How general anesthesia reduces pain

General anesthesia is medication that suppresses pain and renders patients unconscious during surgery, but whether pain suppression is simply a side effect of loss of consciousness has been unclear. Fan Wang and colleagues have now identified the circuits linked to pain suppression under anesthesia in mouse models, showing that this effect is separable from the unconscious state itself.

“Existing literature suggests that the brain may contain a switch that can turn off pain perception,” explains Fan Wang, a professor at Duke University and lead author of the study. “I had always wanted to find this switch, and it occurred to me that general anesthetics may activate this switch to produce analgesia.”

Wang, who will join the McGovern Institute in January 2021, set out to test this idea with her student, Thuy Hua, and postdoc, Bin Chen.

Pain suppressor

Loss of pain, or analgesia, is an important property of anesthetics that helps to make surgical and invasive medical procedures humane and bearable. In spite of their long use in the medical world, there is still very little understanding of how anesthetics work. It has generally been assumed that a side effect of loss of consciousness is analgesia, but several recent observations have brought this idea into question, and suggest that changes in consciousness might be separable from pain suppression.

A key clue that analgesia is separable from general anesthesia comes from the accounts of patients that regain consciousness during surgery. After surgery, these patients can recount conversations between staff or events that occurred in the operating room, despite not feeling any pain. In addition, some general anesthetics, such as ketamine, can be deployed at low concentrations for pain suppression without loss of consciousness.

Following up on these leads, Wang and colleagues set out to uncover which neural circuits might be involved in suppressing pain during exposure to general anesthetics. Using CANE, a procedure developed by Wang that can detect which neurons activate in response to an event, Wang discovered a new population of GABAergic neurons activated by general anesthetic in the mouse central amygdala.

These neurons become activated in response to different anesthetics, including ketamine, dexmedetomidine, and isoflurane. Using optogenetics to manipulate the activity state of these neurons, Wang and her lab found that they led to marked changes in behavioral responses to painful stimuli.

“The first time we used optogenetics to turn on these cells, a mouse that was in the middle of taking care of an injury simply stopped and started walked around with no sign of pain,” Wang explains.

Specifically, activating these cells blocks pain in multiple models and tests, whereas inhibiting these neurons rendered mice aversive to gentle touch — suggesting that they are involved in a newly uncovered central pain circuit.

The study has implications for both anesthesia and pain. It shows that general anesthetics have complex, multi-faceted effects and that the brain may contain a central pain suppression system.

“We want to figure out how diverse general anesthetics activate these neurons,” explains Wang. “That way we can find compounds that can specifically activate these pain-suppressing neurons without sedation. We’re now also testing whether placebo analgesia works by activating these same central neurons.”

The study also has implications for addiction as it may point to an alternative system for central pain suppression that could be a target of drugs that do not have the devastating side effects of opioids.

Fan Wang joins the McGovern Institute

The McGovern Institute is pleased to announce that Fan Wang, currently a Professor at Duke University, will be joining its team of investigators in 2021. Wang is well-known for her work on sensory perception, pain, and behavior. She takes a broad, and very practical approach to these questions, knowing that sensory perception has broad implications for biomedicine when it comes to pain management, addiction, anesthesia, and hypersensitivity.

“McGovern is a dream place for doing innovative and transformative neuroscience.” – Fan Wang

“I am so thrilled that Fan is coming to the McGovern Institute,” says Robert Desimone, director of the institute and the Doris and Don Berkey Professor of Neuroscience at MIT. “I’ve followed her work for a number of years, and she is making inroads into questions that are relevant to a number of societal problems, such as how we can turn off the perception of chronic pain.”

Wang brings with her a range of techniques developed in her lab, including CANE, which precisely highlights neurons that become activated in response to a stimulus. CANE is highlighting new neuronal subtypes in long-studied brain regions such as the amygdala, and recently elucidated previously undefined neurons in the lateral parabrachial nucleus involved in pain processing.

“I am so excited to join the McGovern Institute,” says Wang. “It is a dream place for doing innovative and transformative neuroscience. McGovern researchers are known for using the most cutting-edge, multi-disciplinary technologies to understand how the brain works. I can’t wait to join the team.”

Wang earned her PhD in 1998 with Richard Axel at Columbia University, subsequently conducting postdoctoral research at Stanford University with Mark Tessier-Lavigne. Wang joined Duke University as a Professor in the Department of Neurobiology in 2003, and was later appointed the Morris N. Broad Distinguished Professor of Neurobiology at Duke University School of Medicine. Wang will join the McGovern Institute as an investigator in January 2021.

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.

Virtual Tour of Wang Lab

Explaining repetitive behavior linked to amphetamine use

Repetitive movements such as nail-biting and pacing are very often seen in humans and animals under the influence of habit-forming drugs. Studies at the McGovern Institute have found that these repetitive behaviors may be due to a breakdown in communication between neurons in the striatum – a deep brain region linked to habit and movement, among other functions.

The Graybiel lab has a long-standing interest in habit formation and the effects of addiction on brain circuits related to the striatum, a key part of the basal ganglia. The Graybiel lab previously found remarkably strong correlations between gene expression levels in specific parts of the striatum and exposure to psychomotor stimulants such as amphetamine and cocaine. The longer the exposure to stimulant, the more repetitive behavior in models, and the more brain circuits changed. These findings held across animal models.

The lab has found that if they train animals to develop habits, they can completely block these repetitive behaviors using targeted inhibition or excitation of the circuits. They even could block repetitive movement patterns in a mouse model of obsessive-compulsive disorder (OCD). These experiments mimicked situations in humans in which drugs or anxiety-inducing experiences can lead to habits and repetitive movement patterns—from nail-biting to much more dangerous habitual actions.

Ann Graybiel (right) at work in the lab with research scientist Jill Crittenden. Photo: Justin Knight

Why would these circuits exist in the brain if they so often produce “bad” habits and destructive behaviors, as seen in compulsive use of drugs such as opioids or even marijuana? One answer is that we have to be flexible and ready to switch our behavior if something dangerous occurs in the environment. Habits and addictions are, in a way, the extreme pushing of this flexible system in the other direction, toward the rigid and repetitive.

“One important clue is that for many of these habits and repetitive and addictive behaviors, the person isn’t even aware that they are doing the same thing again and again. And if they are not aware, they can’t control themselves and stop,” explains Ann Graybiel, an Institute Professor at MIT. “It is as though the ‘rational brain’ has great difficulty in controlling the ‘habit circuits’ of the brain.” Understanding loss of communication is a central theme in much of the Graybiel lab’s work.

Graybiel, who is also a founding member of the McGovern Institute, is now trying to understand the underlying circuits at the cellular level. The lab is examining the individual components of the striatal circuits linked to selecting actions and motivating movement, circuits that seem to be directly controlled by drugs of abuse.

In groundbreaking early work, Graybiel discovered that the striatum has distinct compartments, striosomes and matrix. These regions are spatially and functionally distinct and separately connect, through striatal projection neurons (SPNs), to motor-control centers or to neurons that release dopamine, a neurotransmitter linked to all drugs of abuse. It is in these components that Graybiel and colleagues have more recently found strong effects of drugs. Indeed opposite changes in gene expression in the striosome SPNs versus the matrix SPNs, raises the possibility that an imbalance in gene regulation leads to abnormally inflexible behaviors caused by drug use.

“It was known that cholinergic interneurons tend to reside along the borders of the two striatal compartments, but whether this cell type mediates communication between the compartments was unknown,” explains first author Jill Crittenden, a research scientist in the Graybiel lab. “We wanted to know whether cholinergic signaling to the two compartments is disrupted by drugs that induce abnormally repetitive behaviors.”

Amphetamine drives gene transcription in striosomes. The top panel shows striosomes (red) are disticnt from matrix (green). Amphetamine treatment activates lead to markers of activation (the immediate early gene c-Fos, red in 2 lower panels) in drug-treated animals (bottom panel), but not controls (middle panel). Image: Jill Crittenden

It was known that cholinergic interneurons are activated by important environmental cues and promote flexible rather than repetitive behavior, how this is related to interaction with SPNs in the striatum was unclear. “Using high-resolution microscopy,” explains Crittenden, “we could see for the first time that cholinergic interneurons send many connections to both striosome and matrix SPNs, well-placed to coordinate signaling directly across the two striatal compartments that appear otherwise isolated.”

Using a technique known as optogenetics, the Graybiel group stimulated mouse cholinergic interneurons and monitored the effects on striatal SPNs in brain tissue. They found that stimulating the interneurons inhibited the ongoing signaling activity that was induced by current injection in matrix and striatal SPNs. However, when examining the brains of animals on high doses of amphetamine and that were displaying repetitive behavior, stimulating the relevant interneurons failed to interrupt evoked activity in SPNs.

Using an inhibitor, the authors were able to show that these neural pathways depend on the nicotinic acetylcholine receptor. Inhibiting this cell-surface signaling receptor had a similar effect to drug intoxication on intercommunication among striatal neurons. Since break down of cholinergic interneuron signaling across striosome and matrix compartments under drug intoxication may reduce behavioral flexibility and cue responsiveness, the work suggests one mechanism for how drugs of abuse hijack action-selection systems of the brain and drive pathological habit-formation.

The Graybiel lab is excited that they can now manipulate these behaviors by manipulating very particular circuits components in the habit circuits. Most recently they have discovered that they can even fully block the effects of stress by manipulating cellular components of these circuits. They now hope to dive deep into these circuits to find out the mystery of how to control them.

“We hope that by pinpointing these circuit elements—which seem to have overlapping effects on habit formation, addiction and stress, we help to guide the development of better therapies for addiction,” explains Graybiel. “We hope to learn about what the use of drugs does to brain circuits with both short term use and long term use. This is an urgent need.”

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.

A new way to deliver drugs with pinpoint targeting

Most pharmaceuticals must either be ingested or injected into the body to do their work. Either way, it takes some time for them to reach their intended targets, and they also tend to spread out to other areas of the body. Now, researchers at the McGovern Institute at MIT and elsewhere have developed a system to deliver medical treatments that can be released at precise times, minimally-invasively, and that ultimately could also deliver those drugs to specifically targeted areas such as a specific group of neurons in the brain.

The new approach is based on the use of tiny magnetic particles enclosed within a tiny hollow bubble of lipids (fatty molecules) filled with water, known as a liposome. The drug of choice is encapsulated within these bubbles, and can be released by applying a magnetic field to heat up the particles, allowing the drug to escape from the liposome and into the surrounding tissue.

The findings are reported today in the journal Nature Nanotechnology in a paper by MIT postdoc Siyuan Rao, Associate Professor Polina Anikeeva, and 14 others at MIT, Stanford University, Harvard University, and the Swiss Federal Institute of Technology in Zurich.

“We wanted a system that could deliver a drug with temporal precision, and could eventually target a particular location,” Anikeeva explains. “And if we don’t want it to be invasive, we need to find a non-invasive way to trigger the release.”

Magnetic fields, which can easily penetrate through the body — as demonstrated by detailed internal images produced by magnetic resonance imaging, or MRI — were a natural choice. The hard part was finding materials that could be triggered to heat up by using a very weak magnetic field (about one-hundredth the strength of that used for MRI), in order to prevent damage to the drug or surrounding tissues, Rao says.

Rao came up with the idea of taking magnetic nanoparticles, which had already been shown to be capable of being heated by placing them in a magnetic field, and packing them into these spheres called liposomes. These are like little bubbles of lipids, which naturally form a spherical double layer surrounding a water droplet.

Electron microscope image shows the actual liposome, the white blob at center, with its magnetic particles showing up in black at its center.
Image courtesy of the researchers

When placed inside a high-frequency but low-strength magnetic field, the nanoparticles heat up, warming the lipids and making them undergo a transition from solid to liquid, which makes the layer more porous — just enough to let some of the drug molecules escape into the surrounding areas. When the magnetic field is switched off, the lipids re-solidify, preventing further releases. Over time, this process can be repeated, thus releasing doses of the enclosed drug at precisely controlled intervals.

The drug carriers were engineered to be stable inside the body at the normal body temperature of 37 degrees Celsius, but able to release their payload of drugs at a temperature of 42 degrees. “So we have a magnetic switch for drug delivery,” and that amount of heat is small enough “so that you don’t cause thermal damage to tissues,” says Anikeeva, who also holds appointments in the departments of Materials Science and Engineering and the Brain and Cognitive Sciences.

In principle, this technique could also be used to guide the particles to specific, pinpoint locations in the body, using gradients of magnetic fields to push them along, but that aspect of the work is an ongoing project. For now, the researchers have been injecting the particles directly into the target locations, and using the magnetic fields to control the timing of drug releases. “The technology will allow us to address the spatial aspect,” Anikeeva says, but that has not yet been demonstrated.

This could enable very precise treatments for a wide variety of conditions, she says. “Many brain disorders are characterized by erroneous activity of certain cells. When neurons are too active or not active enough, that manifests as a disorder, such as Parkinson’s, or depression, or epilepsy.” If a medical team wanted to deliver a drug to a specific patch of neurons and at a particular time, such as when an onset of symptoms is detected, without subjecting the rest of the brain to that drug, this system “could give us a very precise way to treat those conditions,” she says.

Rao says that making these nanoparticle-activated liposomes is actually quite a simple process. “We can prepare the liposomes with the particles within minutes in the lab,” she says, and the process should be “very easy to scale up” for manufacturing. And the system is broadly applicable for drug delivery: “we can encapsulate any water-soluble drug,” and with some adaptations, other drugs as well, she says.

One key to developing this system was perfecting and calibrating a way of making liposomes of a highly uniform size and composition. This involves mixing a water base with the fatty acid lipid molecules and magnetic nanoparticles and homogenizing them under precisely controlled conditions. Anikeeva compares it to shaking a bottle of salad dressing to get the oil and vinegar mixed, but controlling the timing, direction and strength of the shaking to ensure a precise mixing.

Anikeeva says that while her team has focused on neurological disorders, as that is their specialty, the drug delivery system is actually quite general and could be applied to almost any part of the body, for example to deliver cancer drugs, or even to deliver painkillers directly to an affected area instead of delivering them systemically and affecting the whole body. “This could deliver it to where it’s needed, and not deliver it continuously,” but only as needed.

Because the magnetic particles themselves are similar to those already in widespread use as contrast agents for MRI scans, the regulatory approval process for their use may be simplified, as their biological compatibility has largely been proven.

The team included researchers in MIT’s departments of Materials Science and Engineering and Brain and Cognitive Sciences, as well as the McGovern Institute for Brain Research, the Simons Center for Social Brain, and the Research Laboratory of Electronics; the Harvard University Department of Chemistry and Chemical Biology and the John A. Paulsen School of Engineering and Applied Sciences; Stanford University; and the Swiss Federal Institute of Technology in Zurich. The work was supported by the Simons Postdoctoral Fellowship, the U.S. Defense Advanced Research Projects Agency, the Bose Research Grant, and the National Institutes of Health.

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

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.

Alan Jasanoff

Next Generation Brain Imaging

One of the greatest challenges of modern neuroscience is to relate high-level operations of the brain and mind to well-defined biological processes that arise from molecules and cells. The Jasanoff lab is creating a suite of experimental approaches designed to achieve this by permitting brain-wide dynamics of neural signaling and plasticity to be imaged for the first time, with molecular specificity. These potentially transformative approaches use novel probes detectable by magnetic resonance imaging (MRI) and other noninvasive readouts. The probes afford qualitatively new ways to study healthy and pathological aspects of integrated brain function in mechanistically-informative detail, in animals and possibly also people.

Ann Graybiel

Probing the Deep Brain

Ann Graybiel studies the basal ganglia, forebrain structures that are profoundly important for normal brain function. Dysfunction in these regions is implicated in neurologic and neuropsychiatric disorders ranging from Parkinson’s disease and Huntington’s disease to obsessive-compulsive disorder, anxiety and depression, and addiction. Graybiel’s laboratory is uncovering circuits underlying both the neural deficits related to these disorders, as well as the role that the basal ganglia play in guiding normal learning, motivation, and behavior.

John Gabrieli

Images of Mind

John Gabrieli’s goal is to understand the organization of memory, thought, and emotion in the human brain, and to use that understanding to help people live happier, more productive lives. By combining brain imaging with behavioral tests, he studies the neural basis of these abilities in human subjects. One important research theme is to understand the neural basis of learning in children and to identify ways that neuroscience could help to improve learning in the classroom. In collaboration with clinical colleagues, Gabrieli also seeks to use brain imaging to better understand, diagnose, and select treatments for neurological and psychiatric diseases.