MIT team wanted to see if they could replace that entire interface with something different. Instead of electrodes, they decided to try controlling muscle contraction using optical molecular machines via optogenetics.

Two scientists in the lab.
“This could lead to a minimally invasive strategy that would change the game in terms of clinical care for persons suffering from limb pathology,” Hugh Herr says, pictured on left next to Herrera-Arcos.

Using mice as an animal model, the researchers compared the amount of muscle force they could generate using the traditional FES approach with forces generated by their optogenetic method. For the optogenetic studies, they used mice that had already been genetically engineered to express a light-sensitive protein called channelrhodopsin-2. They implanted a small light source near the tibial nerve, which controls muscles of the lower leg.

The researchers measured muscle force as they gradually increased the amount of light stimulation, and found that, unlike FES stimulation, optogenetic control produced a steady, gradual increase in contraction of the muscle.

“As we change the optical stimulation that we deliver to the nerve, we can proportionally, in an almost linear way, control the force of the muscle. This is similar to how the signals from our brain control our muscles. Because of this, it becomes easier to control the muscle compared with electrical stimulation,” Herrera-Arcos says.

Fatigue resistance

Using data from those experiments, the researchers created a mathematical model of optogenetic muscle control. This model relates the amount of light going into the system to the output of the muscle (how much force is generated).

This mathematical model allowed the researchers to design a closed-loop controller. In this type of system, the controller delivers a stimulatory signal, and after the muscle contracts, a sensor can detect how much force the muscle is exerting. This information is sent back to the controller, which calculates if, and how much, the light stimulation needs to be adjusted to reach the desired force.

Using this type of control, the researchers found that muscles could be stimulated for more than an hour before fatiguing, while muscles became fatigued after only 15 minutes using FES stimulation.

One hurdle the researchers are now working to overcome is how to safely deliver light-sensitive proteins into human tissue. Several years ago, Herr’s lab reported that in rats, these proteins can trigger an immune response that inactivates the proteins and could also lead to muscle atrophy and cell death.

“A key objective of the K. Lisa Yang Center for Bionics is to solve that problem,” Herr says. “A multipronged effort is underway to design new light-sensitive proteins, and strategies to deliver them, without triggering an immune response.”

As additional steps toward reaching human patients, Herr’s lab is also working on new sensors that can be used to measure muscle force and length, as well as new ways to implant the light source. If successful, the researchers hope their strategy could benefit people who have experienced strokes, limb amputation, and spinal cord injuries, as well as others who have impaired ability to control their limbs.

“This could lead to a minimally invasive strategy that would change the game in terms of clinical care for persons suffering from limb pathology,” Herr says.

The research was funded by the K. Lisa Yang Center for Bionics at MIT.

Reevaluating an approach to functional brain imaging

by Jennifer Michalowski |

A new way of imaging the brain with magnetic resonance imaging (MRI) does not directly detect neural activity as originally reported, according to scientists at MIT’s McGovern Institute. The method, first described in 2022, generated excitement within the neuroscience community as a potentially transformative approach. But a study from the lab of McGovern Associate Investigator Alan Jasanoff, reported March 27, 2024, in the journal Science Advances, demonstrates that MRI signals produced by the new method are generated in large part by the imaging process itself, not neuronal activity.

A man stands with his arms crossed in front of a board with mathematical equations written on it.
Alan Jasanoff, associate member of the McGovern Institute, and a professor of brain and cognitive sciences, biological engineering, and nuclear science and engineering at MIT. Photo: Justin Knight

Jasanoff explains that having a noninvasive means of seeing neuronal activity in the brain is a long-sought goal for neuroscientists. The functional MRI methods that researchers currently use to monitor brain activity don’t actually detect neural signaling. Instead, they use blood flow changes triggered by brain activity as a proxy. This reveals which parts of the brain are engaged during imaging, but it cannot pinpoint neural activity to precise locations, and it is too slow to truly track neurons’ rapid-fire communications.

So when a team of scientists reported in Science a new MRI method called DIANA, for “direct imaging of neuronal activity,” neuroscientists paid attention. The authors claimed that DIANA detected MRI signals in the brain that corresponded to the electrical signals of neurons, and that it acquired signals far faster than the methods now used for functional MRI.

“Everyone wants this,” Jasanoff says. “If we could look at the whole brain and follow its activity with millisecond precision and know that all the signals that we’re seeing have to do with cellular activity, this would be just wonderful. It could tell us all kinds of things about how the brain works and what goes wrong in disease.”

Jasanoff adds that from the initial report, it was not clear what brain changes DIANA was detecting to produce such a rapid readout of neural activity. Curious, he and his team began to experiment with the method. “We wanted to reproduce it, and we wanted to understand how it worked,” he says.

Decoding DIANA

Recreating the MRI procedure reported by DIANA’s developers, postdoctoral researcher Valerie Doan Phi Van imaged the brain of a rat as an electric stimulus was delivered to one paw. Phi Van says she was excited to see an MRI signal appear in the brain’s sensory cortex, exactly when and where neurons were expected to respond to the sensation on the paw. “I was able to reproduce it,” she says. “I could see the signal.”

With further tests of the system, however, her enthusiasm waned. To investigate the source of the signal, she disconnected the device used to stimulate the animal’s paw, then repeated the imaging. Again, signals showed up in the sensory processing part of the brain. But this time, there was no reason for neurons in that area to be activated. In fact, Phi Van found, the MRI produced the same kinds of signals when the animal inside the scanner was replaced with a tube of water. It was clear DIANA’s functional signals were not arising from neural activity.

Phi Van traced the source of the specious signals to the pulse program that directs DIANA’s imaging process, detailing the sequence of steps the MRI scanner uses to collect data. Embedded within DIANA’s pulse program was a trigger for the device that delivers sensory input to the animal inside the scanner. That synchronizes the two processes, so the stimulation occurs at a precise moment during data acquisition. That trigger appeared to be causing signals that DIANA’s developers had concluded indicated neural activity.

It was clear DIANA’s functional signals were not arising from neural activity.

Phi Van altered the pulse program, changing the way the stimulator was triggered. Using the updated program, the MRI scanner detected no functional signal in the brain in response to the same paw stimulation that had produced a signal before. “If you take this part of the code out, then the signal will also be gone. So that means the signal we see is an artifact of the trigger,” she says.

Jasanoff and Phi Van went on to find reasons why other researchers have struggled to reproduce the results of the original DIANA report, noting that the trigger-generated signals can disappear with slight variations in the imaging process. With their postdoctoral colleague Sajal Sen, they also found evidence that cellular changes that DIANA’s developers had proposed might give rise to a functional MRI signal were not related to neuronal activity.

Jasanoff and Phi Van say it was important to share their findings with the research community, particularly as efforts continue to develop new neuroimaging methods. “If people want to try to repeat any part of the study or implement any kind of approach like this, they have to avoid falling into these pits,” Jasanoff says. He adds that they admire the authors of the original study for their ambition: “The community needs scientists who are willing to take risks to move the field ahead.”

Beyond the brain

by Jennifer Michalowski |

This story also appears in the Spring 2024 issue of BrainScan.

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Like many people, graduate student Guillermo Herrera-Arcos found himself working from home in the spring of 2020. Surrounded by equipment he’d hastily borrowed from the lab, he began testing electrical components he would need to control muscles in a new way. If it worked, he and colleagues in Hugh Herr’s lab might have found a promising strategy for restoring movement when signals from the brain fail to reach the muscles, such as after a spinal cord injury or stroke.

Man holds a fiber that is illuminated with blue light at its tip.
Guillermo Herrera-Arcos, a graduate student in Hugh Herr’s lab, is developing an optical technology with the potential to restore movement in people with spinal cord injury or stroke. Photo: Steph Stevens

Herrera-Arcos and Herr’s work is one way McGovern neuroscientists are working at the interface of brain and machine. Such work aims to enable better ways of understanding and treating injury and disease, offering scientists tools to manipulate neural signaling as well as to replace its function when it is lost.

Restoring movement

The system Herrera-Arcos and Herr were developing wouldn’t be the first to bypass the brain to move muscles. Neuroprosthetic devices that use electricity to stimulate muscle-activating motor neurons are sometimes used during rehabilitation from an injury, helping patients maintain muscle mass when they can’t use their muscles on their own. But existing neuroprostheses lack the precision of the body’s natural movement system. They send all-or-nothing signals that quickly tire muscles out.

TWo men looking at a computer screen, one points to the image on the screen.
Hugh Herr (left) and graduate student Guillermo Herrera-Arco at work in the lab. Photo: Steph Stevens

Researchers attribute that fatigue to an unnatural recruitment of neurons and muscle fibers. Electrical signals go straight to the largest, most powerful components of the system, even when smaller units could do the job. “You turn up the stimulus and you get no force, and then suddenly, you get too much force. And then fatigue, a lack of controllability, and so on,” Herr explains. The nervous system, in contrast, calls first on small motor units and recruits larger ones only when needed to generate more force.

Optical solution

In hopes of recreating this strategic pattern of muscle activation, Herr and Herrera-Arcos turned to a technique pioneered by McGovern Investigator Edward Boyden that has become common research: controlling neural activity with light. To put neurons under their control, researchers equip them with light-sensitive proteins. The cells can then be switched on or off within milliseconds using an optic fiber.

When a return to the lab enabled Herr and Herrera-Arcos to test their idea, they were thrilled with the results. Using light to switch on motor neurons and stimulate a single muscle in mice, they recreated the nervous system’s natural muscle activation pattern. Consequently, fatigue did not set in nearly as quickly as it would with an electrically-activated system. Herrera-Arcos says he set out to measure the force generated by the muscle and how long it took to fatigue, and he had to keep extending his experiments: After an hour of light stimulation, it was still going strong.

To optimize the force generated by the system, the researchers used feedback from the muscle to modulate the intensity of the neuron-activating light. Their success suggests this type of closed-loop system could enable fatigue-resistant neuroprostheses for muscle control.

“The field has been struggling for many decades with the challenge of how to control living muscle tissue,” Herr says. “So the idea that this could be solved is very, very exciting.”

There’s work to be done to translate what the team has learned into practical neuroprosthetics for people who need them. To use light to stimulate human motor neurons, light-sensitive proteins will need to be delivered to those cells. Figuring out how to do that safely is a high priority at the K. Lisa Yang Center for Bionics, which Herr co-directs with Boyden, and might lead to better ways of obtaining tactile and proprioceptive feedback from prosthetic limbs, as well as to control muscles for the restoration of natural movements after spinal cord injury. “It would be a game changer for a number of conditions,” Herr says.

Gut-brain connection

While Herr’s team works where the nervous system meets the muscle, researchers in Polina Anikeeva’s lab are exploring the brain’s relationship with an often-overlooked part of the nervous system — the hundreds of millions of neurons in the gut.

“Classically, when we think of brain function in neuroscience, it is always studied in the framework of how the brain interacts with the surrounding environment and how it integrates different stimuli,” says Atharva Sahasrabudhe, a graduate student in the group. “But the brain does not function in a vacuum. It’s constantly getting and integrating signals from the peripheral organs.”

Man smiles at camera while holding up tiny devices.
Atharva Sahasrabudhe holds some of the fiber technology he developed in the Anikeeva lab. Photo: Steph Stevens

The nervous system has a particularly pronounced presence in the gut. Neurons embedded within the walls of the gastrointestinal (GI) tract monitor local conditions and relay information to the brain. This mind-body connection may help explain the GI symptoms associated with some brain-related conditions, including Parkinson’s disease, mood disorders, and autism. Researchers have yet to untangle whether GI symptoms help drive these conditions, are a consequence of them, or are coincidental. Either way, Anikeeva says, “if there is a GI connection, maybe we can tap into this connection to improve the quality of life of affected individuals.”

Flexible fibers

At the K. Lisa Yang Brain-Body Center that Anikeeva directs, studying how the gut communicates with the brain is a high priority. But most of neuroscientists’ tools are designed specifically to investigate the brain. To explore new territory, Sahasrabudhe devised a device that is compatible with the long and twisty GI tract of a mouse.

The new tool is a slender, flexible fiber equipped with light emitters for activating subsets of cells and tiny channels for delivering nutrients or drugs. To access neurons dispersed throughout the GI tract, its wirelessly controlled components are embedded along its length. A more rigid probe at one end of the device is designed to monitor and manipulate neural activity in the brain, so researchers can follow the nervous system’s swift communications across the gut-brain axis.

Scientists on Anikeeva’s team are deploying the device to investigate how gut-brain communications contribute to several conditions. Postdoctoral researcher Sharmelee Selvaraji is focused on Parkinson’s disease. Like many scientists, she wonders whether the neurodegenerative movement disorder might actually start in the gut. There’s a molecular link: the misshapen protein that sickens brain cells in patients with Parkinson’s disease has been found aggregating in the gut, too. And the constipation and other GI problems that are common complaints for people with Parkinson’s disease usually start decades before the onset of motor symptoms. She hopes that by investigating gut-brain communications in a mouse model of the disease, she will uncover important clues about its origins and progression.

“We’re trying to observe the effects of Parkinson’s in the gut, and then eventually, we may be able to intervene at an earlier stage to slow down the disease progression, or even cure it,” says Selvaraji.

Meanwhile, colleagues in the lab are exploring related questions about gut-brain communications in mouse models of autism, anxiety disorders, and addiction. Others continue to focus on technology development, adding new capabilities to the gut-brain probe or applying similar engineering principles to new problems.

“We are realizing that the brain is very much connected to the rest of the body,” Anikeeva says. “There is now a lot of effort in the lab to create technology suitable for a variety of really interesting organs that will help us study brain-body connections.”