Study finds neurons that encode the outcomes of actions

When we make complex decisions, we have to take many factors into account. Some choices have a high payoff but carry potential risks; others are lower risk but may have a lower reward associated with them.

A new study from MIT sheds light on the part of the brain that helps us make these types of decisions. The research team found a group of neurons in the brain’s striatum that encodes information about the potential outcomes of different decisions. These cells become particularly active when a behavior leads a different outcome than what was expected, which the researchers believe helps the brain adapt to changing circumstances.

“A lot of this brain activity deals with surprising outcomes, because if an outcome is expected, there’s really nothing to be learned. What we see is that there’s a strong encoding of both unexpected rewards and unexpected negative outcomes,” says Bernard Bloem, a former MIT postdoc and one of the lead authors of the new study.

Impairments in this kind of decision-making are a hallmark of many neuropsychiatric disorders, especially anxiety and depression. The new findings suggest that slight disturbances in the activity of these striatal neurons could swing the brain into making impulsive decisions or becoming paralyzed with indecision, the researchers say.

Rafiq Huda, a former MIT postdoc, is also a lead author of the paper, which appears in Nature Communications. Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research, is the senior author of the study.

Learning from experience

The striatum, located deep within the brain, is known to play a key role in making decisions that require evaluating outcomes of a particular action. In this study, the researchers wanted to learn more about the neural basis of how the brain makes cost-benefit decisions, in which a behavior can have a mixture of positive and negative outcomes.

Striosomes (red) appear and then disappear as the view moves deeper into the striatum. Video courtesy of the researchers

To study this kind of decision-making, the researchers trained mice to spin a wheel to the left or the right. With each turn, they would receive a combination of reward (sugary water) and negative outcome (a small puff of air). As the mice performed the task, they learned to maximize the delivery of rewards and to minimize the delivery of air puffs. However, over hundreds of trials, the researchers frequently changed the probabilities of getting the reward or the puff of air, so the mice would need to adjust their behavior.

As the mice learned to make these adjustments, the researchers recorded the activity of neurons in the striatum. They had expected to find neuronal activity that reflects which actions are good and need to be repeated, or bad and that need to be avoided. While some neurons did this, the researchers also found, to their surprise, that many neurons encoded details about the relationship between the actions and both types of outcomes.

The researchers found that these neurons responded more strongly when a behavior resulted in an unexpected outcome, that is, when turning the wheel in one direction produced the opposite outcome as it had in previous trials. These “error signals” for reward and penalty seem to help the brain figure out that it’s time to change tactics.

Most of the neurons that encode these error signals are found in the striosomes — clusters of neurons located in the striatum. Previous work has shown that striosomes send information to many other parts of the brain, including dopamine-producing regions and regions involved in planning movement.

“The striosomes seem to mostly keep track of what the actual outcomes are,” Bloem says. “The decision whether to do an action or not, which essentially requires integrating multiple outcomes, probably happens somewhere downstream in the brain.”

Making judgments

The findings could be relevant not only to mice learning a task, but also to many decisions that people have to make every day as they weigh the risks and benefits of each choice. Eating a big bowl of ice cream after dinner leads to immediate gratification, but it might contribute to weight gain or poor health. Deciding to have carrots instead will make you feel healthier, but you’ll miss out on the enjoyment of the sweet treat.

“From a value perspective, these can be considered equally good,” Bloem says. “What we find is that the striatum also knows why these are good, and it knows what are the benefits and the cost of each. In a way, the activity there reflects much more about the potential outcome than just how likely you are to choose it.”

This type of complex decision-making is often impaired in people with a variety of neuropsychiatric disorders, including anxiety, depression, schizophrenia, obsessive-compulsive disorder, and posttraumatic stress disorder. Drug abuse can also lead to impaired judgment and impulsivity.

“You can imagine that if things are set up this way, it wouldn’t be all that difficult to get mixed up about what is good and what is bad, because there are some neurons that fire when an outcome is good and they also fire when the outcome is bad,” Graybiel says. “Our ability to make our movements or our thoughts in what we call a normal way depends on those distinctions, and if they get blurred, it’s real trouble.”

The new findings suggest that behavioral therapy targeting the stage at which information about potential outcomes is encoded in the brain may help people who suffer from those disorders, the researchers say.

The research was funded by the National Institutes of Health/National Institute of Mental Health, the Saks Kavanaugh Foundation, the William N. and Bernice E. Bumpus Foundation, the Simons Foundation, the Nancy Lurie Marks Family Foundation, the National Eye Institute, the National Institute of Neurological Disease and Stroke, the National Science Foundation, the Simons Foundation Autism Research Initiative, and JSPS KAKENHI.

What’s happening in your brain when you’re spacing out?

This story is adapted from a News@Northeastern post.

We all do it. One second you’re fully focused on the task in front of you, a conversation with a friend, or a professor’s lecture, and the next second your mind is wandering to your dinner plans.

But how does that happen?

“We spend so much of our daily lives engaged in things that are completely unrelated to what’s in front of us,” says Aaron Kucyi, neuroscientist and principal research scientist in the department of psychology at Northeastern. “And we know very little about how it works in the brain.”

So Kucyi and colleagues at Massachusetts General Hospital, Boston University, and the McGovern Institute at MIT started scanning people’s brains using functional magnetic resonance imaging (fMRI) to get an inside look. Their results, published Friday in the journal Nature Communications, add complexity to our understanding of the wandering mind.

It turns out that spacing out might not deserve the bad reputation that it receives. Many more parts of the brain seem to be engaged in mind-wandering than previously thought, supporting the idea that it’s actually a quite dynamic and fundamental function of our psychology.

“Many of those things that we do when we’re spacing out are very adaptive and important to our lives,” says Kucyi, the paper’s first author. We might be drafting an email in our heads while in the shower, or trying to remember the host’s spouse’s name while getting dressed for a party. Moments when our minds wander can allow space for creativity and planning for the future, he says, so it makes sense that many parts of the brain would be engaged in that kind of thinking.

But mind wandering may also be detrimental, especially for those suffering from mental illness, explains the study’s senior author, Susan Whitfield-Gabrieli. “For many of us, mind wandering may be a healthy, positive and constructive experience, like reminiscing about the past, planning for the future, or engaging in creative thinking,” says Whitfield-Gabrieli, a professor of psychology at Northeastern University and a McGovern Institute research affiliate. “But for those suffering from mental illness such as depression, anxiety or psychosis, reminiscing about the past may transform into ruminating about the past, planning for the future may become obsessively worrying about the future and creative thinking may evolve into delusional thinking.”

Identifying the brain circuits associated with mind wandering, she says, may reveal new targets and better treatment options for people suffering from these disorders.

McGovern research affiliate Susan Whitfield-Gabrieli in the Martinos Imaging Center.

Inside the wandering mind

To study wandering minds, the researchers first had to set up a situation in which people were likely to lose focus. They recruited test subjects at the McGovern Institute’s Martinos Imaging Center to complete a simple, repetitive, and rather boring task. With an fMRI scanner mapping their brain activity, participants were instructed to press a button whenever an image of a city scene appeared on a screen in front of them and withhold a response when a mountain image appeared.

Throughout the experiment, the subjects were asked whether they were focused on the task at hand. If a subject said their mind was wandering, the researchers took a close look at their brain scans from right before they reported loss of focus. The data was then fed into a machine-learning algorithm to identify patterns in the neurological connections involved in mind-wandering (called “stimulus-independent, task-unrelated thought” by the scientists).

Scientists previously identified a specialized system in the brain considered to be responsible for mind-wandering. Called the “default mode network,” these parts of the brain activated when someone’s thoughts were drifting away from their immediate surroundings and deactivated when they were focused. The other parts of the brain, that theory went, were quiet when the mind was wandering, says Kucyi.

The researchers used a technique called “connectome-based predictive modeling” to identify patterns in the brain connections involved in mind-wandering. Image courtesy of the researchers.

The “default mode network” did light up in Kucyi’s data. But parts of the brain associated with other functions also appeared to activate when his subjects reported that their minds had wandered.

For example, the “default mode network” and networks in the brain related to controlling or maintaining a train of thought also seemed to be communicating with one another, perhaps helping explain the ability to go down a rabbit hole in your mind when you’re distracted from a task. There was also a noticeable lack of communication between the “default mode network” and the systems associated with sensory input, which makes sense, as the mind is wandering away from the person’s immediate environment.

“It makes sense that virtually the whole brain is involved,” Kucyi says. “Mind-wandering is a very complex operation in the brain and involves drawing from our memory, making predictions about the future, dynamically switching between topics that we’re thinking about, fluctuations in our mood, and engaging in vivid visual imagery while ignoring immediate visual input,” just to name a few functions.

The “default mode network” still seems to be key, Kucyi says. Virtual computer analysis suggests that if you took the regions of the brain in that network out of the equation, the other brain regions would not be able to pick up the slack in mind-wandering.

Kucyi, however, didn’t just want to identify regions of the brain that lit up when someone said their mind was wandering. He also wanted to be able to use that generalized pattern of brain activity to be able to predict whether or not a subject would say that their focus had drifted away from the task in front of them.

That’s where the machine-learning analysis of the data came in. The idea, Kucyi says, is that “you could bring a new person into the scanner and not even ask them whether they were mind-wandering or not, and have a good estimate from their brain data whether they were.”

The ADHD brain

To test the patterns identified through machine learning, the researchers brought in a new set of test subjects – people diagnosed with ADHD. When the fMRI scans lit up the parts of the brain Kucyi and his colleagues had identified as engaged in mind-wandering in the first part of the study, the new test subjects reported that their thoughts had drifted from the images of cities and mountains in front of them. It worked.

Kucyi doesn’t expect fMRI scans to become a new way to diagnose ADHD, however. That wasn’t the goal. Perhaps down the road it could be used to help develop treatments, he suggests. But this study was focused on “informing the biological mechanisms behind it.”

John Gabrieli, a co-author on the study and director of the imaging center at MIT’s McGovern Institute, adds that “there is recent evidence that ADHD patients with more mind-wandering have many more everyday practical and clinical difficulties than ADHD patients with less mind-wandering. This is the first evidence about the brain basis for that important difference, and points to what neural systems ought to be the targets of intervention to help ADHD patients who struggle the most.”

For Kucyi, the study of “mind-wandering” goes beyond ADHD. And the contents of those straying thoughts may be telling, he says.

“We just asked people whether they were focused on the task or away from the task, but we have no idea what they were thinking about,” he says. “What are people thinking about? For example, are those more positive thoughts or negative thoughts?” Such answers, which he hopes to explore in future research, could help scientists better understand other pathologies such as depression and anxiety, which often involve rumination on upsetting or worrisome thoughts.

Whitfield-Gabrieli and her team are already exploring whether behavioral interventions, such as mindfulness based real-time fMRI neurofeedback, can be used to help train people suffering from mental illness to modulate their own brain networks and reduce hallucinations, ruminations, and other troubling symptoms.

“We hope that our research will have clinical implications that extend far beyond the potential for identifying treatment targets for ADHD,” she says.

The pursuit of reward

View the interactive version of this story in our Spring 2021 issue of BrainScan.

The brain circuits that influence our decisions, cognitive functions, and ultimately, our actions are intimately connected with the circuits that give rise to our motivations. By exploring these relationships, scientists at McGovern are seeking knowledge that might suggest new strategies for changing our habits or treating motivation-disrupting conditions such as depression and addiction.

Risky decisions

MIT Institute Professor Ann Graybiel. Photo: Justin Knight

In Ann Graybiel’s lab, researchers have been examining how the brain makes choices that carry both positive and negative consequences — deciding to take on a higher-paying but more demanding job, for example. Psychologists call these dilemmas approach-avoidance conflicts, and resolving them not only requires weighing the good versus the bad, but also motivation to engage with the decision.

Emily Hueske, a research scientist in the Graybiel lab, explains that everyone has their own risk tolerance when it comes to such decisions, and certain psychiatric conditions, including depression and anxiety disorders, can shift the tipping point at which a person chooses to “approach” or “avoid.”

Studies have shown that neurons in the striatum (see image below), a region deep in the brain involved in both motivation and movement, activate as we grapple with these decisions. Graybiel traced this activity even further, to tiny compartments within the striatum called striosomes.

(She discovered striosomes many years ago and has been studying their function for decades.)

A motivational switch

In 2015, Graybiel’s team manipulated striosome signaling within genetically engineered mice and changed the way animals behave in approach-avoidance conflict situations. Taking cues from an assessment used to evaluate approach-avoidance behavior in patients, they presented mice with opportunities to obtain chocolate while experiencing unwelcome exposure in a brightly lit area.

Experimentally activating neurons in striosomes had a dramatic effect, causing mice to venture into brightly lit areas that they would normally avoid. With striosomal circuits switched on, “this animal all of a sudden is like a different creature,” Graybiel says.

Two years later, they found that chronic stress and other factors can also disrupt this signaling and change the choices animals make.

An image of the mouse striatum showing clusters of striosomes (red and yellow). Image: Graybiel lab

Age of ennui

This November, Alexander Friedman, who worked as a research scientist in the Graybiel lab, and Hueske reported in Cell that they found an age-related decline in motivation-modulated learning in mice and rats. Neurons within striosomes became more active than the cells that surround them as animals learned to assign positive and negative values to potential choices. And older mice were less engaged than their younger counterparts in the type of learning required to make these cost-benefit analyses. A similar lack of motivation was observed in a mouse model of Huntington’s disease, a neurodegenerative disorder that is often associated with mood
disturbances in patients.

“This coincides with our previous findings that striosomes are critically important for decisions that involve a conflict.”

“This coincides with our previous findings that striosomes are critically important for decisions that involve a conflict,” says Friedman, who is now an assistant professor at the University of Texas at El Paso.

Graybiel’s team is continuing to investigate these uniquely positioned compartments in the brain, expecting to shed light on the mechanisms that underlie both learning and motivation.

“There’s no learning without motivation, and in fact, motivation can be influenced by learning,” Hueske says. “The more you learn, the more excited you might be to engage in the task. So the two are intertwined.”

The aging brain

Researchers in John Gabrieli’s lab are also seeking to understand the circuits that link motivation to learning, and recently, his team reported that they, too, had found an age-related decline in motivation-modulated learning.

Studies in young adults have shown that memory improves when the brain circuits that process motivation and memory interact. Gabrieli and neurologist Maiya Geddes, who worked in Gabrieli’s lab as a postdoctoral fellow, wondered whether this holds true in older adults, particularly as memory declines.

To find out, the team recruited 40 people to participate in a brain imaging study. About half of the participants were between the ages of 18 and 30, while the others were between the ages of 49 and 84. While inside an fMRI scanner, each participant was asked to commit certain words to memory and told their success would determine how much money they received for participating in the experiment.

Diminished drive

MRI scan
Younger adults show greater activation in the reward-related regions of the brain during incentivized memory tasks compared to older adults. Image: Maiya Geddes

Not surprisingly, when participants were asked 24 hours later to recall the words, the younger group performed better overall than the older group. In young people, incentivized memory tasks triggered activity in parts of the brain involved in both memory and motivation. But in older adults, while these two parts of the brain could be activated independently, they did not seem to be communicating with one another.

“It seemed that the older adults, at least in terms of their brain response, did care about the kind of incentives that we were offering,” says Geddes, who is now an assistant professor at McGill University. “But for whatever reason, that wasn’t allowing them to benefit in terms of improved memory performance.”

Since the study indicates the brain still can anticipate potential rewards, Geddes is now exploring whether other sources of motivation, such as social rewards, might more effectively increase healthful decisions and behaviors in older adults.

Circuit control

Understanding how the brain generates and responds to motivation is not only important for improving learning strategies. Lifestyle choices such as exercise and social engagement can help people preserve cognitive function and improve their quality of life as they age, and Gabrieli says activating the right motivational circuits could help encourage people to implement healthy changes.

By pinpointing these motivational circuits in mice, Graybiel hopes that her research will lead to better treatment strategies for people struggling with motivational challenges, including Parkinson’s disease. Her team is now exploring whether striosomes serve as part of a value-sensitive switch, linking our intentions to dopamine-containing neurons in the midbrain that can modulate our actions.

“Perhaps this motivation is critical for the conflict resolution, and striosomes combine two worlds, dopaminergic motivation and cortical knowledge, resulting in motivation to learn,” Friedman says.

“Now we know that these challenges have a biological basis, and that there are neural circuits that can promote or reduce our feeling of motivational energy,” explains Graybiel. “This realization in itself is a major step toward learning how we can control these circuits both behaviorally and by highly selective therapeutic targeting.”

New molecular therapeutics center established at MIT’s McGovern Institute

More than one million Americans are diagnosed with a chronic brain disorder each year, yet effective treatments for most complex brain disorders are inadequate or even nonexistent.

A major new research effort at MIT’s McGovern Institute aims to change how we treat brain disorders by developing innovative molecular tools that precisely target dysfunctional genetic, molecular, and circuit pathways.

The K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience was established at MIT through a $28 million gift from philanthropist Lisa Yang and MIT alumnus Hock Tan ’75. Yang is a former investment banker who has devoted much of her time to advocacy for individuals with disabilities and autism spectrum disorders. Tan is President and CEO of Broadcom, a global technology infrastructure company. This latest gift brings Yang and Tan’s total philanthropy to MIT to more than $72 million.

Lisa Yang (center) and MIT alumnus Hock Tan ’75 with their daughter Eva (far left) pictured at the opening of the Hock E. Tan and K. Lisa Yang Center for Autism Research in 2017. Photo: Justin Knight

“In the best MIT spirit, Lisa and Hock have always focused their generosity on insights that lead to real impact,” says MIT President L. Rafael Reif. “Scientifically, we stand at a moment when the tools and insights to make progress against major brain disorders are finally within reach. By accelerating the development of promising treatments, the new center opens the door to a hopeful new future for all those who suffer from these disorders and those who love them. I am deeply grateful to Lisa and Hock for making MIT the home of this pivotal research.”

Engineering with precision

Research at the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience will initially focus on three major lines of investigation: genetic engineering using CRISPR tools, delivery of genetic and molecular cargo across the blood-brain barrier, and the translation of basic research into the clinical setting. The center will serve as a hub for researchers with backgrounds ranging from biological engineering and genetics to computer science and medicine.

“Developing the next generation of molecular therapeutics demands collaboration among researchers with diverse backgrounds,” says Robert Desimone, McGovern Institute Director and Doris and Don Berkey Professor of Neuroscience at MIT. “I am confident that the multidisciplinary expertise convened by this center will revolutionize how we improve our health and fight disease in the coming decade. Although our initial focus will be on the brain and its relationship to the body, many of the new therapies could have other health applications.”

There are an estimated 19,000 to 22,000 genes in the human genome and a third of those genes are active in the brain–the highest proportion of genes expressed in any part of the body.

Variations in genetic code have been linked to many complex brain disorders, including depression and Parkinson’s. Emerging genetic technologies, such as the CRISPR gene editing platform pioneered by McGovern Investigator Feng Zhang, hold great potential in both targeting and fixing these errant genes. But the safe and effective delivery of this genetic cargo to the brain remains a challenge.

Researchers within the new Yang-Tan Center will improve and fine-tune CRISPR gene therapies and develop innovative ways of delivering gene therapy cargo into the brain and other organs. In addition, the center will leverage newly developed single cell analysis technologies that are revealing cellular targets for modulating brain functions with unprecedented precision, opening the door for noninvasive neuromodulation as well as the development of medicines. The center will also focus on developing novel engineering approaches to delivering small molecules and proteins from the bloodstream into the brain. Desimone will direct the center and some of the initial research initiatives will be led by Associate Professor of Materials Science and Engineering Polina Anikeeva; Ed Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT; Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT; and Feng Zhang, James and Patricia Poitras Professor of Neuroscience at MIT.

Building a research hub

“My goal in creating this center is to cement the Cambridge and Boston region as the global epicenter of next-generation therapeutics research. The novel ideas I have seen undertaken at MIT’s McGovern Institute and Broad Institute of MIT and Harvard leave no doubt in my mind that major therapeutic breakthroughs for mental illness, neurodegenerative disease, autism and epilepsy are just around the corner,” says Yang.

Center funding will also be earmarked to create the Y. Eva Tan Fellows program, named for Tan and Yang’s daughter Eva, which will support fellowships for young neuroscientists and engineers eager to design revolutionary treatments for human diseases.

“We want to build a strong pipeline for tomorrow’s scientists and neuroengineers,” explains Hock Tan. “We depend on the next generation of bright young minds to help improve the lives of people suffering from chronic illnesses, and I can think of no better place to provide the very best education and training than MIT.”

The molecular therapeutics center is the second research center established by Yang and Tan at MIT. In 2017, they launched the Hock E. Tan and K. Lisa Yang Center for Autism Research, and, two years later, they created a sister center at Harvard Medical School, with the unique strengths of each institution converging toward a shared goal: understanding the basic biology of autism and how genetic and environmental influences converge to give rise to the condition, then translating those insights into novel treatment approaches.

All tools developed at the molecular therapeutics center will be shared globally with academic and clinical researchers with the goal of bringing one or more novel molecular tools to human clinical trials by 2025.

“We are hopeful that our centers, located in the heart of the Cambridge-Boston biotech ecosystem, will spur further innovation and fuel critical new insights to our understanding of health and disease,” says Yang.

 

Fan Wang

Sensing the World

The Wang lab studies the neural circuit basis of sensory perception. Wang is specifically interested in uncovering the neural circuits underlying: (1) Active touch sensation including the tactile processing stream and motor control of touch sensors on the face, (2) pain sensation including both sensory-discriminative and affective aspects of pain and (3) general anesthesia including the process of active pain-suppression. Wang uses a range of techniques to gain traction on these questions, including genetic, viral, electrophysiology, and in vivo imaging.

COMMANDing drug delivery

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

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

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

Fine targeting

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

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

“Accurate delivery of drugs to reach these targets is really important to ensure optimal efficacy and avoid off-target adverse effects. Our new system, called COMMAND, determines how best to dose targets,” says Michael Cima, senior author on the study and the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research.

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

COMMAND response

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

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

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

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

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

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

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

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

Saxe Lab examines social impact of COVID-19

After being forced to relocate from their MIT dorms during the COVID19 crisis, two members of the Saxe lab are now applying their psychology skills to study the impact of mandatory relocation and social isolation on mental health.

“When ‘social distancing’ measures hit MIT, we tried to process how the implementation of these policies would impact the landscape of our social lives,” explains graduate student Heather Kosakowski, who conceived of the study late one evening with undergraduate Michelle Hung.  This landscape is broad, examining the effects of being uprooted and physically relocated from a place, but also changes in social connections, including friendships and even dating life.

MIT undergrad Michelle Hung in the Saxe lab. Photo: Michelle Hung

“I started speculating about how my life and the lives of other MIT students would change,” says Hung. “I was overwhelmed, sad, and scared. But then we realized that we were actually equipped to find the answers to our questions by conducting a study.”

Together, Kosakowski and Hung developed a survey to measure how the social behavior of MIT students, postdocs, and staff is changing over the course of the pandemic. Survey questions were designed to measure loneliness and other aspects of mental health. The survey was sent to members of the MIT community and shared on social media in mid-March, when the pandemic hit the US, and MIT made the unprecedented decision to send students home, shift to online instruction, and dramatically ramp down operations on campus.

More than 500 people responded to the initial survey, ranging in age from 18 to 60, living in cities and countries around the world. Many but not all of those who responded were affiliated with MIT. Kosakowski and Hung are sending follow-up surveys to participants every two weeks and the team plans to collect data for the duration of the pandemic.

“Throwing myself into creating the survey was a way to cope with feeling sad about leaving a community I love,” explains Hung, who flew home to California in March and admits that she struggles with feelings of loneliness now that she’s off campus.

Although it is too soon to form any conclusions about their research, Hung predicts that feelings of loneliness may actually diminish over the course of the pandemic.

“Humans have an impressive ability to adapt to change,” she says. “And I think in this virtual world, people will find novel ways to stay connected that we couldn’t have predicted.”

Whether we find ourselves feeling more or less lonely as this COVID-19 crisis comes to an end, both Kosakowski and Hung agree that it will fundamentally change life as we know it.

The Saxe lab is looking for more survey participants. To learn more about this study or to participate in the survey, click here.

 

Researchers achieve remote control of hormone release

Abnormal levels of stress hormones such as adrenaline and cortisol are linked to a variety of mental health disorders, including depression and posttraumatic stress disorder (PTSD). MIT researchers have now devised a way to remotely control the release of these hormones from the adrenal gland, using magnetic nanoparticles.

This approach could help scientists to learn more about how hormone release influences mental health, and could eventually offer a new way to treat hormone-linked disorders, the researchers say.

“We’re looking how can we study and eventually treat stress disorders by modulating peripheral organ function, rather than doing something highly invasive in the central nervous system,” says Polina Anikeeva, an MIT professor of materials science and engineering and of brain and cognitive sciences.

To achieve control over hormone release, Dekel Rosenfeld, an MIT-Technion postdoc in Anikeeva’s group, has developed specialized magnetic nanoparticles that can be injected into the adrenal gland. When exposed to a weak magnetic field, the particles heat up slightly, activating heat-responsive channels that trigger hormone release. This technique can be used to stimulate an organ deep in the body with minimal invasiveness.

Anikeeva and Alik Widge, an assistant professor of psychiatry at the University of Minnesota and a former research fellow at MIT’s Picower Institute for Learning and Memory, are the senior authors of the study. Rosenfeld is the lead author of the paper, which appears today in Science Advances.

Controlling hormones

Anikeeva’s lab has previously devised several novel magnetic nanomaterials, including particles that can release drugs at precise times in specific locations in the body.

In the new study, the research team wanted to explore the idea of treating disorders of the brain by manipulating organs that are outside the central nervous system but influence it through hormone release. One well-known example is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response in mammals. Hormones secreted by the adrenal gland, including cortisol and adrenaline, play important roles in depression, stress, and anxiety.

“Some disorders that we consider neurological may be treatable from the periphery, if we can learn to modulate those local circuits rather than going back to the global circuits in the central nervous system,” says Anikeeva, who is a member of MIT’s Research Laboratory of Electronics and McGovern Institute for Brain Research.

As a target to stimulate hormone release, the researchers decided on ion channels that control the flow of calcium into adrenal cells. Those ion channels can be activated by a variety of stimuli, including heat. When calcium flows through the open channels into adrenal cells, the cells begin pumping out hormones. “If we want to modulate the release of those hormones, we need to be able to essentially modulate the influx of calcium into adrenal cells,” Rosenfeld says.

Unlike previous research in Anikeeva’s group, in this study magnetothermal stimulation was applied to modulate the function of cells without artificially introducing any genes.

To stimulate these heat-sensitive channels, which naturally occur in adrenal cells, the researchers designed nanoparticles made of magnetite, a type of iron oxide that forms tiny magnetic crystals about 1/5000 the thickness of a human hair. In rats, they found these particles could be injected directly into the adrenal glands and remain there for at least six months. When the rats were exposed to a weak magnetic field — about 50 millitesla, 100 times weaker than the fields used for magnetic resonance imaging (MRI) — the particles heated up by about 6 degrees Celsius, enough to trigger the calcium channels to open without damaging any surrounding tissue.

The heat-sensitive channel that they targeted, known as TRPV1, is found in many sensory neurons throughout the body, including pain receptors. TRPV1 channels can be activated by capsaicin, the organic compound that gives chili peppers their heat, as well as by temperature. They are found across mammalian species, and belong to a family of many other channels that are also sensitive to heat.

This stimulation triggered a hormone rush — doubling cortisol production and boosting noradrenaline by about 25 percent. That led to a measurable increase in the animals’ heart rates.

Treating stress and pain

The researchers now plan to use this approach to study how hormone release affects PTSD and other disorders, and they say that eventually it could be adapted for treating such disorders. This method would offer a much less invasive alternative to potential treatments that involve implanting a medical device to electrically stimulate hormone release, which is not feasible in organs such as the adrenal glands that are soft and highly vascularized, the researchers say.

Another area where this strategy could hold promise is in the treatment of pain, because heat-sensitive ion channels are often found in pain receptors.

“Being able to modulate pain receptors with this technique potentially will allow us to study pain, control pain, and have some clinical applications in the future, which hopefully may offer an alternative to medications or implants for chronic pain,” Anikeeva says. With further investigation of the existence of TRPV1 in other organs, the technique can potentially be extended to other peripheral organs such as the digestive system and the pancreas.

The research was funded by the U.S. Defense Advance Research Projects Agency ElectRx Program, a Bose Research Grant, the National Institutes of Health BRAIN Initiative, and a MIT-Technion fellowship.

Brain biomarkers predict mood and attention symptoms

Mood and attentional disorders amongst teens are an increasing concern, for parents, society, and for peers. A recent Pew research center survey found conditions such as depression and anxiety to be the number one concern that young students had about their friends, ranking above drugs or bullying.

“We’re seeing an epidemic in teen anxiety and depression,” explains McGovern Research Affiliate Susan Whitfield-Gabrieli.

“Scientists are finding a huge increase in suicide ideation and attempts, something that hit home for me as a mother of teens. Emergency rooms in hospitals now have guards posted outside doors of these teenagers that attempted suicide—this is a pressing issue,” explains Whitfield-Gabrieli who is also director of the Northeastern University Biomedical Imaging Center and a member of the Poitras Center for Psychiatric Disorders Research.

Finding new methods for discovering early biomarkers for risk of psychiatric disorders would allow early interventions and avoid reaching points of crisis such as suicide ideation or attempts. In research published recently in JAMA Psychiatry, Whitfield-Gabrieli and colleagues found that signatures predicting future development of depression and attentional symptoms can be detected in children as young as seven years old.

Long-term view

While previous work had suggested that there may be biomarkers that predict development of mood and attentional disorders, identifying early biomarkers prior to an onset of illness requires following a cohort of pre-teens from a young age, and monitoring them across years. This effort to have a proactive, rather than reactive, approach to the development of symptoms associated with mental disorders is exactly the route Whitfield-Gabrieli and colleagues took.

“One of the exciting aspects of this study is that the cohort is not pre-selected for already having symptoms of psychiatric disorders themselves or even in their family,” explained Whitfield-Gabrieli. “It’s an unbiased cohort that we followed over time.”

McGovern research affiliate Susan Whitfield-Gabrieli has discovered early brain biomarkers linked to psychiatric disorders.

In some past studies, children were pre-selected, for example a major depressive disorder diagnosis in the parents, but Whitfield-Gabrieli and colleagues, Silvia Bunge from Berkeley and Laurie Cutting from Vanderbilt, recruited a range of children without preconditions, and examined them at age 7, then again 4 years later. The researchers examined resting state functional connectivity, and compared this to scores on the child behavioral checklist (CBCL), allowing them to relate differences in the brain to a standardized analysis of behavior that can be linked to psychiatric disorders. The CBCL is used both in research and in the clinic and his highly predictive of disorders including ADHD, so that changes in the brain could be related to changes in a widely used clinical scoring system.

“Over the four years, some people got worse, some got better, and some stayed the same according the CBCL. We could relate this directly to differences in brain networks, and could identify at age 7 who would get worse,” explained Whitfield-Gabrieli.

Brain network changes

The authors analyzed differences in resting state network connectivity, regions across the brain that rise and fall in activity level together, as visualized using fMRI. Reduced connectivity between these regions may allow us to get a handle on reduced “top-down” control of neural circuits. The dorsolateral prefrontal region is linked to executive function, external attention, and emotional control. Increased connection with the medial prefrontal cortex is known to be present in attention deficit hyperactivity disorder (ADHD), while a reduced connection to a different brain region, the sgACC, is seen in major depressive disorder. The question remained as to whether these changes can be seen prior to the onset of diagnosable attentional or mood disorders.

Whitfield-Gabrieli and colleagues found that these resting state networks varied in the brains of children that would later develop anxiety/depression and ADHD symptoms. Weaker scores in connectivity between the dorsolateral and medial prefrontal cortical regions tended to be seen in children whose attention scores went on to improve. Analysis of the resting state networks above could differentiate those who would have typical attentional behavior by age 11 versus those that went on to develop ADHD.

Whitfield-Gabrieli has replicated this finding in an independent sample of children and she is continuing to expand the analysis and check the results, as well as follow this cohort into the future. Should changes in resting state networks be a consistent biomarker, the next step is to initiate interventions prior to the point of crisis.

“We’ve recently been able to use mindfulness interventions, and show these reduce self-perceived stress and amygdala activation in response to fear, and we are also testing the effect of exercise interventions,” explained Whitfield-Gabrieli. “The hope is that by using predictive biomarkers we can augment children’s lifestyles with healthy interventions that can prevent risk converting to a psychiatric disorder.”

Can fMRI reveal insights into addiction and treatments?

Many debilitating conditions like depression and addiction have biological signatures hidden in the brain well before symptoms appear.  What if brain scans could be used to detect these hidden signatures and determine the most optimal treatment for each individual? McGovern Investigator John Gabrieli is interested in this question and wrote about the use of imaging technologies as a predictive tool for brain disorders in a recent issue of Scientific American.

page from Scientific American article
McGovern Investigator John Gabrieli pens a story for Scientific American about the potential for brain imaging to predict the onset of mental illness.

“Brain scans show promise in predicting who will benefit from a given therapy,” says Gabrieli, who is also the Grover Hermann Professor in Brain and Cognitive Sciences at MIT. “Differences in neural activity may one day tell clinicians which depression treatment will be most effective for an individual or which abstinent alcoholics will relapse.”

Gabrieli cites research which has shown that half of patients treated for alcohol abuse go back to drinking within a year of treatment, and similar reversion rates occur for stimulants such as cocaine. Failed treatments may be a source of further anxiety and stress, Gabrieli notes, so any information we can glean from the brain to pinpoint treatments or doses that would help would be highly informative.

Current treatments rely on little scientific evidence to support the length of time needed in a rehabilitation facility, he says, but “a number suggest that brain measures might foresee who will succeed in abstaining after treatment has ended.”

Further data is needed to support this idea, but Gabrieli’s Scientific American piece makes the case that the use of such a technology may be promising for a range of addiction treatments including abuse of alcohol, nicotine, and illicit drugs.

Gabrieli also believes brain imaging has the potential to reshape education. For example, educational interventions targeting dyslexia might be more effective if personalized to specific differences in the brain that point to the source of the learning gap.

But for the prediction sciences to move forward in mental health and education, he concludes, the research community must design further rigorous studies to examine these important questions.