Researcher: John Gabrieli

Bridging the gap between research and the classroom

by Stefanie Koperniak |

In a moment more reminiscent of a Comic-Con event than a typical MIT symposium, Shawn Robinson, senior research associate at the University of Wisconsin at Madison, helped kick off the first-ever MIT Science of Reading event dressed in full superhero attire as Doctor Dyslexia Dude — the star of a graphic novel series he co-created to engage and encourage young readers, rooted in his own experiences as a student with dyslexia.

The event, co-sponsored by the MIT Integrated Learning Initiative (MITili) and the McGovern Institute for Brain Research at MIT, took place earlier this month and brought together researchers, educators, administrators, parents, and students to explore how scientific research can better inform educational practices and policies — equipping teachers with scientifically-based strategies that may lead to better outcomes for students.

Professor John Gabrieli, MITili director, explained the great need to focus the collective efforts of educators and researchers on literacy.

“Reading is critical to all learning and all areas of knowledge. It is the first great educational experience for all children, and can shape a child’s first sense of self,” he said. “If reading is a challenge or a burden, it affects children’s social and emotional core.”

A great divide

Reading is also a particularly important area to address because so many American students struggle with this fundamental skill. More than six out of every 10 fourth graders in the United States are not proficient readers, and changes in reading scores for fourth and eighth graders have increased only slightly since 1992, according to the National Assessment of Education Progress.

Gabrieli explained that, just as with biomedical research, where there can be a “valley of death” between basic research and clinical application, the same seems to apply to education. Although there is substantial current research aiming to better understand why students might have difficulty reading in the ways they are currently taught, the research often does not necessarily shape the practices of teachers — or how the teachers themselves are trained to teach.

This divide between the research and practical applications in the classroom might stem from a variety of factors. One issue might be the inaccessibility of research publications that are available for free to all — as well as the general need for scientific findings to be communicated in a clear, accessible, engaging way that can lead to actual implementation. Another challenge is the stark difference in pacing between scientific research and classroom teaching. While research can take years to complete and publish, teachers have classrooms full of students — all with different strengths and challenges — who urgently need to learn in real time.

Natalie Wexler, author of “The Knowledge Gap,” described some of the obstacles to getting the findings of cognitive science integrated into the classroom as matters of “head, heart, and habit.” Teacher education programs tend to focus more on some of the outdated psychological models, like Piaget’s theory of cognitive development, and less on recent cognitive science research. Teachers also have to face the emotional realities of working with their students, and might be concerned that a new approach would cause students to feel bored or frustrated. In terms of habit, some new, evidence-based approaches may be, in a practical sense, difficult for teachers to incorporate into the classroom.

“Teaching is an incredibly complex activity,” noted Wexler.

From labs to classrooms

Throughout the day, speakers and panelists highlighted some key insights gained from literacy research, along with some of the implications these might have on education.

Mark Seidenberg, professor of psychology at the University of Wisconsin at Madison and author of “Language at the Speed of Sight,” discussed studies indicating the strong connection between spoken and printed language.

“Reading depends on speech,” said Seidenberg. “Writing systems are codes for expressing spoken language … Spoken language deficits have an enormous impact on children’s reading.”

The integration of speech and reading in the brain increases with reading skill. For skilled readers, the patterns of brain activity (measured using functional magnetic resonance imaging) while comprehending spoken and written language are very similar. Becoming literate affects the neural representation of speech, and knowledge of speech affects the representation of print — thus the two become deeply intertwined.

In addition, researchers have found that the language of books, even for young children, include words and expressions that are rarely encountered in speech to children. Therefore, reading aloud to children exposes them to a broader range of linguistic expressions — including more complex ones that are usually only taught much later. Thus reading to children can be especially important, as research indicates that better knowledge of spoken language facilitates learning to read.

Although behavior and performance on tests are often used as indicators of how well a student can read, neuroscience data can now provide additional information. Neuroimaging of children and young adults identifies brain regions that are critical for integrating speech and print, and can spot differences in the brain activity of a child who might be especially at-risk for reading difficulties. Brain imaging can also show how readers’ brains respond to certain reading and comprehension tasks, and how they adapt to different circumstances and challenges.

“Brain measures can be more sensitive than behavioral measures in identifying true risk,” said Ola Ozernov-Palchik, a postdoc at the McGovern Institute.

Ozernov-Palchik hopes to apply what her team is learning in their current studies to predict reading outcomes for other children, as well as continue to investigate individual differences in dyslexia and dyslexia-risk using behavior and neuroimaging methods.

Identifying certain differences early on can be tremendously helpful in providing much-needed early interventions and tailored solutions. Many speakers noted the problem with the current “wait-to-fail” model of noticing that a child has a difficult time reading in second or third grade, and then intervening. Research suggests that earlier intervention could help the child succeed much more than later intervention.

Speakers and panelists spoke about current efforts, including Reach Every Reader (a collaboration between MITili, the Harvard Graduate School of Education, and the Florida Center for Reading Research), that seek to provide support to students by bringing together education practitioners and scientists.

“We have a lot of information, but we have the challenge of how to enact it in the real world,” said Gabrieli, noting that he is optimistic about the potential for the additional conversations and collaborations that might grow out of the discussions of the Science of Reading event. “We know a lot of things can be better and will require partnerships, but there is a path forward.”

Alumnus gives MIT $4.5 million to study effects of cannabis on the brain

by MIT School of Science |

The following news is adapted from a press release issued in conjunction with Harvard Medical School.

Charles R. Broderick, an alumnus of MIT and Harvard University, has made gifts to both alma maters to support fundamental research into the effects of cannabis on the brain and behavior.

The gifts, totaling $9 million, represent the largest donation to date to support independent research on the science of cannabinoids. The donation will allow experts in the fields of neuroscience and biomedicine at MIT and Harvard Medical School to conduct research that may ultimately help unravel the biology of cannabinoids, illuminate their effects on the human brain, catalyze treatments, and inform evidence-based clinical guidelines, societal policies, and regulation of cannabis.

Lagging behind legislation

With the increasing use of cannabis both for medicinal and recreational purposes, there is a growing concern about critical gaps in knowledge.

In 2017, the National Academies of Sciences, Engineering, and Medicine issued a report calling upon philanthropic organizations, private companies, public agencies and others to develop a “comprehensive evidence base” on the short- and long-term health effects — both beneficial and harmful — of cannabis use.

“Our desire is to fill the research void that currently exists in the science of cannabis,” says Broderick, who was an early investor in Canada’s medical marijuana market.

Broderick is the founder of Uji Capital LLC, a family office focused on quantitative opportunities in global equity capital markets. Identifying the growth of the Canadian legal cannabis market as a strategic investment opportunity, Broderick took equity positions in Tweed Marijuana Inc. and Aphria Inc., which have since grown into two of North America’s most successful cannabis companies. Subsequently, Broderick made a private investment in and served as a board member for Tokyo Smoke, a cannabis brand portfolio, which merged in 2017 to create Hiku Brands, where he served as chairman. Hiku Brands was acquired by Canopy Growth Corp. in 2018.

Through the Broderick gifts to Harvard Medical School and MIT’s School of Science through the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research, the Broderick funds will support independent studies of the neurobiology of cannabis; its effects on brain development, various organ systems and overall health, including treatment and therapeutic contexts; and cognitive, behavioral and social ramifications.

“I want to destigmatize the conversation around cannabis — and, in part, that means providing facts to the medical community, as well as the general public,” says Broderick, who argues that independent research needs to form the basis for policy discussions, regardless of whether it is good for business. “Then we’re all working from the same information. We need to replace rhetoric with research.”

MIT: Focused on brain health and function

The gift to MIT from Broderick will provide $4.5 million over three years to support independent research for four scientists at the McGovern and Picower institutes.

Two of these researchers — John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research; and Myriam Heiman, the Latham Family Associate Professor of Neuroscience at the Picower Institute — will separately explore the relationship between cannabis and schizophrenia.

Gabrieli, who directs the Martinos Imaging Center at MIT, will monitor any potential therapeutic value of cannabis for adults with schizophrenia using fMRI scans and behavioral studies.

“The ultimate goal is to improve brain health and wellbeing,” says Gabrieli. “And we have to make informed decisions on the way to this goal, wherever the science leads us. We need more data.”

Heiman, who is a molecular neuroscientist, will study how chronic exposure to phytocannabinoid molecules THC and CBD may alter the developmental molecular trajectories of cell types implicated in schizophrenia.

“Our lab’s research may provide insight into why several emerging lines of evidence suggest that adolescent cannabis use can be associated with adverse outcomes not seen in adults,” says Heiman.

In addition to these studies, Gabrieli also hopes to investigate whether cannabis can have therapeutic value for autism spectrum disorders, and Heiman plans to look at whether cannabis can have therapeutic value for Huntington’s disease.

MIT Institute Professor Ann Graybiel has proposed to study the cannabinoid 1 (CB1) receptor, which mediates many of the effects of cannabinoids. Her team recently found that CB1 receptors are tightly linked to dopamine — a neurotransmitter that affects both mood and motivation. Graybiel, who is also a member of the McGovern Institute, will examine how CB1 receptors in the striatum, a deep brain structure implicated in learning and habit formation, may influence dopamine release in the brain. These findings will be important for understanding the effects of cannabis on casual users, as well as its relationship to addictive states and neuropsychiatric disorders.

Earl Miller, Picower Professor of Neuroscience at the Picower Institute, will study effects of cannabinoids on both attention and working memory. His lab has recently formulated a model of working memory and unlocked how anesthetics reduce consciousness, showing in both cases a key role in the brain’s frontal cortex for brain rhythms, or the synchronous firing of neurons. He will observe how these rhythms may be affected by cannabis use — findings that may be able to shed light on tasks like driving where maintenance of attention is especially crucial.

Harvard Medical School: Mobilizing basic scientists and clinicians to solve an acute biomedical challenge 

The Broderick gift provides $4.5 million to establish the Charles R. Broderick Phytocannabinoid Research Initiative at Harvard Medical School, funding basic, translational and clinical research across the HMS community to generate fundamental insights about the effects of cannabinoids on brain function, various organ systems, and overall health.

The research initiative will span basic science and clinical disciplines, ranging from neurobiology and immunology to psychiatry and neurology, taking advantage of the combined expertise of some 30 basic scientists and clinicians across the school and its affiliated hospitals.

The epicenter of these research efforts will be the Department of Neurobiology under the leadership of Bruce Bean and Wade Regehr.

“I am excited by Bob’s commitment to cannabinoid science,” says Regehr, professor of neurobiology in the Blavatnik Institute at Harvard Medical School. “The research efforts enabled by Bob’s vision set the stage for unraveling some of the most confounding mysteries of cannabinoids and their effects on the brain and various organ systems.”

Bean, Regehr, and fellow neurobiologists Rachel Wilson and Bernardo Sabatini, for example, focus on understanding the basic biology of the cannabinoid system, which includes hundreds of plant and synthetic compounds as well as naturally occurring cannabinoids made in the brain.

Cannabinoid compounds activate a variety of brain receptors, and the downstream biological effects of this activation are astoundingly complex, varying by age and sex, and complicated by a person’s physiologic condition and overall health. This complexity and high degree of variability in individual biology has hampered scientific understanding of the positive and negative effects of cannabis on the human body. Bean, Regehr, and colleagues have already made critical insights showing how cannabinoids influence cell-to-cell communication in the brain.

“Even though cannabis products are now widely available, and some used clinically, we still understand remarkably little about how they influence brain function and neuronal circuits in the brain,” says Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at HMS. “This gift will allow us to conduct critical research into the neurobiology of cannabinoids, which may ultimately inform new approaches for the treatment of pain, epilepsy, sleep and mood disorders, and more.”

To propel research findings from lab to clinic, basic scientists from HMS will partner with clinicians from Harvard-affiliated hospitals, bringing together clinicians and scientists from disciplines including cardiology, vascular medicine, neurology, and immunology in an effort to glean a deeper and more nuanced understanding of cannabinoids’ effects on various organ systems and the body as a whole, rather than just on isolated organs.

For example, Bean and colleague Gary Yellen, who are studying the mechanisms of action of antiepileptic drugs, have become interested in the effects of cannabinoids on epilepsy, an interest they share with Elizabeth Thiele, director of the pediatric epilepsy program at Massachusetts General Hospital. Thiele is a pioneer in the use of cannabidiol for the treatment of drug-resistant forms of epilepsy. Despite proven clinical efficacy and recent FDA approval for rare childhood epilepsies, researchers still do not know exactly how cannabidiol quiets the misfiring brain cells of patients with the seizure disorder. Understanding its mechanism of action could help in developing new agents for treating other forms of epilepsy and other neurologic disorders.

John Gabrieli

Images of Mind

John Gabrieli’s goal is to understand the organization of memory, thought, and emotion in the human brain. In collaboration with clinical colleagues, Gabrieli uses brain imaging to better understand, diagnose, and select treatments for neurological and psychiatric diseases.

A major focus of the Gabrieli lab is the neural basis of learning in children. His team found structural differences in the brains of young children who are at risk for reading difficulties, even before they start learning to read. By studying these differences in children, Gabrieli hopes to identify ways to improve learning in the classroom and inform effective educational policies and practices.

Gabrieli is also interested in using the tools of neuroscience to personalize medicine. His team showed that brain scans can identify children who are vulnerable to depression before symptoms even appear, opening the possibility of earlier interventions to prevent episodes of depression. Brain scans may also help help predict which individuals with social anxiety disorder are most likely to benefit from a particular therapeutic intervention. Gabrieli’s team continues to explore the role of neuroimaging in other brain disorders, including schizophrenia, addiction, and bipolar disorder.

His team also studies a range of other research topics, including new strategies to cope with emotional stress, the benefits of mindfulness for academic performance and mental health, and the value of embracing neurodiversity to better understand autism.

Brain activity pattern may be early sign of schizophrenia

Anne Trafton |

Schizophrenia, a brain disorder that produces hallucinations, delusions, and cognitive impairments, usually strikes during adolescence or young adulthood. While some signs can suggest that a person is at high risk for developing the disorder, there is no way to definitively diagnose it until the first psychotic episode occurs.

MIT neuroscientists working with researchers at Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and the Shanghai Mental Health Center have now identified a pattern of brain activity correlated with development of schizophrenia, which they say could be used as a marker to diagnose the disease earlier.

“You can consider this pattern to be a risk factor. If we use these types of brain measurements, then maybe we can predict a little bit better who will end up developing psychosis, and that may also help tailor interventions,” says Guusje Collin, a visiting scientist at MIT’s McGovern Institute for Brain Research and the lead author of the paper.

The study, which appeared in the journal Molecular Psychiatry on Nov. 8, was performed at the Shanghai Mental Health Center. Susan Whitfield-Gabrieli, a visiting scientist at the McGovern Institute and a professor of psychology at Northeastern University, is one of the principal investigators for the study, along with Jijun Wang of the Shanghai Mental Health Center, William Stone of Beth Israel Deaconess Medical Center, the late Larry Seidman of Beth Israel Deaconess Medical Center, and Martha Shenton of Brigham and Women’s Hospital.

Abnormal connections

Before they experience a psychotic episode, characterized by sudden changes in behavior and a loss of touch with reality, patients can experience milder symptoms such as disordered thinking. This kind of thinking can lead to behaviors such as jumping from topic to topic at random, or giving answers unrelated to the original question. Previous studies have shown that about 25 percent of people who experience these early symptoms go on to develop schizophrenia.

The research team performed the study at the Shanghai Mental Health Center because the huge volume of patients who visit the hospital annually gave them a large enough sample of people at high risk of developing schizophrenia.

The researchers followed 158 people between the ages of 13 and 34 who were identified as high-risk because they had experienced early symptoms. The team also included 93 control subjects, who did not have any risk factors. At the beginning of the study, the researchers used functional magnetic resonance imaging (fMRI) to measure a type of brain activity involving “resting state networks.” Resting state networks consist of brain regions that preferentially connect with and communicate with each other when the brain is not performing any particular cognitive task.

“We were interested in looking at the intrinsic functional architecture of the brain to see if we could detect early aberrant brain connectivity or networks in individuals who are in the clinically high-risk phase of the disorder,” Whitfield-Gabrieli says.

One year after the initial scans, 23 of the high-risk patients had experienced a psychotic episode and were diagnosed with schizophrenia. In those patients’ scans, taken before their diagnosis, the researchers found a distinctive pattern of activity that was different from the healthy control subjects and the at-risk subjects who had not developed psychosis.

For example, in most people, a part of the brain known as the superior temporal gyrus, which is involved in auditory processing, is highly connected to brain regions involved in sensory perception and motor control. However, in patients who developed psychosis, the superior temporal gyrus became more connected to limbic regions, which are involved in processing emotions. This could help explain why patients with schizophrenia usually experience auditory hallucinations, the researchers say.

Meanwhile, the high-risk subjects who did not develop psychosis showed network connectivity nearly identical to that of the healthy subjects.

Early intervention

This type of distinctive brain activity could be useful as an early indicator of schizophrenia, especially since it is possible that it could be seen in even younger patients. The researchers are now performing similar studies with younger at-risk populations, including children with a family history of schizophrenia.

“That really gets at the heart of how we can translate this clinically, because we can get in earlier and earlier to identify aberrant networks in the hopes that we can do earlier interventions, and possibly even prevent psychiatric disorders,” Whitfield-Gabrieli says.

She and her colleagues are now testing early interventions that could help to combat the symptoms of schizophrenia, including cognitive behavioral therapy and neural feedback. The neural feedback approach involves training patients to use mindfulness meditation to reduce activity in the superior temporal gyrus, which tends to increase before and during auditory hallucinations.

The researchers also plan to continue following the patients in the current study, and they are now analyzing some additional data on the white matter connections in the brains of these patients, to see if those connections might yield additional differences that could also serve as early indicators of disease.

The research was funded by the National Institutes of Health, the Ministry of Science and Technology of China, and the Poitras Center for Psychiatric Disorders Research at MIT. Collin was supported by a Marie Curie Global Fellowship grant from the European Commission.

Is it worth the risk?

by Shannon Fischer |

During the Klondike Gold Rush, thousands of prospectors climbed Alaska’s dangerous Chilkoot Pass in search of riches. McGovern scientists are exploring how a once-overlooked part of the brain might be at the root of cost-benefit decisions like these. McGovern researchers are studying how the brain balances risk and reward to make decisions.

Is it worth speeding up on the highway to save a few minutes’ time? How about accepting a job that pays more, but requires longer hours in the office?

Scientists call these types of real-life situations cost-benefit conflicts. Choosing well is an essential survival ability—consider the animal that must decide when to expose itself to predation to gather more food.

Now, McGovern researchers are discovering that this fundamental capacity to make decisions may originate in the basal ganglia—a brain region once considered unimportant to the human
experience—and that circuits associated with this structure may play a critical role in determining our state of mind.

Anatomy of decision-making

A few years back, McGovern investigator Ann Graybiel noticed that in the brain imaging literature, a specific part of the cortex called the pregenual anterior cingulate cortex or pACC, was implicated in certain psychiatric disorders as well as tasks involving cost-benefit decisions. Thanks to her now classic neuroanatomical work defining the complex anatomy and function of the basal ganglia, Graybiel knew that the pACC projected back into the basal ganglia—including its largest cluster of neurons, the striatum.

The striatum sits beneath the cortex, with a mouse-like main body and curving tail. It seems to serve as a critical way-station, communicating with both the brain’s sensory and motor areas above, and the limbic system (linked to emotion and memory) below. Running through the striatum are striosomes, column-like neurochemical compartments. They wire down to a small, but important part of the brain called the substantia nigra, which houses the huge majority of the brain’s dopamine neurons—a key neurochemical heavily involved, much like the basal ganglia as a whole, in reward, learning, and movement. The pACC region related to mood control targeted these striosomes, setting up a communication line from the neocortex to the dopamine neurons.

Graybiel discovered these striosomes early in her career, and understood them to have distinct wiring from other compartments in the striatum, but picking out these small, hard-to-find striosomes posed a technological challenge—so it was exciting to have this intriguing link to the pACC and mood disorders.

Working with Ken-ichi Amemori, then a research scientist in her lab, she adapted a common human cost-benefit conflict test for macaque monkeys. The monkeys could elect to receive a food treat, but the treat would always be accompanied by an annoying puff of air to the eyes. Before they decided, a visual cue told them exactly how much treat they could get, and exactly how strong the air puff would be, so they could choose if the treat was worth it.

Normal monkeys varied their choices in a fairly rational manner, rejecting the treat whenever it seemed like the air puff was too strong, or the treat too small to be worth it—and this corresponded with activity in the pACC neurons. Interestingly, they found that some pACC neurons respond more when animals approach the combined offers, while other pACC neurons
fire more when the animals avoid the offers. “It is as though there are two opposing armies. And the one that wins, controls the state of the animal.” Moreover, when Graybiel’s team electrically stimulated these pACC neurons, the animals begin to avoid the offers, even offers that they normally would approach. “It is as though when the stimulation is on, they think the future is worse than it really is,” Graybiel says.

Intriguingly, this effect only worked in situations where the animal had to weigh the value of a cost against a benefit. It had no effect on a decision between two negatives or two positives, like two different sizes of treats. The anxiety drug diazepam also reversed the stimulatory effect, but again, only on cost-benefit choices. “This particular kind of mood-influenced cost-benefit
decision-making occurs not only under conflict conditions but in our regular day to day lives. For example: I know that if I eat too much chocolate, I might get fat, but I love it, I want it.”

Glass half empty

Over the next few years, Graybiel, with another research scientist in her lab, Alexander Friedman, unraveled the circuit behind the macaques’ choices. They adapted the test for rats and mice,
so that they could more easily combine the cellular and molecular technologies needed to study striosomes, such as optogenetics and mouse engineering.

They found that the cortex (specifically, the pre-limbic region of the prefrontal cortex in rodents) wires onto both striosomes and fast-acting interneurons that also target the striosomes. In a
healthy circuit, these interneurons keep the striosomes in check by firing off fast inhibitory signals, hitting the brakes before the striosome can get started. But if the researchers broke that corticalstriatal connection with optogenetics or chronic stress, the animals became reckless, going for the high-risk, high-reward arm of the maze like a gambler throwing caution to the wind. If they amplified this inhibitory interneuron activity, they saw the opposite effect. With these techniques, they could block the effects of prior chronic stress.

This summer, Graybiel and Amemori published another paper furthering the story and returning to macaques. It was still too difficult to hit striosomes, and the researchers could only stimulate the striatum more generally. However, they replicated the effects in past studies.

Many electrodes had no effect, a small number made the monkeys choose the reward more often. Nearly a quarter though made the monkeys more avoidant—and this effect correlated with a change in the macaques’ brainwaves in a manner reminiscent of patients with depression.

But the surprise came when the avoidant-producing stimulation was turned off, the effects lasted unexpectedly long, only returning to normal on the third day.

Graybiel was stunned. “This is very important, because changes in the brain can get set off and have a life of their own,” she says. “This is true for some individuals who have had a terrible experience, and then live with the aftermath, even to the point of suffering from post-traumatic stress disorder.”

She suspects that this persistent state may actually be a form of affect, or mood. “When we change this decision boundary, we’re changing the mood, such that the animal overestimates cost, relative to benefit,” she explains. “This might be like a proxy state for pessimistic decision-making experienced during anxiety and depression, but may also occur, in a milder form, in you and me.”

Graybiel theorizes that this may tie back into the dopamine neurons that the striosomes project to: if this avoidance behavior is akin to avoidance observed in rodents, then they are stimulating a circuit that ultimately projects to dopamine neurons of the substantia nigra. There, she believes, they could act to suppress these dopamine neurons, which in turn project to the rest of the brain, creating some sort of long-term change in their neural activity. Or, put more simply, stimulation of these circuits creates a depressive funk.

Bottom up

Three floors below the Graybiel lab, postdoc Will Menegas is in the early stages of his own work untangling the role of dopamine and the striatum in decision-making. He joined Guoping Feng’s lab this summer after exploring the understudied “tail of the striatum” at Harvard University.

While dopamine pathways influence many parts of the brain, examination of connections to the striatum have largely focused on the frontmost part of the striatum, associated with valuations.

But as Menegas showed while at Harvard, dopamine neurons that project to the rear of the striatum are different. Those neurons get their input from parts of the brain associated with general arousal and sensation—and instead of responding to rewards, they respond to novelty and intense stimuli, like air puffs and loud noises.

In a new study published in Nature Neuroscience, Menegas used a neurotoxin to disrupt the dopamine projection from the substantia nigra to the posterior striatum to see how this circuit influences behavior. Normal mice approach novel items cautiously and back away after sniffing at them, but the mice in Menegas’ study failed to back away. They stopped avoiding a port that gave an air puff to the face and they didn’t behave like normal mice when Menegas dropped a strange or new object—say, a lego—into their cage. Disrupting the nigral-posterior striatum
seemed to turn off their avoidance habit.

“These neurons reinforce avoidance the same way that canonical dopamine neurons reinforce approach,” Menegas explains. It’s a new role for dopamine, suggesting that there may be two different and distinct systems of reinforcement, led by the same neuromodulator in different parts of the striatum.

This research, and Graybiel’s discoveries on cost-benefit decision circuits, share clear parallels, though the precise links between the two phenomena are yet to be fully determined. Menegas plans to extend this line of research into social behavior and related disorders like autism in marmoset monkeys.

“Will wants to learn the methods that we use in our lab to work on marmosets,” Graybiel says. “I think that working together, this could become a wonderful story, because it would involve social interactions.”

“This a very new angle, and it could really change our views of how the reward system works,” Feng says. “And we have very little understanding of social circuits so far and especially in higher organisms, so I think this would be very exciting. Whatever we learn, it’s going to be new.”

Human choices

Based on their preexisting work, Graybiel’s and Menegas’ projects are well-developed—but they are far from the only McGovern-based explorations into ways this brain region taps into our behaviors. Maiya Geddes, a visiting scientist in John Gabrieli’s lab, has recently published a paper exploring the little-known ways that aging affects the dopamine-based nigral-striatum-hippocampus learning and memory systems.

In Rebecca Saxe’s lab, postdoc Livia Tomova just kicked off a new pilot project using brain imaging to uncover dopamine-striatal circuitry behind social craving in humans and the urge to rejoin peers. “Could there be a craving response similar to hunger?” Tomova wonders. “No one has looked yet at the neural mechanisms of this.”

Graybiel also hopes to translate her findings into humans, beginning with collaborations at the Pizzagalli lab at McLean Hospital in Belmont. They are using fMRI to study whether patients
with anxiety and depression show some of the same dysfunctions in the cortico-striatal circuitry that she discovered in her macaques.

If she’s right about tapping into mood states and affect, it would be an expanded role for the striatum—and one with significant potential therapeutic benefits. “Affect state” colors many psychological functions and disorders, from memory and perception, to depression, chronic stress, obsessive-compulsive disorder, and PTSD.

For a region of the brain once dismissed as inconsequential, McGovern researchers have shown the basal ganglia to influence not only our choices but our state of mind—suggesting that this “primitive” brain region may actually be at the heart of the human experience.

 

 

Can the brain recover after paralysis?

by The Brain |

Why is it that motor skills can be gained after paralysis but vision cannot recover in similar ways? – Ajay, Puppala

Thank you so much for this very important question, Ajay. To answer, I asked two local experts in the field, Pawan Sinha who runs the vision research lab at MIT, and Xavier Guell, a postdoc in John Gabrieli’s lab at the McGovern Institute who also works in the ataxia unit at Massachusetts General Hospital.

“Simply stated, the prospects of improvement, whether in movement or in vision, depend on the cause of the impairment,” explains Sinha. “Often, the cause of paralysis is stroke, a reduction in blood supply to a localized part of the brain, resulting in tissue damage. Fortunately, the brain has some ability to rewire itself, allowing regions near the damaged one to take on some of the lost functionality. This rewiring manifests itself as improvements in movement abilities after an initial period of paralysis. However, if the paralysis is due to spinal-cord transection (as was the case following Christopher Reeve’s tragic injury in 1995), then prospects for improvement are diminished.”

“Turning to the domain of sight,” continues Sinha, “stroke can indeed cause vision loss. As with movement control, these losses can dissipate over time as the cortex reorganizes via rewiring. However, if the blindness is due to optic nerve transection, then the condition is likely to be permanent. It is also worth noting that many cases of blindness are due to problems in the eye itself. These include corneal opacities, cataracts and retinal damage. Some of these conditions (corneal opacities and cataracts) are eminently treatable while others (typically those associated with the retina and optic nerve) still pose challenges to medical science.”

You might be wondering what makes lesions in the eye and spinal cord hard to overcome. Some systems (the blood, skin, and intestine are good examples) contain a continuously active stem cell population in adults. These cells can divide and replenish lost cells in damaged regions. While “adult-born” neurons can arise, elements of a degenerating or damaged retina, optic nerve, or spinal cord cannot be replaced as easily lost skin cells can. There is currently a very active effort in the stem cell community to understand how we might be able to replace neurons in all cases of neuronal degeneration and injury using stem cell technologies. To further explore lesions that specifically affect the brain, and how these might lead to a different outcome in the two systems, I turned to Xavier Guell.

“It might be true that visual deficits in the population are less likely to recover when compared to motor deficits in the population. However, the scientific literature seems to indicate that our body has a similar capacity to recover from both motor and visual injuries,” explains Guell. “The reason for this apparent contradiction is that visual lesions are usually not in the cerebral cortex (but instead in other places such as the retina or the lens), while motor lesions in the cerebral cortex are more common. In fact, a large proportion of people who suffer a stroke will have damage in the motor aspects of the cerebral cortex, but no damage in the visual aspects of the cerebral cortex. Crucially, recovery of neurological functions is usually seen when lesions are in the cerebral cortex or in other parts of the cerebrum or cerebellum. In this way, while our body has a similar capacity to recover from both motor and visual injuries, motor injuries are more frequently located in the parts of our body that have a better capacity to regain function (specifically, the cerebral cortex).”

In short, some cells cannot be replaced in either system, but stem cell research provides hope there. That said, there is remarkable plasticity in the brain, so when the lesion is located there, we can see recovery with training.

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

Charting the cerebellum

Anne Trafton |

Small and tucked away under the cerebral hemispheres toward the back of the brain, the human cerebellum is still immediately obvious due to its distinct structure. From Galen’s second century anatomical description to Cajal’s systematic analysis of its projections, the cerebellum has long drawn the eyes of researchers studying the brain.  Two parallel studies from MIT’s McGovern institute have recently converged to support an unexpectedly complex level of non-motor cerebellar organization, that would not have been predicted from known motor representation regions.

Historically the cerebellum has primarily been considered to impact motor control and coordination. Think of this view as the cerebellum being the chain on a bicycle, registering what is happening up front in the cortex, and relaying the information so that the back wheel moves at a coordinated pace. This simple view has been questioned as cerebellar circuits have been traced to the basal ganglia and to neocortical regions via the thalamus. This new view suggests the cerebellum is a hub in a complex network, with potentially higher and non-motor functions including cognition and reward-based learning.

A collaboration between the labs of John Gabrieli, Investigator at the McGovern Institute for Brain Research and Jeremy Schmahmann, of the Ataxia Unit at Massachusetts General Hospital and Harvard Medical School, has now used functional brain imaging to give new insight into the cerebellar organization of non-motor roles, including working memory, language, and, social and emotional processing. In a complementary paper, a collaboration between Sheeba Anteraper of MIT’s Martinos Imaging Center and Gagan Joshi of the Alan and Lorraine Bressler Clinical and Research Program at Massachusetts General Hospital, has found changes in connectivity that occur in the cerebellum in autism spectrum disorder (ASD).

A more complex map of the cerebellum

Published in NeuroImage, and featured on the cover, the first study was led by author Xavier Guell, a postdoc in the Gabrieli and Schmahmann labs. The authors used fMRI data from the Human Connectome Project to examine activity in different regions of the cerebellum during specific tasks and at rest. The tasks used extended beyond motor activity to functions recently linked to the cerebellum, including working memory, language, and social and emotional processing. As expected, the authors saw that two regions assigned by other methods to motor activity were clearly modulated during motor tasks.

“Neuroscientists in the 1940s and 1950s described a double representation of motor function in the cerebellum, meaning that two regions in each hemisphere of the cerebellum are engaged in motor control,” explains Guell. “That there are two areas of motor representation in the cerebellum remains one of the most well-established facts of cerebellar macroscale physiology.”

When it came to assigning non-motor tasks, to their surprise, the authors identified three representations that localized to different regions of the cerebellum, pointing to an unexpectedly complex level of organization.

Guell explains the implications further. “Our study supports the intriguing idea that while two parts of the cerebellum are simultaneously engaged in motor tasks, three other parts of the cerebellum are simultaneously engaged in non-motor tasks. Our predecessors coined the term “double motor representation,” and we may now have to add “triple non-motor representation” to the dictionary of cerebellar neuroscience.”

A serendipitous discussion

What happened next, over a discussion of data between Xavier Guell and Sheeba Arnold Anteraper of the McGovern Institute for Brain Research that culminated in a paper led by Anteraper, illustrates how independent strands can meet and reinforce to give a fuller scientific picture.

The findings by Guell and colleagues made the cover of NeuroImage.
The findings by Guell and colleagues made the cover of NeuroImage.

Anteraper and colleagues examined brain images from high-functioning ASD patients, and looked for statistically-significant patterns, letting the data speak rather than focusing on specific ‘candidate’ regions of the brain. To her surprise, networks related to language were highlighted, as well as the cerebellum, regions that had not been linked to ASD, and that seemed at first sight not to be relevant. Scientists interested in language processing, immediately pointed her to Guell.

“When I went to meet him,” says Anteraper, “I saw immediately that he had the same research paper that I’d been reading on his desk. As soon as I showed him my results, the data fell into place and made sense.”

After talking with Guell, they realized that the same non-motor cerebellar representations he had seen, were independently being highlighted by the ASD study.

“When we study brain function in neurological or psychiatric diseases we sometimes have a very clear notion of what parts of the brain we should study” explained Guell, ”We instead asked which parts of the brain have the most abnormal patterns of functional connectivity to other brain areas? This analysis gave us a simple, powerful result. Only the cerebellum survived our strict statistical thresholds.”

The authors found decreased connectivity within the cerebellum in the ASD group, but also decreased strength in connectivity between the cerebellum and the social, emotional and language processing regions in the cerebral cortex.

“Our analysis showed that regions of disrupted functional connectivity mapped to each of the three areas of non-motor representation in the cerebellum. It thus seems that the notion of two motor and three non-motor areas of representation in the cerebellum is not only important for understanding how the cerebellum works, but also important for understanding how the cerebellum becomes dysfunctional in neurology and psychiatry.”

Guell says that many questions remain to be answered. Are these abnormalities in the cerebellum reproducible in other datasets of patients diagnosed with ASD? Why is cerebellar function (and dysfunction) organized in a pattern of multiple representations? What is different between each of these representations, and what is their distinct contribution to diseases such as ASD? Future work is now aimed at unraveling these questions.

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.”

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.

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.