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The Learning Brain

by Shannon Fischer |

“There’s a slogan in education,” says McGovern Investigator John Gabrieli. “The first three years are learning to read, and after that you read to learn.”

For John Gabrieli, learning to read represents one of the most important milestones in a child’s life. Except, that is, when a child can’t. Children who cannot learn to read adequately by the first grade have a 90 percent chance of still reading poorly in the fourth grade, and 75 percent odds of struggling in high school. For the estimated 10 percent of schoolchildren with a reading disability, that struggle often comes with a host of other social and emotional challenges: anxiety, damaged self-esteem, increased risk for poverty and eventually, encounters with the criminal justice system.

Most reading interventions focus on classical dyslexia, which is essentially a coding problem—trouble moving letters into sound patterns in the brain. But other factors, such as inadequate vocabulary and lack of practice opportunities, hinder reading too. The diagnosis can be subjective, and for those who are diagnosed, the standard treatments help only some students. “Every teacher knows half to two-thirds have a good response, the other third don’t,” Gabrieli says. “It’s a mystery. And amazingly there’s been almost no progress on that.”

For the last two decades, Gabrieli has sought to unravel the neuroscience behind learning and reading disabilities and, ultimately, convert that understanding into new and better education
interventions—a sort of translational medicine for the classroom.

The Home Effect

In 2011, when Julia Leonard was a research assistant in Gabrieli’s lab, she planned to go into pediatrics. But she became drawn to the lab’s education projects and decided to join the lab as
a graduate student to learn more. By 2015, she helped coauthor a landmark study with postdoc Allyson Mackey, that sought neural markers for the academic “achievement gap,” which separates higher socioeconomic status (SES) children from their disadvantaged peers. It was the first study to make a connection between SES-linked differences in brain structure and educational markers. Specifically, they found children from wealthier backgrounds had thicker cortical brain regions, which correlated with better academic achievement.

“Being a doctor is a really awesome and powerful career,” she says. “But I was more curious about the research that could cause bigger changes in children’s lives.”

Leonard collaborated with Rachel Romeo, another graduate student in the Gabrieli lab who wanted to understand the powerful effect of SES on the developing brain. Romeo had a distinctive background in speech pathology and literacy, where she’d observed wealthier students progressing more quickly compared to their disadvantaged peers.

Their research is revealing a fascinating picture. In a 2017 study, Romeo compared how reading-disabled children from low and high SES backgrounds fared after an intensive summer reading intervention. Low SES children in the intervention improved most in their reading, and MRI scans revealed their brains also underwent greater structural changes in response to the intervention. Higher SES children did not appear to change much, either in skill or brain structure.

“In the few studies that have looked at SES effects on treatment outcomes,” Romeo says, “the research suggests that higher SES kids would show the most improvement. We were surprised to
find that this wasn’t true.” She suspects that the midsummer timing of the intervention may account for this. Lower SES kids’ performance often suffer most during a “summer slump,”
and would therefore have the greatest potential to improve from interventions at this time.

However, in another study this year, Leonard uncovered unique brain differences in lower-SES children. Only among lower-SES children was better reasoning ability associated with thicker
cortex in a key part of the brain. Same behavior, different neural signatures.

“So this becomes a really interesting basic science question,” Leonard says. “Does the brain support cognition the same way across everyone, or does it differ based on how you grow up?”

Not a One-Size-Fits-All

Critics of such “educational neuroscience” have highlighted the lack of useful interventions produced by this research. Gabrieli agrees that so far, little has emerged. “The painful thing is the slowness of this work. It’s mind-boggling,” Gabrieli admits. Every intervention requires all the usual human research requirements, plus coordinating with schools, parents, teachers, and so on. “It’s a huge process to do even the smallest intervention,” he explains. Partly because of that, the field is still relatively new.

But he disagrees with the idea that nothing will come from this research. Gabrieli’s lab previously identified neural markers in children who will go on to develop reading disabilities. These markers could even predict who would or would not respond to standard treatments that focus on phonetic letter-sound coding.

Romeo and Leonard’s work suggests that varied etiologies underlie reading disabilities, which may be the key. “For so long people have thought that reading disorders were just a unitary construct: kids are bad at reading, so let’s fix that with a one-size-fits-all treatment,” Romeo says.

Such findings may ultimately help resource-strapped schools target existing phonetic training rather than enrolling all struggling readers in the same program, to see some still fail.

Think Spaces

At the Oliver Hazard Perry School, a public K-8 school located on the South Boston waterfront, teachers like Colleen Labbe have begun to independently navigate similar problems as they try
to reach their own struggling students.

“A lot of times we look at assessments and put students in intervention groups like phonics,” Labbe says. “But it’s important to also ask what is happening for these students on their way to school and at home.”

For Labbe and Perry Principal Geoffrey Rose, brain science has proven transformative. They’ve embraced literature on neuroplasticity—the idea that brains can change if teachers find the right combination of intervention and circumstances, like the low-SES students who benefited in Romeo and Leonard’s study.

“A big myth is that the brain can’t grow and change, and if you can’t reach that student, you pass them off,” Labbe says.

The science has also been empowering to her students, validating their own powers of self-change. “I tell the kids, we’re going to build the goop!” she says, referring to the brain’s ability to make new connections.

“All kids can learn,” Rose agrees. “But the flip of that is, can all kids do school?” His job, he says, is to make sure they can.

The classrooms at Perry are a mix of students from different cultures and socioeconomic backgrounds, so he and Labbe have focused on helping teachers find ways to connect with these children and help them manage their stresses and thus be ready to learn. Teachers here are armed with “scaffolds”—digestible neuro- and cognitive science aids culled from Rose’s postdoctoral studies at Boston College’s Professional School Administrator Program for school leaders. These encourage teachers to be more aware of cultural differences and tendencies in themselves and their students, to better connect.

There are also “Think Spaces” tucked into classroom corners. “Take a deep breath and be calm,” read posters at these soothing stations, which are equipped with de-stressing tools, like squeezable balls, play-dough, and meditation-inspiring sparkle wands. It sounds trivial, yet studies have shown that poverty-linked stressors like food and home insecurity take a toll on emotion and memory-linked brain areas like the amygdala and hippocampus.

In fact, a new study by Clemens Bauer, a postdoc in Gabrieli’s lab, argues that mindfulness training can help calm amygdala hyperactivity, help lower self-perceived stress, and boost attention. His study was conducted with children enrolled in a Boston charter school.

Taking these combined approaches, Labbe says, she’s seen one of her students rise from struggling at the lowest levels of instruction, to thriving by year end. Labbe’s focus on understanding the girl’s stressors, her family environment, and what social and emotional support she really needed was key. “Now she knows she can do it,” Labbe says.

Rose and Labbe only wish they could better bridge the gap between educators like themselves and brain scientists like Gabrieli. To help forge these connections, Rose recently visited Gabrieli’s lab and looks forward to future collaborations. Brain research will provide critical insights into teaching strategy, he says, but the gap is still wide.

From Lab to Classroom

“I’m hugely impressed by principals and teachers who are passionately interested in understanding the brain,” Gabrieli says. Fortunately, new efforts are bridging educators and scientists.

This March, Gabrieli and the MIT Integrated Learning Initiative—MITili, which he also directs—announced a $30 million-dollar grant from the Chan Zuckerberg Initiative for a collaboration
between MIT, the Harvard Graduate School of Education, and Florida State University.

The grant aims to translate some of Gabrieli’s work into more classrooms. Specifically, he hopes to produce better diagnostics that can identify children at risk for dyslexia and other learning
disabilities before they even learn to read.

He hopes to also provide rudimentary diagnostics that identify the source of struggle, be it classic dyslexia, lack of home support, stress, or maybe a combination of factors. That in turn,
could guide treatment—standard phonetic care for some children, versus alternatives: social support akin to Labbe’s efforts, reading practice, or maybe just vocabulary-boosting conversation time with adults.

“We want to get every kid to be an adequate reader by the end of the third grade,” Gabrieli says. “That’s the ultimate goal for me: to help all children become learners.”

Michale Fee receives McKnight Technological Innovations in Neuroscience Award

Anne Trafton |

McGovern Institute investigator Michale Fee has been selected to receive a 2018 McKnight Technological Innovations in Neuroscience Award for his research on “new technologies for imaging and analyzing neural state-space trajectories in freely-behaving small animals.”

“I am delighted to get support from the McKnight Foundation,” says Fee, who is also the Glen V. and Phyllis F. Dorflinger Professor in the Department of Brain and Cognitive Neurosciences at MIT. “We’re very excited about this project which aims to develop technology that will be a great help to the broader neuroscience community.”

Fee studies the neural mechanisms by which the brain, specifically that of juvenile songbirds, learns complex sequential behaviors. The way that songbirds learn a song through trial and error is analogous to humans learning complex behaviors, such as riding a bicycle. While it would be insightful to link such learning to neural activity, current methods for monitoring neurons can only monitor a limited field of neurons, a big issue since such learning and behavior involve complex interactions between larger circuits. While a wider field of view for recordings would help decipher neural changes linked to this learning paradigm, current microscopy equipment is large relative to a juvenile songbird, and microscopes that can record neural activity generally constrain the behavior of small animals. Ideally, technologies need to be lightweight (about 1 gram) and compact in size (the size of a dime), a far cry from current larger microscopes that weigh in at 3 grams. Fee hopes to be able to break these technical boundaries and miniaturize the recording equipment thus allowing recording of more neurons in naturally behaving small animals.

“We are thrilled that the McKnight Foundation has chosen to support this project. The technology that Michale’s developing will help to better visualize and understand the circuits underlying learning,” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research.

In addition to development and miniaturization of the microscopy hardware itself, the award will support the development of technology that helps analyze the resulting images, so that the neuroscience community at large can more easily deploy and use the technology.

Are eyes the window to the soul?

Anne Trafton |

Covert attention has been defined as shifting attention without shifting the eyes. The notion that we can internally pay attention to an object in a scene without making eye movements to it has been a cornerstone of the fields of psychology and cognitive neuroscience, which attempt to understand mental phenomena that are purely internal to the mind, divorced from movements of the eyes or limbs. A study from the McGovern Institute for Brain Research at MIT now questions the dissociation of eye movements from attention in this context, finding that microsaccades precede modulation of specific brain regions associated with attention. In other words, a small shift of the eyes is linked to covert attention, after all.

Seeing the world through human eyes, which have a focused, high-acuity center to the field of vision, requires saccades (rapid movements of the eyes that move between points of fixation). Saccades help to piece together important information in an overall scene and are closely linked to attention shifts, at least in the case of overt attention. In the case of covert attention, the view has been different since this type of attention can shift while the gaze is fixed. Microsaccades are tiny movements of the eyes that are made when subjects maintain fixation on an object.

“Microsaccades are typically so small, that they are ignored by many researchers.” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research and lead author on the study. “We went in and tested what they might represent by linking them to attentional firing in particular brain regions.”

In the study from Desimone and his team, the authors used an infrared eye-tracking system to follow microsaccades in awake macaques. The authors monitored activity in cortical regions of the brain linked to visual attention, including area V4. The authors saw increased neuronal firing in V4, but only when preceded by a microsaccade toward the attended stimulus. This effect on neuronal activity vanished when a microsaccade was directed away from the stimulus. The authors also saw increased firing in the inferior temporal (IT) cortex after a microsaccade, and even found that attention to an object amongst a ‘clutter’ of different visual objects, finding that attention to a specific object in the group was preceded by a microsaccade.

“I expected some links between microsaccades and covert attention,” says lead author of the study Eric Lowet, now a postdoctoral fellow at Boston University. “However, the magnitude of the effect and the precise link to microsaccade onset was surprising to me and the lab. Furthermore, to see these effects also in the IT cortex, which has large receptive fields and is involved in higher-order visual cognition, was striking”.

Why was this strong effect previously missed? The separation of eye movement and attention is so core to the concept of covert attention, that studies often actively seek to separate the visual stimulus by directing attention to a target outside the receptive field of vision, while the subject’s gaze is maintained on a fixation stimulus. The authors are the first to directly test microsaccades toward and away from an attended stimulus, and it was this set up, and the difference in neuronal firing upon separating these eye movements, that allowed them to draw the conclusions made.

“When we first separated attention effects on V4 firing rates by the direction of the microsaccade relative to the attended stimulus,” Lowet explains, “I realized this analysis was a game changer.”

The study suggests several future directions of study that are being pursued by the Desimone lab. Low frequency rhythmic (in the delta and theta range) sampling has been suggested as a possible explanation for attentional modulation. According to this idea, people sample visual scenes rhythmically, with an intrinsic sampling interval of about a quarter of a second.

“We do not know whether microsaccades and delta/theta rhythms have a common generator,” points out Karthik Srinivasan, a co-author on the study and a scientist at the McGovern Institute. “But if they do, what brain areas are the source of such a generator? Are the low frequency rhythms observed merely the frequency-analytic manifestation of microsaccades or are they linked?”

These are intriguing future steps for analysis that can be addressed in light of the current study which points to microsaccades as an important marker for visual attention and cognitive processes. Indeed, some of the previously hidden aspects of our cognition are revealed through our motor behavior after all.

Does our ability to learn new things stop at a certain age?

by The Brain |

This is actually a neuromyth, but it has some basis in scientific research. People’s endorsement of this statement is likely due to research indicating that there is a high level of synaptogenesis (formation of connections between neurons) between ages 0-3, that some skills (learning a new language, for example) do diminish with age, and some events in brain development, such as connections in the visual system, are tied to exposure to a stimulus, such as light. That said, it is clear that a new language can be learned later in life, and at the level of synaptogenesis, we now know that synaptic connections are plastic.

If you thought this statement was true, you’re not alone. Indeed, a 2017 study by McGrath and colleagues found that 18% of the public (N = 3,045) and 19% of educators (N = 598) believed this statement was correct.

Learn more about how teachers and McGovern researchers are working to target learning interventions well past so-called “critical periods” for learning.

Chronic neural implants modulate microstructures in the brain with pinpoint accuracy

Anne Trafton |

Post by Windy Pham

The diversity of structures and functions of the brain is becoming increasingly realized in research today. Key structures exist in the brain that regulate emotion, anxiety, happiness, memory, and mobility. These structures can come in a huge variety of shapes and sizes and can all be physically near one another. Dysfunction of these structures and circuits linking them are common causes of many neurologic and neuropsychiatric diseases. For example, the substantia nigra is only a few millimeters in size yet is crucial for movement and coordination. Destruction of substantia nigra neurons is what causes motor symptoms in Parkinson’s disease.

New technologies such as optogenetics have allowed us to identify similar microstructures in the brain. However, these techniques rely on liquid infusions into the brain, which prepare the regions to be studied to respond to light. These infusions are done with large needles, which do not have the fine control to target specific regions. Clinical therapy has also lagged behind. New drug therapies aimed at treating these conditions are delivered orally, which results in drug distribution throughout the brain, or through large needle-cannulas, which do not have the fine control to accurately dose specific regions. As a result, patients of neurologic and psychiatric disorders frequently fail to respond to therapies due to poor drug delivery to diseased regions.

A new study addressing this problem has been published in Proceedings of the National Academy of Sciences. The lead author is Khalil Ramadi, a medical engineering and medical physics (MEMP) PhD candidate in the Harvard-MIT Program in Health Sciences and Technology (HST). For this study, Khalil and his thesis advisor, Michael Cima, the David H. Koch Professor of Engineering within the Department of Materials Science and Engineering and the Koch Institute for Integrative Cancer Research, and associate dean of innovation in the School of Engineering, collaborated with Institute Professors Robert Langer and Ann Graybiel, an Investigator at the McGovern Institute of Brain Research to tackle this issue.

The team developed tools to enable targeted delivery of nanoliters of drugs to deep brain structures through chronically implanted microprobes. They also developed nuclear imaging techniques using positron emission tomography (PET) to measure the volume of the brain region targeted with each infusion. “Drugs for disorders of the central nervous system are nonspecific and get distributed throughout the brain,” Cima says. “Our animal studies show that volume is a critical factor when delivering drugs to the brain, as important as the total dose delivered. Using microcannulas and microPET imaging, we can control the area of brain exposed to these drugs, improving targeting accuracy double time comparing to the traditional methods used today.”

The researchers were also able to design cannulas that are MRI-compatible and implanted up to one year in rats. Implanting these cannulas with micropumps allowed the researchers to remotely control the behavior of animals. Significantly, they found that varying the volume infused alone had a profound effect on behavior induced, even if the total drug dose delivered stayed constant. These results show that regulation of volume delivery to brain region is extremely important in influencing brain activity. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more effective treatment in human patients.

 

 

Advancing knowledge in medical and genetic sciences

Anne Trafton |

Research proposals from Laurie Boyer, associate professor of biology; Matt Shoulders, the Whitehead Career Development Associate Professor of Chemistry; and Feng Zhang, associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering, Patricia and James Poitras ’63 Professor in Neuroscience, investigator at the McGovern Institute for Brain Research, and core member of the Broad Institute, have recently been selected for funding by the G. Harold and Leila Y. Mathers Foundation. These three grants from the Mathers Foundation will enable, over the next three years, key projects in the researchers’ respective labs.

Regenerative medicine holds great promise for treating heart failure, but that promise is unrealized, in part, due to a lack of sufficient understanding of heart development at the mechanistic level. Boyer’s research aims to achieve a deep, mechanistic understanding of the gene control switches that coordinate normal heart development. She then aims to leverage this knowledge and design effective strategies for rewiring faulty circuits in aging and disease.

“We are very grateful to receive support and recognition of our work from the Mathers Foundation,” said Boyer. “This award will allow us to build upon our prior work and to embark upon high risk projects that could ultimately change how we think about treating diseases resulting from faulty wiring of gene expression programs.”

Shoulders’ goal, with this support from the Mathers Foundation, is to elucidate underlying causes of osteoarthritis. There is currently no cure for osteoarthritis, which is perhaps the most common aging-related disease and is characterized by a progressive deterioration of joint cartilage culminating in inflammation, debilitating pain, and joint dysfunction. The Shoulders Group aims to test a new model for osteoarthritis — specifically, the concept that a collapse of proteostasis in aging cartilage cells creates an unrecoverable cartilage repair defect, thus initiating a self-amplifying, destructive feedback loop leading to pathology. Proteostasis collapse in aging cells is a well-known, disease-causing phenomenon that has previously been considered primarily in the context of neurodegenerative disorders. If correct, the proteostasis collapse model for osteoarthritis could one day lead to a novel class of therapeutic options for the disease.

“We are delighted to receive this generous support from the Mathers Foundation, which makes it possible for us to pursue an outside-the-box, high-risk/high-impact idea regarding the origins of osteoarthritis,” said Shoulders. “The research we are now able to pursue will not only provide fundamental, molecular-level insights into joint function, but also could change how we think about this widespread disease.”

Many genetic diseases are caused by the change of just a single base of DNA. Zhang is a leader in the field of genome editing, and he and his team have developed an array of tools based on the microbial immune CRISPR-Cas systems that can manipulate DNA and RNA in human cells. Together, these tools are changing the way molecular biology research is conducted, and they hold immense potential as therapeutic agents to correct thousands of genetic diseases. Now, with the support of the Mathers Foundation, Zhang is working to realize this potential by developing a CRISPR-based therapeutic that works at the level of RNA and offers a safe, effective route to treating a range of diseases, including diseases of the brain and central nervous system, which are difficult to treat with existing gene therapies.

“The generous support from the Mathers Foundation allows us the freedom to explore this exciting new direction for CRISPR-based technologies,” Zhang stated.

Known for their generosity and philanthropy, G. Harold and Leila Y. Mathers created their foundation with the goal of distributing their wealth among sustainable, charitable causes, with a particular interest in basic scientific research. The Mathers Foundation, whose ongoing mission is to advance knowledge in the life sciences by sponsoring scientific research and applying learnings and discoveries to benefit mankind, has issued grants since 1982.

How music lessons can improve language skills

Anne Trafton |

Many studies have shown that musical training can enhance language skills. However, it was unknown whether music lessons improve general cognitive ability, leading to better language proficiency, or if the effect of music is more specific to language processing.

A new study from MIT has found that piano lessons have a very specific effect on kindergartners’ ability to distinguish different pitches, which translates into an improvement in discriminating between spoken words. However, the piano lessons did not appear to confer any benefit for overall cognitive ability, as measured by IQ, attention span, and working memory.

“The children didn’t differ in the more broad cognitive measures, but they did show some improvements in word discrimination, particularly for consonants. The piano group showed the best improvement there,” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research and the senior author of the paper.

The study, performed in Beijing, suggests that musical training is at least as beneficial in improving language skills, and possibly more beneficial, than offering children extra reading lessons. The school where the study was performed has continued to offer piano lessons to students, and the researchers hope their findings could encourage other schools to keep or enhance their music offerings.

Yun Nan, an associate professor at Beijing Normal University, is the lead author of the study, which appears in the Proceedings of the National Academy of Sciences the week of June 25.

Other authors include Li Liu, Hua Shu, and Qi Dong, all of Beijing Normal University; Eveline Geiser, a former MIT research scientist; Chen-Chen Gong, an MIT research associate; and John Gabrieli, the Grover M. Hermann Professor in Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research.

Benefits of music

Previous studies have shown that on average, musicians perform better than nonmusicians on tasks such as reading comprehension, distinguishing speech from background noise, and rapid auditory processing. However, most of these studies have been done by asking people about their past musical training. The MIT researchers wanted to perform a more controlled study in which they could randomly assign children to receive music lessons or not, and then measure the effects.

They decided to perform the study at a school in Beijing, along with researchers from the IDG/McGovern Institute at Beijing Normal University, in part because education officials there were interested in studying the value of music education versus additional reading instruction.

“If children who received music training did as well or better than children who received additional academic instruction, that could a justification for why schools might want to continue to fund music,” Desimone says.

The 74 children participating in the study were divided into three groups: one that received 45-minute piano lessons three times a week; one that received extra reading instruction for the same period of time; and one that received neither intervention. All children were 4 or 5 years old and spoke Mandarin as their native language.

After six months, the researchers tested the children on their ability to discriminate words based on differences in vowels, consonants, or tone (many Mandarin words differ only in tone). Better word discrimination usually corresponds with better phonological awareness — the awareness of the sound structure of words, which is a key component of learning to read.

Children who had piano lessons showed a significant advantage over children in the extra reading group in discriminating between words that differ by one consonant. Children in both the piano group and extra reading group performed better than children who received neither intervention when it came to discriminating words based on vowel differences.

The researchers also used electroencephalography (EEG) to measure brain activity and found that children in the piano group had stronger responses than the other children when they listened to a series of tones of different pitch. This suggest that a greater sensitivity to pitch differences is what helped the children who took piano lessons to better distinguish different words, Desimone says.

“That’s a big thing for kids in learning language: being able to hear the differences between words,” he says. “They really did benefit from that.”

In tests of IQ, attention, and working memory, the researchers did not find any significant differences among the three groups of children, suggesting that the piano lessons did not confer any improvement on overall cognitive function.

Aniruddh Patel, a professor of psychology at Tufts University, says the findings also address the important question of whether purely instrumental musical training can enhance speech processing.

“This study answers the question in the affirmative, with an elegant design that directly compares the effect of music and language instruction on young children. The work specifically relates behavioral improvements in speech perception to the neural impact of musical training, which has both theoretical and real-world significance,” says Patel, who was not involved in the research.

Educational payoff

Desimone says he hopes the findings will help to convince education officials who are considering abandoning music classes in schools not to do so.

“There are positive benefits to piano education in young kids, and it looks like for recognizing differences between sounds including speech sounds, it’s better than extra reading. That means schools could invest in music and there will be generalization to speech sounds,” Desimone says. “It’s not worse than giving extra reading to the kids, which is probably what many schools are tempted to do — get rid of the arts education and just have more reading.”

Desimone now hopes to delve further into the neurological changes caused by music training. One way to do that is to perform EEG tests before and after a single intense music lesson to see how the brain’s activity has been altered.

The research was funded by the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the Interdiscipline Research Funds of Beijing Normal University, and the Fundamental Research Funds for the Central Universities.

How the brain performs flexible computations

Anne Trafton |

Humans can perform a vast array of mental operations and adjust their behavioral responses based on external instructions and internal beliefs. For example, to tap your feet to a musical beat, your brain has to process the incoming sound and also use your internal knowledge of how the song goes.

MIT neuroscientists have now identified a strategy that the brain uses to rapidly select and flexibly perform different mental operations. To make this discovery, they applied a mathematical framework known as dynamical systems analysis to understand the logic that governs the evolution of neural activity across large populations of neurons.

“The brain can combine internal and external cues to perform novel computations on the fly,” says Mehrdad Jazayeri, the Robert A. Swanson Career Development Professor of Life Sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study. “What makes this remarkable is that we can make adjustments to our behavior at a much faster time scale than the brain’s hardware can change. As it turns out, the same hardware can assume many different states, and the brain uses instructions and beliefs to select between those states.”

Previous work from Jazayeri’s group has found that the brain can control when it will initiate a movement by altering the speed at which patterns of neural activity evolve over time. Here, they found that the brain controls this speed flexibly based on two factors: external sensory inputs and adjustment of internal states, which correspond to knowledge about the rules of the task being performed.

Evan Remington, a McGovern Institute postdoc, is the lead author of the paper, which appears in the June 6 edition of Neuron. Other authors are former postdoc Devika Narain and MIT graduate student Eghbal Hosseini.

Ready, set, go

Neuroscientists believe that “cognitive flexibility,” or the ability to rapidly adapt to new information, resides in the brain’s higher cortical areas, but little is known about how the brain achieves this kind of flexibility.

To understand the new findings, it is useful to think of how switches and dials can be used to change the output of an electrical circuit. For example, in an amplifier, a switch may select the sound source by controlling the input to the circuit, and a dial may adjust the volume by controlling internal parameters such as a variable resistance. The MIT team theorized that the brain similarly transforms instructions and beliefs to inputs and internal states that control the behavior of neural circuits.

To test this, the researchers recorded neural activity in the frontal cortex of animals trained to perform a flexible timing task called “ready, set, go.” In this task, the animal sees two visual flashes — “ready” and “set” — that are separated by an interval anywhere between 0.5 and 1 second, and initiates a movement — “go” — some time after “set.” The animal has to initiate the movement such that the “set-go” interval is either the same as or 1.5 times the “ready-set” interval. The instruction for whether to use a multiplier of 1 or 1.5 is provided in each trial.

Neural signals recorded during the “set-go” interval clearly carried information about both the multiplier and the measured length of the “ready-set” interval, but the nature of these representations seemed bewilderingly complex. To decode the logic behind these representations, the researchers used the dynamical systems analysis framework. This analysis is used in the study of a wide range of physical systems, from simple electrical circuits to space shuttles.

The application of this approach to neural data in the “ready, set, go” task enabled Jazayeri and his colleagues to discover how the brain adjusts the inputs to and initial conditions of frontal cortex to control movement times flexibly. A switch-like operation sets the input associated with the correct multiplier, and a dial-like operation adjusts the state of neurons based on the “ready-set” interval. These two complementary control strategies allow the same hardware to produce different behaviors.

David Sussillo, a research scientist at Google Brain and an adjunct professor at Stanford University, says a key to the study was the research team’s development of new mathematical tools to analyze huge amounts of data from neuron recordings, allowing the researchers to uncover how a large population of neurons can work together to perform mental operations related to timing and rhythm.

“They have very rigorously brought the dynamical systems approach to the problem of timing,” says Sussillo, who was not involved in the research.

“A bridge between behavior and neurobiology”

Many unanswered questions remain about how the brain achieves this flexibility, the researchers say. They are now trying to find out what part of the brain sends information about the multiplier to the frontal cortex, and they also hope to study what happens in these neurons as they first learn tasks that require them to respond flexibly.

“We haven’t connected all the dots from behavioral flexibility to neurobiological details. But what we have done is to establish an algorithmic understanding based on the mathematics of dynamical systems that serves as a bridge between behavior and neurobiology,” Jazayeri says.

The researchers also hope to explore whether this type of model could help to explain behavior of other parts of the brain that have to perform computations flexibly.

The research was funded by the National Institutes of Health, the Sloan Foundation, the Klingenstein Foundation, the Simons Foundation, the McKnight Foundation, the Center for Sensorimotor Neural Engineering, and the McGovern Institute.

Ed Boyden and Feng Zhang named Howard Hughes Medical Institute Investigators

Anne Trafton |

Two members of the MIT faculty were named Howard Hughes Medical Institute (HHMI) investigators today. Ed Boyden and Feng Zhang join a community of 300 HHMI scientists who are “transforming biology and medicine, one discovery at a time.” Both researchers have been instrumental in recognizing, developing, and sharing robust tools with broad utility that have revolutionized the life sciences.

“We are thrilled that Ed and Feng are being recognized in this way” says Robert Desimone, director of the McGovern Institute for Brain Research at MIT. “Being named to the investigator program recognizes their previous achievements and allows them to follow the innovative path that is a trait of their research.”

HHMI selects new Investigators to join its flagship program through periodic competitions. In choosing researchers to join its investigator program, HHMI specifically aims to select ‘people, not projects’ and identifies trail blazers in the biomedical sciences. The organization provides support for an unusual length of time, seven years with a renewal process at the end of that period, thus giving selected scientists the time and freedom to tackle difficult and important biological questions. HHMI-affiliated scientists continue to work at their home institution. The HHMI Investigator program currently funds 300 scientists at 60 research institutions across the United States.

Ed Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT, has pioneered a number of technologies that allow visualization and manipulation of complex biological systems. Boyden worked, along with Karl Deisseroth and Feng Zhang, on optogenetics, a system that leverages microbial opsins to manipulate neuronal activity using light. This technology has transformed our ability to examine neuronal function in vivo. Boyden’s work initiated optogenetics, then extended it into a multicolor, high-speed, and noninvasive toolbox. Subsequent technological advances developed by Boyden and his team include expansion microscopy, an imaging strategy that overcomes the limits of light microscopy by expanding biological specimens in a controlled fashion. Boyden’s team also recently developed a directed evolution system that is capable of robotically screening hundreds of thousands of mutated proteins for specific properties within hours. He and his team recently used the system to develop a high-performance fluorescent voltage indicator.

“I am honored and excited to become an HHMI investigator,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research and an associate professor in the Program in Media Arts and Sciences at the MIT Media Lab; the MIT Department of Brain and Cognitive Sciences; and the MIT Department of Biological Engineering. “This will give my group the ability to open up completely new areas of science, in a way that would not be possible with traditional funding.”

Feng Zhang is a molecular biologist focused on building new tools for probing the human brain. As a graduate student, Zhang was part of the team that developed optogenetics. Zhang went on to develop other innovative tools. These achievements include the landmark deployment of the microbial CRISPR-Cas9 system for genome engineering in eukaryotic cells. The ease and specificity of the system has led to its widespread use. Zhang has continued to mine bacterial CRISPR systems for additional enzymes with useful properties, leading to the discovery of Cas13, which targets RNA, rather than DNA. By leveraging the unique properties of Cas13, Zhang and his team created a precise RNA editing tool, which may potentially be a safer way to treat genetic diseases because the genome does not need to be cut, as well as a molecular detection system, termed SHERLOCK, which can sense trace amounts of genetic material, such as viruses.

“It is so exciting to join this exceptional scientific community,” says Zhang, “and be given this opportunity to pursue our research into engineering natural systems.”

Zhang is the James and Patricia Poitras Professor of Neuroscience at MIT, an associate professor in the MIT departments of Brain and Cognitive Sciences and Biological Engineering, an investigator at the McGovern Institute for Brain Research, and a core member of the Broad Institute of MIT and Harvard.

The MIT Media Lab, Broad Institute of MIT and Harvard, and MIT departments of Brain and Cognitive Sciences and Biological Engineering contributed to this article.

Yanny or Laurel?

Anne Trafton |

“Yanny” or “Laurel?” Discussion around this auditory version of “The Dress” has divided the internet this week.

In this video, brain and cognitive science PhD students Dana Boebinger and Kevin Sitek, both members of the McGovern Institute, unpack the science — and settle the debate. The upshot? Our brain is faced with a myriad of sensory cues that it must process and make sense of simultaneously. Hearing is no exception, and two brains can sometimes “translate” soundwaves in very different ways.