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

Welcoming the first McGovern Fellows

Anne Trafton |

We are delighted to kick off the new year by welcoming Omar Abuddayeh and Jonathan Gootenberg as the first members of our new McGovern Institute Fellows Program. The fellows program is a recently launched initiative that supports highly-talented and selected postdocs that are ready to initiate their own research program.

As McGovern Fellows, the pair will be given space, time, and support to help them follow scientific research directions of their own choosing. This provides an alternative to the traditional postdoctoral research route.

Abudayyeh and Gootenberg both defended their thesis in the fall of 2018, and graduated from the lab of Feng Zhang, who is the James and Patricia Poitras Professor of Neuroscience at MIT, a McGovern investigator and core member of the Broad Institute. During their time in the Zhang lab, Abudayyeh and Gootenberg worked on projects that sought and found new tools based on enzymes mined from bacterial CRISPR systems. Cas9 is the original programmable single-effector DNA-editing enzyme, and the new McGovern Fellows worked on teams that actively looked for CRISPR enzymes with properties distinct from and complementary to Cas9. In the course of their thesis work, they helped to identify RNA-guided RNA editing factors such as the Cas13 family. This work led to the development of the REPAIR system, which is capable of editing RNA, thus providing a CRISPR-based therapeutic avenue that is not based on permanent, heritable changes to the genome. In addition, they worked on a Cas13-based diagnostic system called SHERLOCK that can detect specific nucleic acid sequences. SHERLOCK is able to detect the presence of infectious agents such as Zika virus in an easily-deployable lateral flow format, similar to a pregnancy test.

We are excited to see the directions that the new McGovern Fellows take as they now arrive at the institute, and will keep you posted on scientific findings as they emerge from their labs.

 

Plugging into the brain

by Sabbi Lall |

Driven by curiosity and therapeutic goals, Anikeeva leaves no scientific stone unturned in her drive to invent neurotechnology.

The audience sits utterly riveted as Polina Anikeeva highlights the gaps she sees in the landscape of neural tools. With a background in optoelectronics, she has a decidedly unique take on the brain.

“In neuroscience,” says Anikeeva, “we are currently applying silicon-based neural probes with the elastic properties of a knife to a delicate material with the consistency of chocolate pudding—the brain.”

A key problem, summarized by Anikeeva, is that these sharp probes damage tissue, making such interfaces unreliable and thwarting long term brain studies of processes including development and aging. The state of the art is even grimmer in the clinic. An avid climber, Anikeeva recalls a friend sustaining a spinal cord injury. “She made a remarkable recovery,” explains Anikeeva, “but seeing the technology being used to help her was shocking. Not even the simplest electronic tools were used, it was basically lots of screws and physical therapy.” This crude approach, compared to the elegant optoelectronic tools familiar to Anikeeva, sparked a drive to bring advanced materials technology to biological systems.

Outside the box

As the group breaks up after the seminar, the chatter includes boxes, more precisely, thinking outside of them. An associate professor in material sciences and engineering at MIT, Anikeeva’s interest in neuroscience recently led to a McGovern Institute appointment. She sees her journey to neurobiology as serendipitous, having earned her doctorate designing light-emitting devices at MIT.

“I wanted to work on tools that don’t exist, and neuroscience seemed like an obvious choice. Neurons communicate in part through membrane voltage changes and as an electronics designer, I felt that I should be able to use voltage.”

Comfort at the intersection of sciences requires, according to Anikeeva, clarity and focus, also important in her chief athletic pursuits, running and climbing. Through long distant running, Anikeeva finds solitary time (“assuming that no one can chase me”) and the clarity to consider complicated technical questions. Climbing hones something different, absolute focus in the face of the often-tangled information that comes with working at scientific intersections.

“When climbing, you can only think about one thing, your next move. Only the most important thoughts float up.”

This became particularly important when, in Yosemite National Park, she made the decision to go up, instead of down, during an impending thunderstorm. Getting out depended on clear focus, despite imminent hypothermia and being exposed “on one of the tallest features in the area, holding large quantities of metal.” Polina and her climbing partner made it out, but her summary of events echoes her research philosophy: “What you learn and develop is a strong mindset where you don’t do the comfortable thing, the easy thing. Instead you always find, and execute, the most logical strategy.”

In this vein, Anikeeva’s research pursues two very novel, but exceptionally logical, paths to brain research and therapeutics: fiber development and magnetic nanomaterials.

Drawing new fibers

Walking into Anikeeva’s lab, the eye is immediately drawn to a robust metal frame containing, upon closer scrutiny, recognizable parts: a large drill bit, a motor, a heating element. This custom-built machine applies principles from telecommunications to draw multifunctional fibers using more “brain-friendly” materials.

“We start out with a macroscopic model, a preform, of the device that we ultimately want,” explains Anikeeva.

This “preform” is a transparent block of polymers, composites, and soft low-melting temperature metals with optical and electrical properties needed in the final fiber. “So, this could include
electrodes for recording, optical channels for optogenetics, microfluidics for drug delivery, and one day even components that allow chemical or mechanical sensing.” After sitting in a vacuum to remove gases and impurities, the two-inch by one-inch preform arrives at the fiber-drawing tower.

“Then we heat it and pull it, and the macroscopic model becomes a kilometer-long fiber with a lateral dimension of microns, even nanometers,” explains Anikeeva. “Take one of your hairs, and imagine that inside there are electrodes for recording, there are microfluidic channels to infuse drugs, optical channels for stimulation. All of this is combined in a single miniature form
factor, and it can be quite flexible and even stretchable.”

Construction crew

Anikeeva’s lab comprises an eclectic mix of 21 researchers from over 13 different countries, and a range of expertises, including materials science, chemistry, electrical and mechanical engineering, and neuroscience. In 2011, Andres Canales, a materials scientist from Mexico, was the second person to join Anikeeva’s lab.

“There was only an idea, a diagram,” explains Canales. “I didn’t want to work on biology when I arrived at MIT, but talking to Polina, seeing the pictures, thinking about what it would entail, I became very excited by the methods and the potential applications she was thinking of.”

Despite the lack of preliminary models, Anikeeva’s ideas were compelling. Elegant as the fibers are, the road involved painstaking, iterative refinement. From a materials perspective, drawing a fiber containing a continuous conductive element was challenging, as was validation of its properties. But the resulting fiber can deliver optogenetics vectors, monitor expression, and then stimulate neuronal activity in a single surgery, removing the spatial and temporal guesswork usually involved in such an experiment.

Seongjun Park, an electrical engineering graduate student in the lab, explains one biological challenge. “For long term recording in the spinal cord, there was even an additional challenge as the fiber needed to be stretchable to respond to the spine’s movement. For this we developed a drawing process compatible with an elastomer.”

The resulting fibers can be deployed chronically without the scar tissue accumulation that usually prevents long-term optical manipulation and drug delivery, making them good candidates for the treatment of brain disorders. The lab’s current papers find that these implanted fibers are useful for three months, and material innovations make them confident that longer time periods are possible.

Magnetic moments

Another wing of Anikeeva’s research aims to develop entirely non-invasive modalities, and use magnetic nanoparticles to stimulate the brain and deliver therapeutics.

“Magnetic fields are probably the best modality for getting any kind of stimulus to deep tissues,” explains Anikeeva, “because biological systems, except for very specialized systems, do not perceive magnetic fields. They go through us unattenuated, and they don’t couple to our physiology.”

In other words, magnetic fields can safely reach deep tissues, including the brain. Upon reaching their tissue targets these fields can be used to stimulate magnetic nanoparticles, which might one day, for example, be used to deliver dopamine to the brains of Parkinson’s disease patients. The alternating magnetic fields being used in these experiments are tiny, 100-1000 times smaller than fields clinically approved for MRI-based brain imaging.

Tiny fields, but they can be used to powerful effect. By manipulating magnetic moments in these nanoparticles, the magnetic field can cause heat dissipation by the particle that can stimulate thermal receptors in the nervous system. These receptors naturally detect heat, chili peppers and vanilla, but Anikeeva’s magnetic nanoparticles act as tiny heaters that activate these receptors, and, in turn, local neurons. This principle has already been used to activate the brain’s reward center in freely moving mice.

Siyuan Rao, a postdoc who works on the magnetic nanoparticles in collaboration with McGovern Investigator Guoping Feng, is unhesitating when asked what most inspires her.

“As a materials scientist, it is really rewarding to see my materials at work. We can remotely modulate mouse behavior, even turn hopeless behavior into motivation.”

Pushing the boundaries

Such collaborations are valued by Anikeeva. Early on she worked with McGovern Investigator Emilio Bizzi to use the above fiber technology in the spinal cord. “It is important to us to not just make these devices,” explains Anikeeva, “but to use them and show ourselves, and our colleagues, the types of experiments that they can enable.”

Far from an assembly line, the researchers in Anikeeva’s lab follow projects from ideation to deployment. “The student that designs a fiber, performs their own behavioral experiments, and data analysis,” says Anikeeva. “Biology is unforgiving. You can trivially design the most brilliant electrophysiological recording probe, but unless you are directly working in the system, it is easy to miss important design considerations.”

Inspired by this, Anikeeva’s students even started a project with Gloria Choi’s group on their own initiative. This collaborative, can-do ethos spreads beyond the walls of the lab, inspiring people around MIT.

“We often work with a teaching instructor, David Bono, who is an expert on electronics and magnetic instruments,” explains Alex Senko, a senior graduate student in the lab. “In his spare time, he helps those of us who work on electrical engineering flavored projects to hunt down components needed to build our devices.”

These components extend to whatever is needed. When a low frequency source was needed, the Anikeeva lab drafted a guitar amplifier.

Queried about difficulties that she faces having chosen to navigate such a broad swath of fields, Anikeeva is focused, as ever, on the unknown, the boundaries of knowledge.

“Honestly, I really, really enjoy it. It keeps me engaged and not bored. Even when thinking about complicated physics and chemistry, I always have eyes on the prize, that this will allow us to address really interesting neuroscience questions.”

With such thinking, and by relentlessly seeking the tools needed to accomplish scientific goals, Anikeeva and her lab continue to avoid the comfortable route, instead using logical routes toward new technologies.

What is CRISPR?

by The Brain |

CRISPR (which stands for Clustered Regularly Interspaced Short Palindromic Repeats) is not actually a single entity, but shorthand for a set of bacterial systems that are found with a hallmarked arrangement in the bacterial genome.

When CRISPR is mentioned, most people are likely thinking of CRISPR-Cas9, now widely known for its capacity to be re-deployed to target sequences of interest in eukaryotic cells, including human cells. Cas9 can be programmed to target specific stretches of DNA, but other enzymes have since been discovered that are able to edit DNA, including Cpf1 and Cas12b. Other CRISPR enzymes, Cas13 family members, can be programmed to target RNA and even edit and change its sequence.

The common theme that makes CRISPR enzymes so powerful, is that scientists can supply them with a guide RNA for a chosen sequence. Since the guide RNA can pair very specifically with DNA, or for Cas13 family members, RNA, researchers can basically provide a given CRISPR enzyme with a way of homing in on any sequence of interest. Once a CRISPR protein finds its target, it can be used to edit that sequence, perhaps removing a disease-associated mutation.

In addition, CRISPR proteins have been engineered to modulate gene expression and even signal the presence of particular sequences, as in the case of the Cas13-based diagnostic, SHERLOCK.

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

Ian Wickersham

Making Connections

Ian Wickersham develops genetic tools that provide more powerful and precise ways to study the organization of the brain. His lab invents techniques for targeting neurons based on their synaptic connectivity and gene expression patterns in order to cause them to express genes that allow the neurons to be studied and controlled by neuroscientists and clinicians. The goal of Wickersham’s work is to provide neuroscience with more effective ways of studying the brain, and potentially to provide clinical neurology with more effective ways of treating disorders of the brain.

Polina Anikeeva

Probing the Mind-Body Connection

Polina Anikeeva develops cutting-edge neurotechnologies to probe the flow of information between the brain and peripheral organs in the body.

The brain and the digestive tract are in constant communication, relaying signals that influence our behavior and mental state. Anikeeva’s lab has developed ultrathin, flexible fibers that probe this extensive communication network. The multifunctional fibers are compatible the body’s soft tissue and are equipped with light emitters for activating subsets of cells and tiny channels for delivering genetic cargo or drugs. By deploying these probes within the gastrointestinal tract, Anikeeva’s team has explored how gut-brain circuits contribute to complex behaviors like decision-making and mood.

Anikeeva’s group is also developing magnetic nanoparticles to modulate neural activity wirelessly. Working in conjunction with biological receptors, these non-invasive nanoscale transducers could replace wires in deep-brain stimulation for Parkinson’s disease, or control stress hormones released by adrenal glands. Ultimately, Anikeeva hopes these novel technologies will improve therapies and predictive diagnostics for achieving healthy minds in healthy bodies.

Ed Boyden

Engineering the Brain

Ed Boyden develops advanced technologies for analyzing, engineering, and simulating brain circuits to reveal and repair the fundamental mechanisms behind complex brain processes.

Boyden may be best known for pioneering optogenetics, a powerful method that enables scientists to control neurons using light. He also led the team that created expansion microscopy, which expands nanoscale features in a cell to make them visible using conventional microscopes. In addition, his lab develops methods so that many signals can be imaged in living cells at the same time. He continues to invent new tools, and works to systematically integrate these tools to enable biologically accurate computer simulations of the brain.

Team invents method to shrink objects to the nanoscale

Anne Trafton |

MIT researchers have invented a way to fabricate nanoscale 3-D objects of nearly any shape. They can also pattern the objects with a variety of useful materials, including metals, quantum dots, and DNA.

“It’s a way of putting nearly any kind of material into a 3-D pattern with nanoscale precision,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology and an associate professor of biological engineering and of brain and cognitive sciences at MIT.

Using the new technique, the researchers can create any shape and structure they want by patterning a polymer scaffold with a laser. After attaching other useful materials to the scaffold, they shrink it, generating structures one thousandth the volume of the original.

These tiny structures could have applications in many fields, from optics to medicine to robotics, the researchers say. The technique uses equipment that many biology and materials science labs already have, making it widely accessible for researchers who want to try it.

Boyden, who is also a member of MIT’s Media Lab, McGovern Institute for Brain Research, and Koch Institute for Integrative Cancer Research, is one of the senior authors of the paper, which appears in the Dec. 13 issue of Science. The other senior author is Adam Marblestone, a Media Lab research affiliate, and the paper’s lead authors are graduate students Daniel Oran and Samuel Rodriques.

Implosion fabrication

Existing techniques for creating nanostructures are limited in what they can accomplish. Etching patterns onto a surface with light can produce 2-D nanostructures but doesn’t work for 3-D structures. It is possible to make 3-D nanostructures by gradually adding layers on top of each other, but this process is slow and challenging. And, while methods exist that can directly 3-D print nanoscale objects, they are restricted to specialized materials like polymers and plastics, which lack the functional properties necessary for many applications. Furthermore, they can only generate self-supporting structures. (The technique can yield a solid pyramid, for example, but not a linked chain or a hollow sphere.)

To overcome these limitations, Boyden and his students decided to adapt a technique that his lab developed a few years ago for high-resolution imaging of brain tissue. This technique, known as expansion microscopy, involves embedding tissue into a hydrogel and then expanding it, allowing for high resolution imaging with a regular microscope. Hundreds of research groups in biology and medicine are now using expansion microscopy, since it enables 3-D visualization of cells and tissues with ordinary hardware.

By reversing this process, the researchers found that they could create large-scale objects embedded in expanded hydrogels and then shrink them to the nanoscale, an approach that they call “implosion fabrication.”

As they did for expansion microscopy, the researchers used a very absorbent material made of polyacrylate, commonly found in diapers, as the scaffold for their nanofabrication process. The scaffold is bathed in a solution that contains molecules of fluorescein, which attach to the scaffold when they are activated by laser light.

Using two-photon microscopy, which allows for precise targeting of points deep within a structure, the researchers attach fluorescein molecules to specific locations within the gel. The fluorescein molecules act as anchors that can bind to other types of molecules that the researchers add.

“You attach the anchors where you want with light, and later you can attach whatever you want to the anchors,” Boyden says. “It could be a quantum dot, it could be a piece of DNA, it could be a gold nanoparticle.”

“It’s a bit like film photography — a latent image is formed by exposing a sensitive material in a gel to light. Then, you can develop that latent image into a real image by attaching another material, silver, afterwards. In this way implosion fabrication can create all sorts of structures, including gradients, unconnected structures, and multimaterial patterns,” Oran says.

Once the desired molecules are attached in the right locations, the researchers shrink the entire structure by adding an acid. The acid blocks the negative charges in the polyacrylate gel so that they no longer repel each other, causing the gel to contract. Using this technique, the researchers can shrink the objects 10-fold in each dimension (for an overall 1,000-fold reduction in volume). This ability to shrink not only allows for increased resolution, but also makes it possible to assemble materials in a low-density scaffold. This enables easy access for modification, and later the material becomes a dense solid when it is shrunk.

“People have been trying to invent better equipment to make smaller nanomaterials for years, but we realized that if you just use existing systems and embed your materials in this gel, you can shrink them down to the nanoscale, without distorting the patterns,” Rodriques says.

Currently, the researchers can create objects that are around 1 cubic millimeter, patterned with a resolution of 50 nanometers. There is a tradeoff between size and resolution: If the researchers want to make larger objects, about 1 cubic centimeter, they can achieve a resolution of about 500 nanometers. However, that resolution could be improved with further refinement of the process, the researchers say.

Better optics

The MIT team is now exploring potential applications for this technology, and they anticipate that some of the earliest applications might be in optics — for example, making specialized lenses that could be used to study the fundamental properties of light. This technique might also allow for the fabrication of smaller, better lenses for applications such as cell phone cameras, microscopes, or endoscopes, the researchers say. Farther in the future, the researchers say that this approach could be used to build nanoscale electronics or robots.

“There are all kinds of things you can do with this,” Boyden says. “Democratizing nanofabrication could open up frontiers we can’t yet imagine.”

Many research labs are already stocked with the equipment required for this kind of fabrication. “With a laser you can already find in many biology labs, you can scan a pattern, then deposit metals, semiconductors, or DNA, and then shrink it down,” Boyden says.

The research was funded by the Kavli Dream Team Program, the HHMI-Simons Faculty Scholars Program, the Open Philanthropy Project, John Doerr, the Office of Naval Research, the National Institutes of Health, the New York Stem Cell Foundation-Robertson Award, the U.S. Army Research Office, K. Lisa Yang and Y. Eva Tan, and the MIT Media Lab.

Meeting of the minds

Anne Trafton |

In the summer of 2006, before their teenage years began, Mahdi Ramadan and Alexi Choueiri were spirited from their homes amid political unrest in Lebanon. Evacuated on short notice by the U.S. Marines, they were among 2,000 refugees transported to the U.S. on the aircraft carrier USS Nashville.

The two never met in their homeland, nor on the transatlantic journey, and after arriving in the U.S. they went their separate ways. Ramadan and his family moved to Seattle, Washington. Choueiri’s family settled in Chandler, Arizona, where they already had some extended family.

Yet their paths converged 11 years later as graduate students in MIT’s Department of Brain and Cognitive Sciences (BCS). One day last fall, on a walk across campus, Ramadan and Choueiri slowly unraveled their connection. With increasing excitement, they narrowed it down by year, by month, and eventually, by boat, to discover just how closely their lives had once come to one another.

Lebanon, the only Middle Eastern country without a desert, enjoys a lush, Mediterranean climate. Amid this natural beauty, though, the country struggles under the weight of deep political and cultural divides that sometimes erupt into conflict.

Despite different Lebanese cultural backgrounds — Ramadan’s family is Muslim and Choueiri’s Christian — they have had remarkably similar experiences as refugees from Lebanon. Both credit those experiences with motivating their interest in neuroscience. Questions about human behavior — How do people form beliefs about the world? Can those beliefs really change? — led them to graduate work at MIT.

In pursuit of knowledge

When they first immigrated to the U.S., school symbolized survival for Ramadan and Choueiri. Not only was education a mode of improving their lives and supporting their families, it was a search for objectivity in their recently upended worlds.

As the family’s primary English speaker, Ramadan became a bulwark for his family in their new country, especially in medical matters; his little sister, Ghida, has cerebral palsy. Though his family has limited financial resources, he emphasizes that both he and his sister have been constantly supported by their parents in pursuit of their educations.

In fact, Ramadan feels motivated by Ghida’s determination to complete her degree in occupational therapy: “That to me is really inspirational, her resilience in the face of her disability and in the face of assumptions that people make about capability. She’s really sassy, she’s really witty, she’s really funny, she’s really intelligent, and she doesn’t see her disability as a disability. She actually thinks it’s an advantage — it actually motivated her to pursue [her education] even more.”

Ramadan hopes his own educational journey, from a low-income evacuee to a neuroscience PhD, can show others like him that success is possible.

Choueiri also relied on academics to adapt to his new world in Arizona. Even in Lebanon, he remembers taking solace from a chaotic world in his education, and once in the U.S., he dove headfirst into his studies.

Choueiri’s hometown in Arizona sometimes felt homogenous, so coming to MIT has been a staggering — and welcome — experience. “The diversity here is phenomenal: meeting people from different cultures, upbringings, countries,” he says. “I love making friends from all over and learning their stories. Being a neuroscientist, I like to know how they were brought up and how their ideas were formed. … It’s like Disneyland for me. I feel like I’m coming to Disneyland every day and high-fiving Mickey Mouse.”

At home at MIT

Ramadan and Choueiri revel in the freedom of thought they have found in their academic home here. They say they feel taken seriously as students and, more importantly, as thinkers. The BCS department values interdisciplinary thought, and cultivates extracurricular student activities like philosophy discussion groups, the development of neuroscience podcasts, and independent, student-led lectures on myriad neuroscience-adjacent topics.

Both students were drawn to neuroscience not only by their experiences as Lebanese-Americans, but by trying to make sense of what happened to them at a young age.

Ramadan became interested in neuroplasticity through self-observation. “You know that feeling of childhood you have where everything is magical and you’re not really aware of things around you? I feel like when I immigrated to the U.S., that feeling went away and I had to become extra-aware of everything because I had to adapt so quickly. So, something that intrigued me about neuroscience is how the brain is able to adapt so quickly and how different experiences can shape and rewire your brain.”

Now in his second year, Ramadan plans to pursue his interest in neuroplasticity in Professor Mehrdad Jazayeri’s lab at the McGovern Institute by investigating how learning changes the brain’s underlying neural circuits; understanding the physical mechanism of plasticity has application to both disease states and artificial intelligence.

Choueiri, a third-year student in the program, is a member of Professor Ed Boyden’s lab at the McGovern Institute. While his interest in neuroscience was similarly driven by his experience as an evacuee, his approach is outward-looking, focused on making sense of people’s choices. Ultimately, the brain controls human ability to perceive, learn, and choose through physiological changes; Choueiri wants to understand not just the human brain, but also the human condition — and to use that understanding to alleviate pain and suffering.

“Growing up in Lebanon, with different religions and war … I became fundamentally interested in human behavior, irrationality, and conflict, and how can we resolve those things … and maybe there’s an objective way to really make sense of where these differences are coming from,” he says. In the Synthetic Neurobiology Group, Choueiri’s research involves developing neurotechnologies to map the molecular interactions of the brain, to reveal the fundamental mechanisms of brain function and repair dysfunction.

Shared identities

As evacuees, Ramadan and Choueiri left their country without notice and without saying goodbye. However, in other ways, their experience was not unlike an immigrant experience. This sometimes makes identifying as a refugee in the current political climate complex, as refugees from Syria and other war-ravaged regions struggle to make a home in the U.S. Still, both believe that sharing their personal experience may help others in difficult positions to see that they do belong in the U.S., and at MIT.

Despite their American identity, Ramadan and Choueiri also share a palpable love for Lebanese culture. They extol the diversity of Lebanese cuisine, which is served mezze-style, making meals an experience full of variety, grilled food, and yogurt dishes. The Lebanese diaspora is another source of great pride for them. Though the population of Lebanon is less than 5 million, as many as 14 million live abroad.

It’s all the more remarkable, then, that Ramadan and Choueiri intersected at MIT, some 6,000 miles from their homeland. The bond they have forged since, through their common heritage, experiences, and interests, is deeply meaningful to both of them.

“I was so happy to find another student who has this story because it allows me to reflect back on those experiences and how they changed me,” says Ramadan. “It’s like a mirror image. … Was it a coincidence, or were our lives so similar that they led to this point?”

This story was written by Bridget E. Begg at MIT’s Office of Graduate Education.

Monitoring electromagnetic signals in the brain with MRI

Anne Trafton |

Researchers commonly study brain function by monitoring two types of electromagnetism — electric fields and light. However, most methods for measuring these phenomena in the brain are very invasive.

MIT engineers have now devised a new technique to detect either electrical activity or optical signals in the brain using a minimally invasive sensor for magnetic resonance imaging (MRI).

MRI is often used to measure changes in blood flow that indirectly represent brain activity, but the MIT team has devised a new type of MRI sensor that can detect tiny electrical currents, as well as light produced by luminescent proteins. (Electrical impulses arise from the brain’s internal communications, and optical signals can be produced by a variety of molecules developed by chemists and bioengineers.)

“MRI offers a way to sense things from the outside of the body in a minimally invasive fashion,” says Aviad Hai, an MIT postdoc and the lead author of the study. “It does not require a wired connection into the brain. We can implant the sensor and just leave it there.”

This kind of sensor could give neuroscientists a spatially accurate way to pinpoint electrical activity in the brain. It can also be used to measure light, and could be adapted to measure chemicals such as glucose, the researchers say.

Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering, and an associate member of MIT’s McGovern Institute for Brain Research, is the senior author of the paper, which appears in the Oct. 22 issue of Nature Biomedical Engineering. Postdocs Virginia Spanoudaki and Benjamin Bartelle are also authors of the paper.

Detecting electric fields

Jasanoff’s lab has previously developed MRI sensors that can detect calcium and neurotransmitters such as serotonin and dopamine. In this paper, they wanted to expand their approach to detecting biophysical phenomena such as electricity and light. Currently, the most accurate way to monitor electrical activity in the brain is by inserting an electrode, which is very invasive and can cause tissue damage. Electroencephalography (EEG) is a noninvasive way to measure electrical activity in the brain, but this method cannot pinpoint the origin of the activity.

To create a sensor that could detect electromagnetic fields with spatial precision, the researchers realized they could use an electronic device — specifically, a tiny radio antenna.

MRI works by detecting radio waves emitted by the nuclei of hydrogen atoms in water. These signals are usually detected by a large radio antenna within an MRI scanner. For this study, the MIT team shrank the radio antenna down to just a few millimeters in size so that it could be implanted directly into the brain to receive the radio waves generated by water in the brain tissue.

The sensor is initially tuned to the same frequency as the radio waves emitted by the hydrogen atoms. When the sensor picks up an electromagnetic signal from the tissue, its tuning changes and the sensor no longer matches the frequency of the hydrogen atoms. When this happens, a weaker image arises when the sensor is scanned by an external MRI machine.

The researchers demonstrated that the sensors can pick up electrical signals similar to those produced by action potentials (the electrical impulses fired by single neurons), or local field potentials (the sum of electrical currents produced by a group of neurons).

“We showed that these devices are sensitive to biological-scale potentials, on the order of millivolts, which are comparable to what biological tissue generates, especially in the brain,” Jasanoff says.

The researchers performed additional tests in rats to study whether the sensors could pick up signals in living brain tissue. For those experiments, they designed the sensors to detect light emitted by cells engineered to express the protein luciferase.

Normally, luciferase’s exact location cannot be determined when it is deep within the brain or other tissues, so the new sensor offers a way to expand the usefulness of luciferase and more precisely pinpoint the cells that are emitting light, the researchers say. Luciferase is commonly engineered into cells along with another gene of interest, allowing researchers to determine whether the genes have been successfully incorporated by measuring the light produced.

Smaller sensors

One major advantage of this sensor is that it does not need to carry any kind of power supply, because the radio signals that the external MRI scanner emits are enough to power the sensor.

Hai, who will be joining the faculty at the University of Wisconsin at Madison in January, plans to further miniaturize the sensors so that more of them can be injected, enabling the imaging of light or electrical fields over a larger brain area. In this paper, the researchers performed modeling that showed that a 250-micron sensor (a few tenths of a millimeter) should be able to detect electrical activity on the order of 100 millivolts, similar to the amount of current in a neural action potential.

Jasanoff’s lab is interested in using this type of sensor to detect neural signals in the brain, and they envision that it could also be used to monitor electromagnetic phenomena elsewhere in the body, including muscle contractions or cardiac activity.

“If the sensors were on the order of hundreds of microns, which is what the modeling suggests is in the future for this technology, then you could imagine taking a syringe and distributing a whole bunch of them and just leaving them there,” Jasanoff says. “What this would do is provide many local readouts by having sensors distributed all over the tissue.”

The research was funded by the National Institutes of Health.

New sensors track dopamine in the brain for more than a year

Anne Trafton |

Dopamine, a signaling molecule used throughout the brain, plays a major role in regulating our mood, as well as controlling movement. Many disorders, including Parkinson’s disease, depression, and schizophrenia, are linked to dopamine deficiencies.

MIT neuroscientists have now devised a way to measure dopamine in the brain for more than a year, which they believe will help them to learn much more about its role in both healthy and diseased brains.

“Despite all that is known about dopamine as a crucial signaling molecule in the brain, implicated in neurologic and neuropsychiatric conditions as well as our ability to learn, it has been impossible to monitor changes in the online release of dopamine over time periods long enough to relate these to clinical conditions,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, and Rober Langer, the David H. Koch Institute Professor and a member of the Koch Institute, are also senior authors of the study. MIT postdoc Helen Schwerdt is the lead author of the paper, which appears in the Sept. 12 issue of Communications Biology.

Long-term sensing

Dopamine is one of many neurotransmitters that neurons in the brain use to communicate with each other. Traditional systems for measuring dopamine — carbon electrodes with a shaft diameter of about 100 microns — can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine.

In 2015, the MIT team demonstrated that tiny microfabricated sensors could be used to measure dopamine levels in a part of the brain called the striatum, which contains dopamine-producing cells that are critical for habit formation and reward-reinforced learning.

Because these probes are so small (about 10 microns in diameter), the researchers could implant up to 16 of them to measure dopamine levels in different parts of the striatum. In the new study, the researchers wanted to test whether they could use these sensors for long-term dopamine tracking.

“Our fundamental goal from the very beginning was to make the sensors work over a long period of time and produce accurate readings from day to day,” Schwerdt says. “This is necessary if you want to understand how these signals mediate specific diseases or conditions.”

To develop a sensor that can be accurate over long periods of time, the researchers had to make sure that it would not provoke an immune reaction, to avoid the scar tissue that interferes with the accuracy of the readings.

The MIT team found that their tiny sensors were nearly invisible to the immune system, even over extended periods of time. After the sensors were implanted, populations of microglia (immune cells that respond to short-term damage), and astrocytes, which respond over longer periods, were the same as those in brain tissue that did not have the probes inserted.

In this study, the researchers implanted three to five sensors per animal, about 5 millimeters deep, in the striatum. They took readings every few weeks, after stimulating dopamine release from the brainstem, which travels to the striatum. They found that the measurements remained consistent for up to 393 days.

“This is the first time that anyone’s shown that these sensors work for more than a few months. That gives us a lot of confidence that these kinds of sensors might be feasible for human use someday,” Schwerdt says.

Paul Glimcher, a professor of physiology and neuroscience at New York University, says the new sensors should enable more researchers to perform long-term studies of dopamine, which is essential for studying phenomena such as learning, which occurs over long time periods.

“This is a really solid engineering accomplishment that moves the field forward,” says Glimcher, who was not involved in the research. “This dramatically improves the technology in a way that makes it accessible to a lot of labs.”

Monitoring Parkinson’s

If developed for use in humans, these sensors could be useful for monitoring Parkinson’s patients who receive deep brain stimulation, the researchers say. This treatment involves implanting an electrode that delivers electrical impulses to a structure deep within the brain. Using a sensor to monitor dopamine levels could help doctors deliver the stimulation more selectively, only when it is needed.

The researchers are now looking into adapting the sensors to measure other neurotransmitters in the brain, and to measure electrical signals, which can also be disrupted in Parkinson’s and other diseases.

“Understanding those relationships between chemical and electrical activity will be really important to understanding all of the issues that you see in Parkinson’s,” Schwerdt says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, the Army Research Office, the Saks Kavanaugh Foundation, the Nancy Lurie Marks Family Foundation, and Dr. Tenley Albright.