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Signs of COVID19 may be hidden in speech signals

by Kylie Foy |

It’s often easy to tell when colleagues are struggling with a cold — they sound sick. Maybe their voices are lower or have a nasally tone. Infections change the quality of our voices in various ways. But MIT Lincoln Laboratory researchers are detecting these changes in Covid-19 patients even when these changes are too subtle for people to hear or even notice in themselves.

By processing speech recordings of people infected with Covid-19 but not yet showing symptoms, these researchers found evidence of vocal biomarkers, or measurable indicators, of the disease. These biomarkers stem from disruptions the infection causes in the movement of muscles across the respiratory, laryngeal, and articulatory systems. A technology letter describing this research was recently published in IEEE Open Journal of Engineering in Medicine and Biology.

While this research is still in its early stages, the initial findings lay a framework for studying these vocal changes in greater detail. This work may also hold promise for using mobile apps to screen people for the disease, particularly those who are asymptomatic.

Talking heads

“I had this ‘aha’ moment while I was watching the news,” says Thomas Quatieri, a senior staff member in the laboratory’s Human Health and Performance Systems Group. Quatieri has been leading the group’s research in vocal biomarkers for the past decade; their focus has been on discovering vocal biomarkers of neurological disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. These diseases, and many others, change the brain’s ability to turn thoughts into words, and those changes can be detected by processing speech signals.

He and his team wondered whether vocal biomarkers might also exist for COVID19. The symptoms led them to think so. When symptoms manifest, a person typically has difficulty breathing. Inflammation in the respiratory system affects the intensity with which air is exhaled when a person talks. This air interacts with hundreds of other potentially inflamed muscles on its journey to speech production. These interactions impact the loudness, pitch, steadiness, and resonance of the voice — measurable qualities that form the basis of their biomarkers.

While watching the news, Quatieri realized there were speech samples in front of him of people who had tested positive for COVID19. He and his colleagues combed YouTube for clips of celebrities or TV hosts who had given interviews while they were COVID19 positive but asymptomatic. They identified five subjects. Then, they downloaded interviews of those people from before they had COVID19, matching audio conditions as best they could.

They then used algorithms to extract features from the vocal signals in each audio sample. “These vocal features serve as proxies for the underlying movements of the speech production systems,” says Tanya Talkar, a PhD candidate in the Speech and Hearing Bioscience and Technology program at Harvard University.

The signal’s amplitude, or loudness, was extracted as a proxy for movement in the respiratory system. For studying movements in the larynx, they measured pitch and the steadiness of pitch, two indicators of how stable the vocal cords are. As a proxy for articulator movements — like those of the tongue, lips, jaw, and more — they extracted speech formants. Speech formants are frequency measurements that correspond to how the mouth shapes sound waves to create a sequence of phonemes (vowels and consonants) and to contribute to a certain vocal quality (nasally versus warm, for example).

They hypothesized that Covid19 inflammation causes muscles across these systems to become overly coupled, resulting in a less complex movement. “Picture these speech subsystems as if they are the wrist and fingers of a skilled pianist; normally, the movements are independent and highly complex,” Quatieri says. Now, picture if the wrist and finger movements were to become stuck together, moving as one. This coupling would force the pianist to play a much simpler tune.

The researchers looked for evidence of coupling in their features, measuring how each feature changed in relation to another in 10 millisecond increments as the subject spoke. These values were then plotted on an eigenspectrum; the shape of this eigenspectrum plot indicates the complexity of the signals. “If the eigenspace of the values forms a sphere, the signals are complex. If there is less complexity, it might look more like a flat oval,” Talkar says.

In the end, they found a decreased complexity of movement in the Covid-19 interviews as compared to the pre-Covid-19 interviews. “The coupling was less prominent between larynx and articulator motion, but we’re seeing a reduction in complexity between respiratory and larynx motion,” Talkar says.

Early detections

These preliminary results hint that biomarkers derived from vocal system coordination can indicate the presence of Covid-19. However, the researchers note that it’s still early to draw conclusions, and more data are needed to validate their findings. They’re working now with a publicly released dataset from Carnegie Mellon University that contains audio samples from individuals who have tested positive for COVID19.

Beyond collecting more data to fuel this research, the team is looking at using mobile apps to implement it. A partnership is underway with Satra Ghosh at the MIT McGovern Institute for Brain Research to integrate vocal screening for Covid-19 into its VoiceUp app, which was initially developed to study the link between voice and depression. A follow-on effort could add this vocal screening into the How We Feel app. This app asks users questions about their daily health status and demographics, with the aim to use these data to pinpoint hotspots and predict the percentage of people who have the disease in different regions of the country. Asking users to also submit a daily voice memo to screen for biomarkers of Covid-19 could potentially help scientists catch on to an outbreak.

“A sensing system integrated into a mobile app could pick up on infections early, before people feel sick or, especially, for these subsets of people who don’t ever feel sick or show symptoms,” says Jeffrey Palmer, who leads the research group. “This is also something the U.S. Army is interested in as part of a holistic Covid-19 monitoring system.” Even after a diagnosis, this sensing ability could help doctors remotely monitor their patients’ progress or monitor the effects of a vaccine or drug treatment.

As the team continues their research, they plan to do more to address potential confounders that could cause inaccuracies in their results, such as different recording environments, the emotional status of the subjects, or other illnesses causing vocal changes. They’re also supporting similar research. The Mass General Brigham Center for COVID Innovation has connected them to international scientists who are following the team’s framework to analyze coughs.

“There are a lot of other interesting areas to look at. Here, we looked at the physiological impacts on the vocal tract. We’re also looking to expand our biomarkers to consider neurophysiological impacts linked to Covid-19, like the loss of taste and smell,” Quatieri says. “Those symptoms can affect speaking, too.”

Nine MIT School of Science professors receive tenure for 2020

by School of Science |

Beginning July 1, nine faculty members in the MIT School of Science have been granted tenure by MIT. They are appointed in the departments of Brain and Cognitive Sciences, Chemistry, Mathematics, and Physics.

Physicist Ibrahim Cisse investigates living cells to reveal and study collective behaviors and biomolecular phase transitions at the resolution of single molecules. The results of his work help determine how disruptions in genes can cause diseases like cancer. Cisse joined the Department of Physics in 2014 and now holds a joint appointment with the Department of Biology. His education includes a bachelor’s degree in physics from North Carolina Central University, concluded in 2004, and a doctoral degree in physics from the University of Illinois at Urbana-Champaign, achieved in 2009. He followed his PhD with a postdoc at the École Normale Supérieure of Paris and a research specialist appointment at the Howard Hughes Medical Institute’s Janelia Research Campus.

Jörn Dunkel is a physical applied mathematician. His research focuses on the mathematical description of complex nonlinear phenomena in a variety of fields, especially biophysics. The models he develops help predict dynamical behaviors and structure formation processes in developmental biology, fluid dynamics, and even knot strengths for sailing, rock climbing and construction. He joined the Department of Mathematics in 2013 after completing postdoctoral appointments at Oxford University and Cambridge University. He received diplomas in physics and mathematics from Humboldt University of Berlin in 2004 and 2005, respectively. The University of Augsburg awarded Dunkel a PhD in statistical physics in 2008.

A cognitive neuroscientist, Mehrdad Jazayeri studies the neurobiological underpinnings of mental functions such as planning, inference, and learning by analyzing brain signals in the lab and using theoretical and computational models, including artificial neural networks. He joined the Department of Brain and Cognitive Sciences in 2013. He achieved a BS in electrical engineering from the Sharif University of Technology in 1994, an MS in physiology at the University of Toronto in 2001, and a PhD in neuroscience from New York University in 2007. Prior to joining MIT, he was a postdoc at the University of Washington. Jazayeri is also an investigator at the McGovern Institute for Brain Research.

Yen-Jie Lee is an experimental particle physicist in the field of proton-proton and heavy-ion physics. Utilizing the Large Hadron Colliders, Lee explores matter in extreme conditions, providing new insight into strong interactions and what might have existed and occurred at the beginning of the universe and in distant star cores. His work on jets and heavy flavor particle production in nuclei collisions improves understanding of the quark-gluon plasma, predicted by quantum chromodynamics (QCD) calculations, and the structure of heavy nuclei. He also pioneered studies of high-density QCD with electron-position annihilation data. Lee joined the Department of Physics in 2013 after a fellowship at CERN and postdoc research at the Laboratory for Nuclear Science at MIT. His bachelor’s and master’s degrees were awarded by the National Taiwan University in 2002 and 2004, respectively, and his doctoral degree by MIT in 2011. Lee is a member of the Laboratory for Nuclear Science.

Josh McDermott investigates the sense of hearing. His research addresses both human and machine audition using tools from experimental psychology, engineering, and neuroscience. McDermott hopes to better understand the neural computation underlying human hearing, to improve devices to assist hearing impaired, and to enhance machine interpretation of sounds. Prior to joining MIT’s Department of Brain and Cognitive Sciences, he was awarded a BA in 1998 in brain and cognitive sciences by Harvard University, a master’s degree in computational neuroscience in 2000 by University College London, and a PhD in brain and cognitive sciences in 2006 by MIT. Between his doctoral time at MIT and returning as a faculty member, he was a postdoc at the University of Minnesota and New York University, and a visiting scientist at Oxford University. McDermott is also an associate investigator at the McGovern Institute for Brain Research and an investigator in the Center for Brains, Minds and Machines.

Solving environmental challenges by studying and manipulating chemical reactions is the focus of Yogesh Surendranath’s research. Using chemistry, he works at the molecular level to understand how to efficiently interconvert chemical and electrical energy. His fundamental studies aim to improve energy storage technologies, such as batteries, fuel cells, and electrolyzers, that can be used to meet future energy demand with reduced carbon emissions. Surendranath joined the Department of Chemistry in 2013 after a postdoc at the University of California at Berkeley. His PhD was completed in 2011 at MIT, and BS in 2006 at the University of Virginia. Suendranath is also a collaborator in the MIT Energy Initiative.

A theoretical astrophysicist, Mark Vogelsberger is interested in large-scale structures of the universe, such as galaxy formation. He combines observational data, theoretical models, and simulations that require high-performance supercomputers to improve and develop detailed models that simulate galaxy diversity, clustering, and their properties, including a plethora of physical effects like magnetic fields, cosmic dust, and thermal conduction. Vogelsberger also uses simulations to generate scenarios involving alternative forms of dark matter. He joined the Department of Physics in 2014 after a postdoc at the Harvard-Smithsonian Center for Astrophysics. Vogelsberger is a 2006 graduate of the University of Mainz undergraduate program in physics, and a 2010 doctoral graduate of the University of Munich and the Max Plank Institute for Astrophysics. He is also a principal investigator in the MIT Kavli Institute for Astrophysics and Space Research.

Adam Willard is a theoretical chemist with research interests that fall across molecular biology, renewable energy, and material science. He uses theory, modeling, and molecular simulation to study the disorder that is inherent to systems over nanometer-length scales. His recent work has highlighted the fundamental and unexpected role that such disorder plays in phenomena such as microscopic energy transport in semiconducting plastics, ion transport in batteries, and protein hydration. Joining the Department of Chemistry in 2013, Willard was formerly a postdoc at Lawrence Berkeley National Laboratory and then the University of Texas at Austin. He holds a PhD in chemistry from the University of California at Berkeley, achieved in 2009, and a BS in chemistry and mathematics from the University of Puget Sound, granted in 2003.

Lindley Winslow seeks to understand the fundamental particles shaped the evolution of our universe. As an experimental particle and nuclear physicist, she develops novel detection technology to search for axion dark matter and a proposed nuclear decay that makes more matter than antimatter. She started her faculty position in the Department of Physics in 2015 following a postdoc at MIT and a subsequent faculty position at the University of California at Los Angeles. Winslow achieved her BA in physics and astronomy in 2001 and PhD in physics in 2008, both at the University of California at Berkeley. She is also a member of the Laboratory for Nuclear Science.

Producing a gaseous messenger molecule inside the body, on demand

by David L. Chandler |

Nitric oxide is an important signaling molecule in the body, with a role in building nervous system connections that contribute to learning and memory. It also functions as a messenger in the cardiovascular and immune systems.

But it has been difficult for researchers to study exactly what its role is in these systems and how it functions. Because it is a gas, there has been no practical way to direct it to specific individual cells in order to observe its effects. Now, a team of scientists and engineers at MIT and elsewhere has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new lines of research on this essential molecule’s effects.

The findings are reported today in the journal Nature Nanotechnology, in a paper by MIT professors Polina Anikeeva, Karthish Manthiram, and Yoel Fink; graduate student Jimin Park; postdoc Kyoungsuk Jin; and 10 others at MIT and in Taiwan, Japan, and Israel.

“It’s a very important compound,” says Anikeeva, who is also an Investigator at the McGovern Institute. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process has been difficult. So far, most studies have resorted to looking at systemic effects, by knocking out genes responsible for the production of enzymes the body uses to produce nitric oxide where it’s needed as a messenger.

But that approach, she says, is “very brute force. This is a hammer to the system because you’re knocking it out not just from one specific region, let’s say in the brain, but you essentially knock it out from the entire organism, and this can have other side effects.”

Others have tried introducing compounds into the body that release nitric oxide as they decompose, which can produce somewhat more localized effects, but these still spread out, and it is a very slow and uncontrolled process.

The team’s solution uses an electric voltage to drive the reaction that produces nitric oxide. This is similar to what is happening on a much larger scale with some industrial electrochemical production processes, which are relatively modular and controllable, enabling local and on-demand chemical synthesis. “We’ve taken that concept and said, you know what? You can be so local and so modular with an electrochemical process that you can even do this at the level of the cell,” Manthiram says. “And I think what’s even more exciting about this is that if you use electric potential, you have the ability to start production and stop production in a heartbeat.”

The team’s key achievement was finding a way for this kind of electrochemically controlled reaction to be operated efficiently and selectively at the nanoscale. That required finding a suitable catalyst material that could generate nitric oxide from a benign precursor material. They found that nitrite offered a promising precursor for electrochemical nitric oxide generation.

“We came up with the idea of making a tailored nanoparticle to catalyze the reaction,” Jin says. They found that the enzymes that catalyze nitric oxide generation in nature contain iron-sulfur centers. Drawing inspiration from these enzymes, they devised a catalyst that consisted of nanoparticles of iron sulfide, which activates the nitric oxide-producing reaction in the presence of an electric field and nitrite. By further doping these nanoparticles with platinum, the team was able to enhance their electrocatalytic efficiency.

To miniaturize the electrocatalytic cell to the scale of biological cells, the team has created custom fibers containing the positive and negative microelectrodes, which are coated with the iron sulfide nanoparticles, and a microfluidic channel for the delivery of sodium nitrite, the precursor material. When implanted in the brain, these fibers direct the precursor to the specific neurons. Then the reaction can be activated at will electrochemically, through the electrodes in the same fiber, producing an instant burst of nitric oxide right at that spot so that its effects can be recorded in real-time.

Device created by the Anikeeva lab. The tube at top is connected to a supply of the precursor material, sodium nitrite, which then passes through a channel in the fiber at the bottom and into the body, which also contains the electrodes to stimulate the release of nitric oxide. The electrodes are connected through the four-pin connector on the left.
Photo: Anikeeva Lab

As a test, they used the system in a rodent model to activate a brain region that is known to be a reward center for motivation and social interaction, and that plays a role in addiction. They showed that it did indeed provoke the expected signaling responses, demonstrating its effectiveness.

Anikeeva says this “would be a very useful biological research platform, because finally, people will have a way to study the role of nitric oxide at the level of single cells, in whole organisms that are performing tasks.” She points out that there are certain disorders that are associated with disruptions of the nitric oxide signaling pathway, so more detailed studies of how this pathway operates could help lead to treatments.

The method could be generalizable, Park says, as a way of producing other molecules of biological interest within an organism. “Essentially we can now have this really scalable and miniaturized way to generate many molecules, as long as we find the appropriate catalyst, and as long as we find an appropriate starting compound that is also safe.” This approach to generating signaling molecules in situ could have wide applications in biomedicine, he says.

“One of our reviewers for this manuscript pointed out that this has never been done — electrolysis in a biological system has never been leveraged to control biological function,” Anikeeva says. “So, this is essentially the beginning of a field that could potentially be very useful” to study molecules that can be delivered at precise locations and times, for studies in neurobiology or any other biological functions. That ability to make molecules on demand inside the body could be useful in fields such as immunology or cancer research, she says.

The project got started as a result of a chance conversation between Park and Jin, who were friends working in different fields — neurobiology and electrochemistry. Their initial casual discussions ended up leading to a full-blown collaboration between several departments. But in today’s locked-down world, Jin says, such chance encounters and conversations have become less likely. “In the context of how much the world has changed, if this were in this era in which we’re all apart from each other, and not in 2018, there is some chance that this collaboration may just not ever have happened.”

“This work is a milestone in bioelectronics,” says Bozhi Tian, an associate professor of chemistry at the University of Chicago, who was not connected to this work. “It integrates nanoenabled catalysis, microfluidics, and traditional bioelectronics … and it solves a longstanding challenge of precise neuromodulation in the brain, by in situ generation of signaling molecules. This approach can be widely adopted by the neuroscience community and can be generalized to other signaling systems, too.”

Besides MIT, the team included researchers at National Chiao Tung University in Taiwan, NEC Corporation in Japan, and the Weizman Institute of Science in Israel. The work was supported by the National Institute for Neurological Disorders and Stroke, the National Institutes of Health, the National Science Foundation, and MIT’s Department of Chemical Engineering.

A focused approach to imaging neural activity in the brain

Anne Trafton |

When neurons fire an electrical impulse, they also experience a surge of calcium ions. By measuring those surges, researchers can indirectly monitor neuron activity, helping them to study the role of individual neurons in many different brain functions.

One drawback to this technique is the crosstalk generated by the axons and dendrites that extend from neighboring neurons, which makes it harder to get a distinctive signal from the neuron being studied. MIT engineers have now developed a way to overcome that issue, by creating calcium indicators, or sensors, that accumulate only in the body of a neuron.

“People are using calcium indicators for monitoring neural activity in many parts of the brain,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology and a professor of biological engineering and of brain and cognitive sciences at MIT. “Now they can get better results, obtaining more accurate neural recordings that are less contaminated by crosstalk.”

To achieve this, the researchers fused a commonly used calcium indicator called GCaMP to a short peptide that targets it to the cell body. The new molecule, which the researchers call SomaGCaMP, can be easily incorporated into existing workflows for calcium imaging, the researchers say.

Boyden is the senior author of the study, which appears today in Neuron. The paper’s lead authors are Research Scientist Or Shemesh, postdoc Changyang Linghu, and former postdoc Kiryl Piatkevich.

Molecular focus

The GCaMP calcium indicator consists of a fluorescent protein attached to a calcium-binding protein called calmodulin, and a calmodulin-binding protein called M13 peptide. GCaMP fluoresces when it binds to calcium ions in the brain, allowing researchers to indirectly measure neuron activity.

“Calcium is easy to image, because it goes from a very low concentration inside the cell to a very high concentration when a neuron is active,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research.

The simplest way to detect these fluorescent signals is with a type of imaging called one-photon microscopy. This is a relatively inexpensive technique that can image large brain samples at high speed, but the downside is that it picks up crosstalk between neighboring neurons. GCaMP goes into all parts of a neuron, so signals from the axons of one neuron can appear as if they are coming from the cell body of a neighbor, making the signal less accurate.

A more expensive technique called two-photon microscopy can partly overcome this by focusing light very narrowly onto individual neurons, but this approach requires specialized equipment and is also slower.

Boyden’s lab decided to take a different approach, by modifying the indicator itself, rather than the imaging equipment.

“We thought, rather than optically focusing light, what if we molecularly focused the indicator?” he says. “A lot of people use hardware, such as two-photon microscopes, to clean up the imaging. We’re trying to build a molecular version of what other people do with hardware.”

In a related paper that was published last year, Boyden and his colleagues used a similar approach to reduce crosstalk between fluorescent probes that directly image neurons’ membrane voltage. In parallel, they decided to try a similar approach with calcium imaging, which is a much more widely used technique.

To target GCaMP exclusively to cell bodies of neurons, the researchers tried fusing GCaMP to many different proteins. They explored two types of candidates — naturally occurring proteins that are known to accumulate in the cell body, and human-designed peptides — working with MIT biology Professor Amy Keating, who is also an author of the paper. These synthetic proteins are coiled-coil proteins, which have a distinctive structure in which multiple helices of the proteins coil together.

Less crosstalk

The researchers screened about 30 candidates in neurons grown in lab dishes, and then chose two — one artificial coiled-coil and one naturally occurring peptide — to test in animals. Working with Misha Ahrens, who studies zebrafish at the Janelia Research Campus, they found that both proteins offered significant improvements over the original version of GCaMP. The signal-to-noise ratio — a measure of the strength of the signal compared to background activity — went up, and activity between adjacent neurons showed reduced correlation.

In studies of mice, performed in the lab of Xue Han at Boston University, the researchers also found that the new indicators reduced the correlations between activity of neighboring neurons. Additional studies using a miniature microscope (called a microendoscope), performed in the lab of Kay Tye at the Salk Institute for Biological Studies, revealed a significant increase in signal-to-noise ratio with the new indicators.

“Our new indicator makes the signals more accurate. This suggests that the signals that people are measuring with regular GCaMP could include crosstalk,” Boyden says. “There’s the possibility of artifactual synchrony between the cells.”

In all of the animal studies, they found that the artificial, coiled-coil protein produced a brighter signal than the naturally occurring peptide that they tested. Boyden says it’s unclear why the coiled-coil proteins work so well, but one possibility is that they bind to each other, making them less likely to travel very far within the cell.

Boyden hopes to use the new molecules to try to image the entire brains of small animals such as worms and fish, and his lab is also making the new indicators available to any researchers who want to use them.

“It should be very easy to implement, and in fact many groups are already using it,” Boyden says. “They can just use the regular microscopes that they already are using for calcium imaging, but instead of using the regular GCaMP molecule, they can substitute our new version.”

The research was primarily funded by the National Institute of Mental Health and the National Institute of Drug Abuse, as well as a Director’s Pioneer Award from the National Institutes of Health, and by Lisa Yang, John Doerr, the HHMI-Simons Faculty Scholars Program, and the Human Frontier Science Program.

COMMANDing drug delivery

by Sabbi Lall |

While we are starting to get a handle on drugs and therapeutics that might to help alleviate brain disorders, efficient delivery remains a roadblock to tackling these devastating diseases. Research from the Graybiel, Cima, and Langer labs now uses a computational approach, one that accounts for the irregular shape of the target brain region, to deliver drugs effectively and specifically.

“Identifying therapeutic molecules that can treat neural disorders is just the first step,” says McGovern Investigator Ann Graybiel.

“There is still a formidable challenge when it comes to precisely delivering the therapeutic to the cells most affected in the disorder,” explains Graybiel, an MIT Institute Professor and a senior author on the paper. “Because the brain is so structurally complex, and subregions are irregular in shape, new delivery approaches are urgently needed.”

Fine targeting

Brain disorders often arise from dysfunction in specific regions. Parkinson’s disease, for example, arise from loss of neurons in a specific forebrain region, the striatum. Targeting such structures is a major therapeutic goal, and demands both overcoming the blood brain barrier, while also being specific to the structures affected by the disorder.

Such targeted therapy can potentially be achieved using intracerebral catheters. While this is a more specific form of delivery compared to systemic administration of a drug through the bloodstream, many brain regions are irregular in shape. This means that delivery throughout a specific brain region using a single catheter, while also limiting the spread of a given drug beyond the targeted area, is difficult. Indeed, intracerebral delivery of promising therapeutics has not led to the desired long-term alleviation of disorders.

“Accurate delivery of drugs to reach these targets is really important to ensure optimal efficacy and avoid off-target adverse effects. Our new system, called COMMAND, determines how best to dose targets,” says Michael Cima, senior author on the study and 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.

3D renderings of simulated multi-bolus delivery to various brain structures (striatum, amygdala, substantia nigra, and hippocampus) with one to four boluses.

COMMAND response

In the case of Parkinson’s disease, implants are available that limit symptoms, but these are only effective in a subset of patients. There are, however, a number of promising potential therapeutic treatments, such as GDNF administration, where long-term, precise delivery is needed to move the therapy forward.

The Graybiel, Cima, and Langer labs developed COMMAND (computational mapping algorithms for neural drug delivery) that helps to target a drug to a specific brain region at multiple sites (multi-bolus delivery).

“Many clinical trials are believed to have failed due to poor drug distribution following intracerebral injection,” explained Khalil Ramadi, PhD ’19, one of the lead researchers on the paper, and a postdoctoral fellow at the Koch and McGovern Institute. “We rationalized that both research experiments and clinical therapies would benefit from computationally optimized infusion, to enable greater consistency across groups and studies, as well as more efficacious therapeutic delivery.”

The COMMAND system finds balance between the twin challenges of drug delivery by maximizing on-target and minimizing off-target delivery. COMMAND is essentially an algorithm that minimizes an error that reflects leakage beyond the bounds of a specific target area, in this case the striatum. A second error is also minimized, and this encapsulates the need to target across this irregularly shaped brain region. The strategy to overcome this is to deliver multiple “boluses” to different areas of the striatum to target this region precisely, yet completely.

“COMMAND applies a simple principle when determining where to place the drug: Maximize the amount of drug falling within the target brain structure and minimize tissues exposed beyond the target region,” explains Ashvin Bashyam, PhD ’19, co-lead author and a former graduate student with Michael Cima at MIT. “This balance is specified based drug properties such as minimum effective therapeutic concentration, toxicity, and diffusivity within brain tissue.”

The number of drug sites applied is kept as low as possible, keeping surgery simple while still providing enough flexibility to cover the target region. In computational simulations, the researchers were able to deliver drugs to compact brain structures, such as the striatum and amygdala, but also broader and more irregular regions, such as hippocampus.

To examine the spatiotemporal dynamics of actual delivery, the researchers used positron emission tomography (PET) and a ‘labeled’ solution, Cu-64, that allowed them to image and follow an infused bolus after delivery with a microprobe. Using this system, the researchers successfully used PET to validate the accuracy of multi-bolus delivery to the rat striatum and its coverage as guided by COMMAND.

“We anticipate that COMMAND can improve researchers’ ability to precisely target brain structures to better understand their function, and become a platform to standardize methods across neuroscience experiments,” explains Graybiel. “Beyond the lab, we hope COMMAND will lay the foundation to help bring multifocal, chronic drug delivery to patients.”

Universal musical harmony

by Sabbi Lall |

Many forms of Western music make use of harmony, or the sound created by certain pairs of notes. A longstanding question is why some combinations of notes are perceived as pleasant while others sound jarring to the ear. Are the combinations we favor a universal phenomenon? Or are they specific to Western culture?

Through intrepid research trips to the remote Bolivian rainforest, the McDermott lab at the McGovern Institute has found that aspects of the perception of note combinations may be universal, even though the aesthetic evaluation of note combination as pleasant or unpleasant is culture-specific.

“Our work has suggested some universal features of perception that may shape musical behavior around the world,” says McGovern Associate Investigator Josh McDermott, senior author of the Nature Communications study. “But it also indicates the rich interplay with cultural influences that give rise to the experience of music.”

Remote learning

Questions about the universality of musical perception are difficult to answer, in part because of the challenge in finding people with little exposure to Western music. McDermott, who is also an associate professor in MIT’s Department of Brain and Cognitive Sciences and an investigator in the Center for Brains Minds and Machines, has found a way to address this problem. His lab has performed a series of studies with the participation of an indigenous population, the Tsimane’, who live in relative isolation from Western culture and have had little exposure to Western music. Accessing the Tsimane’ villages is challenging, as they are scattered throughout the rainforest and only reachable during the dry part of the year.

Left to right Josh McDermott (in vehicle), Alex Durango, Sophie Dolan and Malinda McPherson experiencing a travel delay en route to a Tsimane’ village after a heavy rainfall. Photo: Malinda McPherson

“When we enter a village there is always a crowd of curious children to greet us,” says Malinda McPherson, a graduate student in the lab and lead author of the study. “Tsimane’ are friendly and welcoming, and we have visited some villages several times, so now many people recognize us.”

In a study published in 2019, McDermott’s team found evidence that the brain’s ability to detect musical octaves is not universal, but is gained through cultural experience. And in 2016 they published findings suggesting that the preference for consonance over dissonance is culture-specific. In their new study, the team decided to explore whether aspects of the perception of consonance and dissonance might nonetheless be universally present across cultures.

Music lessons

In Western music, harmony is the sound of two or more notes heard simultaneously. Think of the Leonard Cohen song, Hallelujah, where he sings about harmony (“the fourth, the fifth, the minor fall and the major lift”). A combination of two notes is called an interval, and intervals that are perceived to be the most pleasant (or consonant, like the fourth and the fifth, for example) to the Western ear are generally represented by smaller integer ratios.

Intervals that are related by low integer ratios have fascinated scientists for centuries.

“Such intervals are central to Western music, but are also believed to be a common feature of many musical systems around the world,” McPherson explains. “So intervals are a natural target for cross-cultural research, which can help identify aspects of perception that are and aren’t independent of cultural experience.”

Scientists have been drawn to low integer ratios in music in part because they relate to the frequencies in voices and many instruments, known as ‘overtones’. Overtones from sounds like voices form a particular pattern known as the harmonic series. As it happens, the combination of two concurrent notes related by a low integer ratio partially reproduces this pattern. Because the brain presumably evolved to represent natural sounds, such as voices, it has seemed plausible that intervals with low integer ratios might have special perceptual status across cultures.

Since the Tsimane’ do not generally sing or play music together, meaning they have not been trained to hear or sing in harmony, McPherson and her colleagues were presented with a unique opportunity to explore whether there is anything universal about the perception of musical intervals.

Taking notes

In order to probe the perception of musical intervals, McDermott and colleagues took advantage of the fact that ears accustomed to Western musical harmony often have difficulty picking apart two “consonant” notes when they are played at the same time. This auditory confusion is known as “fusion” in the field. By contrast, two “dissonant” notes are easier to hear as separate.

The tendency of “consonant” notes to be heard by Westerners as fused could reflect their common occurrence in Western music. But it could also be driven by the resemblance of low-integer-ratio note combinations to the harmonic series. This similarity of consonant intervals to the acoustic structure of typical natural sounds raises the possibility that the human brain is biologically tuned to “fuse” consonant notes.

Graduate student and lead author, Malinda McPherson, works with a participant and translator in the field. Photo: Malinda McPherson

To explore this question, the team ran identical sets of experiments on two participant groups: US non-musicians residing in the Boston metropolitan area and Tsimane’ residing in villages in the Amazon rain forest. Listeners heard two concurrent notes separated by a particular musical interval (consonant or dissonant), and were asked to judge whether they heard one or two sounds. The experiment was performed with both synthetic and natural sounds.

They found that like the Boston cohort, the Tsimane’ were more likely to mistake two notes as a single sound if they were consonant than if they were dissonant.

“I was surprised by how similar some of the results in Tsimane’ participants were to those in US participants,” says McPherson, “particularly given the striking differences that we consistently see in preferences for musical intervals.”

When it came to whether consonant intervals were more pleasant than dissonant intervals, the results told a very different story. While the US study participants found consonant intervals more pleasant than dissonant intervals, the Tsimane’ showed no preference, implying that our sense of what is pleasant is shaped by culture.

“The fusion results provide an example of a perceptual effect that could influence musical systems, for instance by creating a natural perceptual contrast to exploit,” explains McDermott. “Hopefully our work helps to show how one can conduct rigorous perceptual experiments in the field and learn things that would be hidden if we didn’t consider populations in other parts of the world.”

Turning lemons into lemonade

by Gayle Lutchen |

When it was announced that all non-research staff were to work from home I think we were all in shock – well, I was in shock.

I always envisioned my role as being tied to actually being on campus in our building.  That said, our headquarters packed up in record time and in one day we were all working from home.  I thrive on a lot of structure in my day, so coordinated a daily check-in meeting with our HQ team. I think that has made a big difference in how we have all acclimated to working at home.

We are still connected, troubleshooting issues, and being incredibly productive.

I spent the first month basically coordinating the ramp-down of the building, so many lists!  Now thankfully, we are looking to the future, and to one day re-engaging with the building.

I see myself as a conduit for information from senior leadership at MIT to our group in MIBR HQ and I continue to brainstorm with staff, gather each morning for coffee, and put forth a glass half-full mentality.  The team I work with is amazing and I feel we keep each other focused and committed to supporting our researchers and faculty, and keeping our cool under challenging circumstances. I’ve also kept up with my workout routine and have started experimenting with different recipes for my family.  I continue to try to turn lemons into lemonade, both at work and home.

Gayle Lutchen has been the Assistant Director for Administration at the McGovern Institute for twenty years. 

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SHERLOCK-based one-step test provides rapid and sensitive COVID-19 detection 

by Sabbi Lall |

A team of researchers at the McGovern Institute for Brain Research at MIT, the Broad Institute of MIT and Harvard, the Ragon Institute, and the Howard Hughes Medical Institute (HHMI) has developed a new diagnostics platform called STOP (SHERLOCK Testing in One Pot) COVID. The test can be run in an hour as a single-step reaction with minimal handling, advancing the CRISPR-based SHERLOCK diagnostic technology closer to a point-of-care or at-home testing tool. The test has not been reviewed or approved by the FDA and is currently for research purposes only.

The team began developing tests for COVID-19 in January after learning about the emergence of a new virus which has challenged the healthcare system in China. The first version of the team’s SHERLOCK-based COVID-19 diagnostics system is already being used in hospitals in Thailand to help screen patients for COVID-19 infection.

The ability to test for COVID-19 at home, or even in pharmacies or places of employment, could be a game-changer for getting people safely back to work and into their communities.

The new test is named “STOPCovid” and is based on the STOP platform. In research it has been shown to enable rapid, accurate, and highly sensitive detection of the COVID-19 virus SARS-CoV-2 with a simple protocol that requires minimal training and uses simple, readily-available equipment, such as test tubes and water baths. STOPCovid has been validated in research settings using nasopharyngeal swabs from patients diagnosed with COVID-19. It has also been tested successfully in saliva samples to which SARS-CoV-2 RNA has been added as a proof-of-principle.

The team is posting the open protocol today on a new website, STOPCovid.science. It is being made openly available in line with the COVID-19 Technology Access Framework organized by Harvard, MIT, and Stanford. The Framework sets a model by which critically important technologies that may help prevent, diagnose, or treat COVID-19 infections may be deployed for the greatest public benefit without delay.

There is an urgent need for widespread, accurate COVID-19 testing to rapidly detect new cases, ideally without the need for specialized lab equipment. Such testing would enable early detection of new infections and drive effective “test-trace-isolate” measures to quickly contain new outbreaks. However, current testing capacity is limited by a combination of requirements for complex procedures and laboratory instrumentation and dependence on limited supplies. STOPCovid can be performed without RNA extraction, and while all patient tests have been performed with samples from nasopharyngeal swabs, preliminary experiments suggest that eventually swabs may not be necessary. Removing these barriers could help enable broad distribution.

“The ability to test for COVID-19 at home, or even in pharmacies or places of employment, could be a game-changer for getting people safely back to work and into their communities,” says Feng Zhang, a co-inventor of the CRISPR genome editing technology, an investigator at the McGovern Institute and HHMI, and a core member at the Broad Institute. “Creating a point-of-care tool is a critically important goal to allow timely decisions for protecting patients and those around them.”

To meet this need, Zhang, McGovern Fellows Omar Abudayyeh and Jonathan Gootenberg, and colleagues initiated a push to develop STOPCovid. They are sharing their findings and packaging reagents so other research teams can rapidly follow up with additional testing or development. The group is also sharing data on the StopCOVID.science website and via a submitted preprint. The website is also a hub where the public can find the latest information on the team’s developments.

McGovern Institute Fellows Jonathan Gootenberg (far left) Omar Abudayyeh and have developed a CRISPR research tool to detect COVID-19 with McGovern Investigator Feng Zhang (far right).
Credit: Justin Knight

How it works

The STOPCovid test combines CRISPR enzymes, programmed to recognize signatures of the SARS-CoV-2 virus, with complementary amplification reagents. This combination allows detection of as few as 100 copies of SARS-CoV-2 virus in a sample. As a result, the STOPCovid test allows for rapid, accurate, and highly sensitive detection of COVID-19 that can be conducted outside clinical laboratory settings.

STOPCovid has been tested on patient nasopharyngeal swab in parallel with clinically-validated tests. In these head-to-head comparisons, STOPCovid detected infection with 97% sensitivity and 100% specificity. Results appear on an easy-to-read strip that is akin to a pregnancy test, in the absence of any expensive or specialized lab equipment. Moreover, the researchers spiked mock SARS-CoV-2 genomes into healthy saliva samples and showed that STOPCovid is capable of sensitive detection from saliva, which would obviate the need for swabs in short supply and potentially make sampling much easier.

“The test aims to ultimately be simple enough that anyone can operate it in low-resource settings, including in clinics, pharmacies, or workplaces, and it could potentially even be put into a turn-key format for use at home,” says Abudayyeh.

Gootenberg adds, “Since STOPCovid can work in less than an hour and does not require any specialized equipment, and if our preliminary results from testing synthetic virus in saliva bear out in patient samples, it could address the need for scalable testing to reopen our society.”

The STOPCovid team during a recent zoom meeting. Image: Omar Abudayyeh

Importantly, the full test — both the viral genome amplification and subsequent detection — can be completed in a single reaction, as outlined on the website, from swabs or saliva. To engineer this, the team tested a number of CRISPR enzymes to find one that works well at the same temperature needed by the enzymes that perform the amplification. Zhang, Abudayyeh, Gootenberg and their teams, including graduate students Julia Joung and Alim Ladha, settled on a protein called AapCas12b, a CRISPR protein from the bacterium Alicyclobacillus acidophilus, responsible for the “off” taste associated with spoiled orange juice. With AapCas12b, the team was able to develop a test that can be performed at a constant temperature and does not require opening tubes midway through the process, a step that often leads to contamination and unreliable test results.

Information sharing and next steps

The team has prepared reagents for 10,000 tests to share with scientists and clinical collaborators for free around the world who want to evaluate the STOPCovid test for potential diagnostic use, and they have set up a website to share the latest data and updates with the scientific and clinical community. Kits and reagents can also be requested via a form on the website.

Acknowledgments: Patient samples were provided by Keith Jerome, Alex Greninger, Robert Bruneau, Mee-li W. Huang, Nam G. Kim, Xu Yu, Jonathan Li, and Bruce Walker. This work was supported by the Patrick J. McGovern Foundation and the McGovern Institute for Brain Research. F.Z is also supported by the NIH (1R01- MH110049 and 1DP1-HL141201 grants); Mathers Foundation; the Howard Hughes Medical Institute; Open Philanthropy Project; J. and P. Poitras; and R. Metcalfe.

Declaration of conflicts of interest: F.Z., O.O.A., J.S.G., J.J., and A.L. are inventors on patent applications related to this technology filed by the Broad Institute, with the specific aim of ensuring this technology can be made freely, widely, and rapidly available for research and deployment. O.O.A., J.S.G., and F.Z. are co-founders, scientific advisors, and hold equity interests in Sherlock Biosciences, Inc. F.Z. is also a co-founder of Editas Medicine, Beam Therapeutics, Pairwise Plants, and Arbor Biotechnologies.

Optogenetics with SOUL

by Sabbi Lall |

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

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

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

Engineering with light

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

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

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

Probing the brain with SOUL

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

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

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

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

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

Family members unite to fight COVID-19

by Sugandha Sharma |

Even before MIT sent out its first official announcement about the COVID-19 crisis, I had already asked permission from my supervisor and taken my computer home so that I could start working from home.

My first and foremost concern was my family and friends. I was born and brought up in India, and then immigrated to Canada, so I have a big and wonderful family spread across both those countries. These countries had a lower number of COVID-19 cases at the time, but I could see what would be coming their way. I was anxious, very anxious. In India, my dad being an anesthetist could be exposed while working in the hospital. In Canada, my uncle who is a physician could be exposed, and on top of that he lives in the same house as my grandparents who are even more vulnerable due to their age. I knew I had to do something.

We started having regular video calls as a family. My mom even led daily online yoga sessions, and the discussions that followed those sessions ensured that we didn’t feel lonely and gave us a sense of purpose. Together, we looked at the statistics in the data from China and Italy, and learned that we needed to flatten the curve due to the lack of medical resources required to meet the need of the hour. We could foresee that more infections would lead to more patients, thus raising the demand for medical resources beyond the amount we had available.

We had several discussions around developing products for helping medical professionals and the general public during this pandemic.

We learned that since no government has enough resources to cope at the time of pandemics, we have to be innovative in trying to make the best use of the limited resources available to us.

Through our discussions and experiences of some of us in the field, we came to the conclusion that the only way to effectively fight COVID-19 is prevention at source. Hence, we started working on a mobile app that uses AI and advanced data analytics to trace contact, determine the risk of infection, and thereby suggest precautions. Luckily we have engineers and computer scientists in our family (my own background is in electrical engineering), so it was easy for us to divide the work.  In our prototype, when people sign-up, they are asked to fill out a short self-assessment form that can be used to identify any symptoms of COVID-19. This data is then used to predict vulnerable areas and to give recommendations to people who might have taken a certain route as shown below.

Sharma’s mobile app showing heatmap of the vulnerable areas in a locality in Toronto, ON (left) and personalized recommendations based on the most recent route taken by an individual (right).

We ended up submitting our proposal and prototype to the COVID-19 challenge launched by Vale (a global mining company) and the winners will be announced in May.

Personally, to be completely honest, I had my times when I broke down due to everything that was going on in the world around me. It’s not easy to see people dying, and losing jobs. My way of staying strong was to make sure that I was doing my best to contribute.

I have set up a beautiful home office for myself and I am focusing on my PhD research, being grateful that I can still continue to do it from home. I have also restarted the joint MIT-Harvard computational neuroscience journal club meetings online, so that members can get access to this wonderful community once again! It was amazing to see from a poll we conducted that 92% of the members of the club wanted the meetings to be re-started online.

These times are unprecedented for my generation, my mom’s generation and even for my grandmother’s generation. I have never seen the world come together in a way I have seen during this pandemic. The kind of response we have seen from our societies and governments across the globe shows that we can make intelligent decisions for the collective good of humanity. For once, we’re all on the same side!

Sugandha (Su) Sharma is a graduate student in the labs of Ila Fiete and Josh Tenenbaum. When she’s not developing a mobile app to fight COVID-19, Su explores the computational and theoretical principles underlying higher level cognition and intelligence in the human brain.

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