July 10, 2014: Massachusetts Secretary of Education Matthew Malone (center) visits the McGovern Institute to learn more about dyslexia research in the Gabrieli lab. Photo: Julie Pryor
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Inside the adult ADHD brain
In the first study to compare patterns of brain activity in adults who recovered from childhood ADHD and those who did not, McGovern Institute neuroscientists have discovered key differences in a brain communication network that is active when the brain is at wakeful rest and not focused on a particular task.
The findings offer evidence of a biological basis for adult ADHD and should help to validate the criteria used to diagnose the disorder, according to the researchers. Read more >>
Noninvasive brain control
Optogenetics, a technology that allows scientists to control brain activity by shining light on neurons, relies on light-sensitive proteins that can suppress or stimulate electrical signals within cells. This technique requires a light source to be implanted in the brain, where it can reach the cells to be controlled.
MIT engineers have now developed the first light-sensitive molecule that enables neurons to be silenced noninvasively, using a light source outside the skull. This makes it possible to do long-term studies without an implanted light source. The protein, known as Jaws, also allows a larger volume of tissue to be influenced at once.
This noninvasive approach could pave the way to using optogenetics in human patients to treat epilepsy and other neurological disorders, the researchers say, although much more testing and development is needed. Led by Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, the researchers described the protein in the June 29 issue of Nature Neuroscience.
Optogenetics, a technique developed over the past 15 years, has become a common laboratory tool for shutting off or stimulating specific types of neurons in the brain, allowing neuroscientists to learn much more about their functions.
The neurons to be studied must be genetically engineered to produce light-sensitive proteins known as opsins, which are channels or pumps that influence electrical activity by controlling the flow of ions in or out of cells. Researchers then insert a light source, such as an optical fiber, into the brain to control the selected neurons.
Such implants can be difficult to insert, however, and can be incompatible with many kinds of experiments, such as studies of development, during which the brain changes size, or of neurodegenerative disorders, during which the implant can interact with brain physiology. In addition, it is difficult to perform long-term studies of chronic diseases with these implants.
Mining nature’s diversity
To find a better alternative, Boyden, graduate student Amy Chuong, and colleagues turned to the natural world. Many microbes and other organisms use opsins to detect light and react to their environment. Most of the natural opsins now used for optogenetics respond best to blue or green light.
Boyden’s team had previously identified two light-sensitive chloride ion pumps that respond to red light, which can penetrate deeper into living tissue. However, these molecules, found in the bacteria Haloarcula marismortui and Haloarcula vallismortis, did not induce a strong enough photocurrent — an electric current in response to light — to be useful in controlling neuron activity.
Chuong set out to improve the photocurrent by looking for relatives of these proteins and testing their electrical activity. She then engineered one of these relatives by making many different mutants. The result of this screen, Jaws, retained its red-light sensitivity but had a much stronger photocurrent — enough to shut down neural activity.
“This exemplifies how the genomic diversity of the natural world can yield powerful reagents that can be of use in biology and neuroscience,” says Boyden, who is a member of MIT’s Media Lab and the McGovern Institute for Brain Research.
Using this opsin, the researchers were able to shut down neuronal activity in the mouse brain with a light source outside the animal’s head. The suppression occurred as deep as 3 millimeters in the brain, and was just as effective as that of existing silencers that rely on other colors of light delivered via conventional invasive illumination.
A key advantage to this opsin is that it could enable optogenetic studies of animals with larger brains, says Garret Stuber, an assistant professor of psychiatry and cell biology and physiology at the University of North Carolina at Chapel Hill.
“In animals with larger brains, people have had difficulty getting behavior effects with optogenetics, and one possible reason is that not enough of the tissue is being inhibited,” he says. “This could potentially alleviate that.”
Restoring vision
Working with researchers at the Friedrich Miescher Institute for Biomedical Research in Switzerland, the MIT team also tested Jaws’s ability to restore the light sensitivity of retinal cells called cones. In people with a disease called retinitis pigmentosa, cones slowly atrophy, eventually causing blindness.
Friedrich Miescher Institute scientists Botond Roska and Volker Busskamp have previously shown that some vision can be restored in mice by engineering those cone cells to express light-sensitive proteins. In the new paper, Roska and Busskamp tested the Jaws protein in the mouse retina and found that it more closely resembled the eye’s natural opsins and offered a greater range of light sensitivity, making it potentially more useful for treating retinitis pigmentosa.
This type of noninvasive approach to optogenetics could also represent a step toward developing optogenetic treatments for diseases such as epilepsy, which could be controlled by shutting off misfiring neurons that cause seizures, Boyden says. “Since these molecules come from species other than humans, many studies must be done to evaluate their safety and efficacy in the context of treatment,” he says.
Boyden’s lab is working with many other research groups to further test the Jaws opsin for other applications. The team is also seeking new light-sensitive proteins and is working on high-throughput screening approaches that could speed up the development of such proteins.
The research at MIT was funded by Jerry and Marge Burnett, the Defense Advanced Research Projects Agency, the Human Frontiers Science Program, the IET A. F. Harvey Prize, the Janet and Sheldon Razin ’59 Fellowship of the MIT McGovern Institute, the New York Stem Cell Foundation-Robertson Investigator Award, the National Institutes of Health, the National Science Foundation, and the Wallace H. Coulter Foundation.
Controlling movement with light
For the first time, MIT neuroscientists have shown they can control muscle movement by applying optogenetics — a technique that allows scientists to control neurons’ electrical impulses with light — to the spinal cords of animals that are awake and alert.
Led by MIT Institute Professor Emilio Bizzi, the researchers studied mice in which a light-sensitive protein that promotes neural activity was inserted into a subset of spinal neurons. When the researchers shone blue light on the animals’ spinal cords, their hind legs were completely but reversibly immobilized. The findings, described in the June 25 issue of PLoS One, offer a new approach to studying the complex spinal circuits that coordinate movement and sensory processing, the researchers say.
In this study, Bizzi and Vittorio Caggiano, a postdoc at MIT’s McGovern Institute for Brain Research, used optogenetics to explore the function of inhibitory interneurons, which form circuits with many other neurons in the spinal cord. These circuits execute commands from the brain, with additional input from sensory information from the limbs.
Previously, neuroscientists have used electrical stimulation or pharmacological intervention to control neurons’ activity and try to tease out their function. Those approaches have revealed a great deal of information about spinal control, but they do not offer precise enough control to study specific subsets of neurons.
Optogenetics, on the other hand, allows scientists to control specific types of neurons by genetically programming them to express light-sensitive proteins. These proteins, called opsins, act as ion channels or pumps that regulate neurons’ electrical activity. Some opsins suppress activity when light shines on them, while others stimulate it.
“With optogenetics, you are attacking a system of cells that have certain characteristics similar to each other. It’s a big shift in terms of our ability to understand how the system works,” says Bizzi, who is a member of MIT’s McGovern Institute.
Muscle control
Inhibitory neurons in the spinal cord suppress muscle contractions, which is critical for maintaining balance and for coordinating movement. For example, when you raise an apple to your mouth, the biceps contract while the triceps relax. Inhibitory neurons are also thought to be involved in the state of muscle inhibition that occurs during the rapid eye movement (REM) stage of sleep.
To study the function of inhibitory neurons in more detail, the researchers used mice developed by Guoping Feng, the Poitras Professor of Neuroscience at MIT, in which all inhibitory spinal neurons were engineered to express an opsin called channelrhodopsin 2. This opsin stimulates neural activity when exposed to blue light. They then shone light at different points along the spine to observe the effects of neuron activation.
When inhibitory neurons in a small section of the thoracic spine were activated in freely moving mice, all hind-leg movement ceased. This suggests that inhibitory neurons in the thoracic spine relay the inhibition all the way to the end of the spine, Caggiano says. The researchers also found that activating inhibitory neurons had no effect on the transmission of sensory information from the limbs to the brain, or on normal reflexes.
“The spinal location where we found this complete suppression was completely new,” Caggiano says. “It has not been shown by any other scientists that there is this front-to-back suppression that affects only motor behavior without affecting sensory behavior.”
“It’s a compelling use of optogenetics that raises a lot of very interesting questions,” says Simon Giszter, a professor of neurobiology and anatomy at Drexel University who was not part of the research team. Among those questions is whether this mechanism behaves as a global “kill switch,” or if the inhibitory neurons form modules that allow for more selective suppression of movement patterns.
Now that they have demonstrated the usefulness of optogenetics for this type of study, the MIT team hopes to explore the roles of other types of spinal cord neurons. They also plan to investigate how input from the brain influences these spinal circuits.
“There’s huge interest in trying to extend these studies and dissect these circuits because we tackled only the inhibitory system in a very global way,” Caggiano says. “Further studies will highlight the contribution of single populations of neurons in the spinal cord for the control of limbs and control of movement.”
The research was funded by the Human Frontier Science Program and the National Science Foundation. Mriganka Sur, the Paul E. and Lilah Newton Professor of Neuroscience at MIT, is also an author of the paper.
McGovern dyslexia research featured on WBUR
Boston’s NPR station, 90.9 WBUR, ran a story this morning about cutting edge dyslexia research as part of their series called “Brain Matters.” They featured John Gabrieli’s brain imaging research, which found differences in a key language structure, even before children start learning to read.
Is this the golden age of neuroscience?
Today, WBUR (Boston’s NPR station) began a 2-month long series on the brain called “Brain Matters.” This morning, they ran a segment which featured interviews with Bob Desimone and Ed Boyden. Desimone was also the featured guest on the Radio Boston, where he fielded questions from callers about the current state of brain research.
As part of this series, WBUR.org posted 12 images that show some of the cutting-edge techniques that scientists are using to try to solve the mystery of the brain. Some of the beautiful images are from McGovern labs. “Brain Matters” also asked 11 young neuroscientists from BU, Harvard and MIT to share what they’re working on — and why their research is important. These interviews are posted on the WBUR website.
When good people do bad things
When people get together in groups, unusual things can happen — both good and bad. Groups create important social institutions that an individual could not achieve alone, but there can be a darker side to such alliances: Belonging to a group makes people more likely to harm others outside the group.
“Although humans exhibit strong preferences for equity and moral prohibitions against harm in many contexts, people’s priorities change when there is an ‘us’ and a ‘them,’” says Rebecca Saxe, an associate professor of cognitive neuroscience at MIT. “A group of people will often engage in actions that are contrary to the private moral standards of each individual in that group, sweeping otherwise decent individuals into ‘mobs’ that commit looting, vandalism, even physical brutality.”
Several factors play into this transformation. When people are in a group, they feel more anonymous, and less likely to be caught doing something wrong. They may also feel a diminished sense of personal responsibility for collective actions.
Saxe and colleagues recently studied a third factor that cognitive scientists believe may be involved in this group dynamic: the hypothesis that when people are in groups, they “lose touch” with their own morals and beliefs, and become more likely to do things that they would normally believe are wrong.
In a study that recently went online in the journal NeuroImage, the researchers measured brain activity in a part of the brain involved in thinking about oneself. They found that in some people, this activity was reduced when the subjects participated in a competition as part of a group, compared with when they competed as individuals. Those people were more likely to harm their competitors than people who did not exhibit this decreased brain activity.
“This process alone does not account for intergroup conflict: Groups also promote anonymity, diminish personal responsibility, and encourage reframing harmful actions as ‘necessary for the greater good.’ Still, these results suggest that at least in some cases, explicitly reflecting on one’s own personal moral standards may help to attenuate the influence of ‘mob mentality,’” says Mina Cikara, a former MIT postdoc and lead author of the NeuroImage paper.
Group dynamics
Cikara, who is now an assistant professor at Carnegie Mellon University, started this research project after experiencing the consequences of a “mob mentality”: During a visit to Yankee Stadium, her husband was ceaselessly heckled by Yankees fans for wearing a Red Sox cap. “What I decided to do was take the hat from him, thinking I would be a lesser target by virtue of the fact that I was a woman,” Cikara says. “I was so wrong. I have never been called names like that in my entire life.”
The harassment, which continued throughout the trip back to Manhattan, provoked a strong reaction in Cikara, who isn’t even a Red Sox fan.
“It was a really amazing experience because what I realized was I had gone from being an individual to being seen as a member of ‘Red Sox Nation.’ And the way that people responded to me, and the way I felt myself responding back, had changed, by virtue of this visual cue — the baseball hat,” she says. “Once you start feeling attacked on behalf of your group, however arbitrary, it changes your psychology.”
Cikara, then a third-year graduate student at Princeton University, started to investigate the neural mechanisms behind the group dynamics that produce bad behavior. In the new study, done at MIT, Cikara, Saxe (who is also an associate member of MIT’s McGovern Institute for Brain Research), former Harvard University graduate student Anna Jenkins, and former MIT lab manager Nicholas Dufour focused on a part of the brain called the medial prefrontal cortex. When someone is reflecting on himself or herself, this part of the brain lights up in functional magnetic resonance imaging (fMRI) brain scans.
A couple of weeks before the study participants came in for the experiment, the researchers surveyed each of them about their social-media habits, as well as their moral beliefs and behavior. This allowed the researchers to create individualized statements for each subject that were true for that person — for example, “I have stolen food from shared refrigerators” or “I always apologize after bumping into someone.”
When the subjects arrived at the lab, their brains were scanned as they played a game once on their own and once as part of a team. The purpose of the game was to press a button if they saw a statement related to social media, such as “I have more than 600 Facebook friends.”
The subjects also saw their personalized moral statements mixed in with sentences about social media. Brain scans revealed that when subjects were playing for themselves, the medial prefrontal cortex lit up much more when they read moral statements about themselves than statements about others, consistent with previous findings. However, during the team competition, some people showed a much smaller difference in medial prefrontal cortex activation when they saw the moral statements about themselves compared to those about other people.
Those people also turned out to be much more likely to harm members of the competing group during a task performed after the game. Each subject was asked to select photos that would appear with the published study, from a set of four photos apiece of two teammates and two members of the opposing team. The subjects with suppressed medial prefrontal cortex activity chose the least flattering photos of the opposing team members, but not of their own teammates.
“This is a nice way of using neuroimaging to try to get insight into something that behaviorally has been really hard to explore,” says David Rand, an assistant professor of psychology at Yale University who was not involved in the research. “It’s been hard to get a direct handle on the extent to which people within a group are tapping into their own understanding of things versus the group’s understanding.”
Getting lost
The researchers also found that after the game, people with reduced medial prefrontal cortex activity had more difficulty remembering the moral statements they had heard during the game.
“If you need to encode something with regard to the self and that ability is somehow undermined when you’re competing with a group, then you should have poor memory associated with that reduction in medial prefrontal cortex signal, and that’s exactly what we see,” Cikara says.
Cikara hopes to follow up on these findings to investigate what makes some people more likely to become “lost” in a group than others. She is also interested in studying whether people are slower to recognize themselves or pick themselves out of a photo lineup after being absorbed in a group activity.
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Air Force Office of Scientific Research, and the Packard Foundation.
Inside the adult ADHD brain
About 11 percent of school-age children in the United States have been diagnosed with attention deficit hyperactivity disorder (ADHD). While many of these children eventually “outgrow” the disorder, some carry their difficulties into adulthood: About 10 million American adults are currently diagnosed with ADHD.
In the first study to compare patterns of brain activity in adults who recovered from childhood ADHD and those who did not, MIT neuroscientists have discovered key differences in a brain communication network that is active when the brain is at wakeful rest and not focused on a particular task. The findings offer evidence of a biological basis for adult ADHD and should help to validate the criteria used to diagnose the disorder, according to the researchers.
Diagnoses of adult ADHD have risen dramatically in the past several years, with symptoms similar to those of childhood ADHD: a general inability to focus, reflected in difficulty completing tasks, listening to instructions, or remembering details.
“The psychiatric guidelines for whether a person’s ADHD is persistent or remitted are based on lots of clinical studies and impressions. This new study suggests that there is a real biological boundary between those two sets of patients,” says MIT’s John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences, and an author of the study, which appears in the June 10 issue of the journal Brain.
Shifting brain patterns
This study focused on 35 adults who were diagnosed with ADHD as children; 13 of them still have the disorder, while the rest have recovered. “This sample really gave us a unique opportunity to ask questions about whether or not the brain basis of ADHD is similar in the remitted-ADHD and persistent-ADHD cohorts,” says Aaron Mattfeld, a postdoc at MIT’s McGovern Institute for Brain Research and the paper’s lead author.
The researchers used a technique called resting-state functional magnetic resonance imaging (fMRI) to study what the brain is doing when a person is not engaged in any particular activity. These patterns reveal which parts of the brain communicate with each other during this type of wakeful rest.
“It’s a different way of using functional brain imaging to investigate brain networks,” says Susan Whitfield-Gabrieli, a research scientist at the McGovern Institute and the senior author of the paper. “Here we have subjects just lying in the scanner. This method reveals the intrinsic functional architecture of the human brain without invoking any specific task.”
In people without ADHD, when the mind is unfocused, there is a distinctive synchrony of activity in brain regions known as the default mode network. Previous studies have shown that in children and adults with ADHD, two major hubs of this network — the posterior cingulate cortex and the medial prefrontal cortex — no longer synchronize.
In the new study, the MIT team showed for the first time that in adults who had been diagnosed with ADHD as children but no longer have it, this normal synchrony pattern is restored. “Their brains now look like those of people who never had ADHD,” Mattfeld says.
“This finding is quite intriguing,” says Francisco Xavier Castellanos, a professor of child and adolescent psychiatry at New York University who was not involved in the research. “If it can be confirmed, this pattern could become a target for potential modification to help patients learn to compensate for the disorder without changing their genetic makeup.”
Lingering problems
However, in another measure of brain synchrony, the researchers found much more similarity between both groups of ADHD patients.
In people without ADHD, when the default mode network is active, another network, called the task positive network, is suppressed. When the brain is performing tasks that require focus, the task positive network takes over and suppresses the default mode network. If this reciprocal relationship degrades, the ability to focus declines.
Both groups of adult ADHD patients, including those who had recovered, showed patterns of simultaneous activation of both networks. This is thought to be a sign of impairment in executive function — the management of cognitive tasks — that is separate from ADHD, but occurs in about half of ADHD patients. All of the ADHD patients in this study performed poorly on tests of executive function. “Once you have executive function problems, they seem to hang in there,” says Gabrieli, who is a member of the McGovern Institute.
The researchers now plan to investigate how ADHD medications influence the brain’s default mode network, in hopes that this might allow them to predict which drugs will work best for individual patients. Currently, about 60 percent of patients respond well to the first drug they receive.
“It’s unknown what’s different about the other 40 percent or so who don’t respond very much,” Gabrieli says. “We’re pretty excited about the possibility that some brain measurement would tell us which child or adult is most likely to benefit from a treatment.”
The research was funded by the Poitras Center for Affective Disorders Research at the McGovern Institute.
Yinqing Li: Solving the Connectome
Yinqing Li is a graduate student in Feng Zhang’s lab and a McGovern Institute Friends Fellow. His career goal is to “solve the connectome.”
Leah Acker: Engineering the Brain
Leah Acker is a McGovern Institute Friends Fellow who earned her PhD working in the labs of Bob Desimone and Ed Boyden. Leah’s projects involve the invention and application of new technologies for less-invasive neuromodulation, and the study of optogenetic control of brain circuits.