Augmented is a Nova PBS documentary that premiered in February 2022, featuring Hugh Herr, the co-director of the K. Lisa Yang Center for Bionics at MIT.
Follow the dramatic personal journey of Hugh Herr, a biophysicist working to create brain-controlled robotic limbs. At age 17, Herr’s legs were amputated after a climbing accident. Frustrated by the crude prosthetic limbs he was given, Herr set out to remedy their design, leading him to a career as an inventor of innovative prosthetic devices. Now, Herr is teaming up with an injured climber and a surgeon at a leading Boston hospital to test a new approach to surgical amputation that allows prosthetic limbs to move and feel like the real thing. Herr’s journey is a powerful tale of innovation and the inspiring story of a personal tragedy transformed into a life-long quest to help others.
Harvard neurobiologist David Ginty, winner of the 2022 Scolnick Prize.
The McGovern Institute for Brain Research announced today that Harvard neurobiologist David D. Ginty has been selected for the 2022 Edward M. Scolnick Prize in Neuroscience. Ginty, who is the Edward R. and Anne G. Lefler Professor of Neurobiology at Harvard Medical School, is being recognized for his fundamental discoveries into the neural mechanisms underlying the sense of touch. The Scolnick Prize is awarded annually by the McGovern Institute for outstanding advances in neuroscience.
“David Ginty has made seminal contributions in basic research that also have important translational implications,” says Robert Desimone, McGovern Institute Director and chair of the selection committee. “His rigorous research has led us to understand how the peripheral nervous system encodes the overall perception of touch, and how molecular mechanisms underlying this can fail in disease states.”
Ginty obtained his PhD in 1989 with Edward Seidel where he studied cell proliferation factors. He went on to a postdoctoral fellowship researching nerve growth factor with John Wagner at the Dana-Farber Cancer Institute and, upon Wagner’s departure to Cornell, transferred to Michael Greenberg’s lab at Harvard Medical School. There, he dissected intracellular signaling pathways for neuronal growth factors and neurotransmitters and developed key antibody reagents to detect activated forms of transcription factors. These antibody tools are now used by labs around the world in the research of neuronal plasticity and brain disorders, including Alzheimer’s disease and schizophrenia.
In 1995, Ginty started his own laboratory at Johns Hopkins University with a focus on the development and functional organization of the peripheral nervous system. Ginty’s group created and applied the latest genetic engineering techniques in mice to uncover how the peripheral nervous system develops and is organized at the molecular, cellular and circuit levels to perceive touch. Most notably, using gene targeting combined with electrophysiological, behavioral and anatomical analyses, the Ginty lab untangled properties and functions of the different types of touch neurons, termed low- and high-threshold mechanoreceptors, that convey distinct aspects of stimulus information from the skin to the central nervous system. Ginty and colleagues also discovered organizational principles of spinal cord and brainstem circuits dedicated to touch information processing, and that integration of signals from the different mechanoreceptor types begins within spinal cord networks before signal transmission to the brain.
In 2013, Ginty joined the faculty of Harvard Medical School where his team applied their genetic tools and techniques to probe the neural basis of touch sensitivity disorders. They discovered properties and functions of peripheral sensory neurons, spinal cord circuits, and ascending pathways that transmit noxious, painful stimuli from the periphery to the brain. They also asked whether abnormalities in peripheral nervous system function lead to touch over-reactivity in cases of autism or in neuropathic pain caused by nerve injury, chemotherapy, or diabetes, where even a soft touch can be aversive or painful. His team found that sensory abnormalities observed in several mouse models of autism spectrum disorder could be traced to peripheral mechanosensory neurons. They also found that reducing the activity of peripheral sensory neurons prevented tactile over-reactivity in these models and even, in some cases, lessened anxiety and abnormal social behaviors. These findings provided a plausible explanation for how sensory dysfunction may contribute to physiological and cognitive impairments in autism. Importantly, this laid the groundwork for a new approach and initiative to identify new potential therapies for disorders of touch and pain.
Ginty was named a Howard Hughes Medical Institute Investigator in 2000 and was elected to the American Academy of Arts and Sciences in 2015 and the National Academy of Sciences in 2017. He shared Columbia University’s Alden W. Spencer Prize with Ardem Patapoutian in 2017 and was awarded the Society for Neuroscience Julius Axelrod Prize in 2021. Ginty is also known for exceptional mentorship. He directed the neuroscience graduate program at Johns Hopkins from 2006 to 2013 and now serves as the associate director of Harvard’s neurobiology graduate program.
The McGovern Institute will award the Scolnick Prize to Ginty on Wednesday, June 1, 2022. At 4:00 pm he will deliver a lecture entitled “The sensory neurons of touch: beauty is skin deep,” to be followed by a reception at the McGovern Institute, 43 Vassar Street (building 46, room 3002) in Cambridge. The event is free and open to the public; registration is required.
This winter, seven new faculty members join the MIT School of Science in the departments of Biology and Brain and Cognitive Sciences.
Siniša Hrvatin studies how animals initiate, regulate, and survive states of stasis, such as torpor and hibernation. To survive extreme environments, many animals have evolved the ability to decrease metabolic rate and body temperature and enter dormant states. His long-term goal is to harness the potential of these biological adaptations to advance medicine. Previously, he identified the neurons that regulate mouse torpor and established a platform for the development of cell-type-specific viral drivers.
Hrvatin earned his bachelor’s degree in biochemical sciences in 2007 and his PhD in stem cell and regenerative medicine in 2013, both from Harvard University. He was then a postdoc in bioengineering at MIT and a postdoc in neurobiology at Harvard Medical School. Hrvatin returns to MIT as an assistant professor of biology and a member of the Whitehead Institute for Biomedical Research.
Sara Prescott investigates how sensory inputs from within the body control mammalian physiology and behavior. Specifically, she uses mammalian airways as a model system to explore how the cells that line the surface of the body communicate with parts of the nervous system. For example, what mechanisms elicit a reflexive cough? Prescott’s research considers the critical questions of how airway insults are detected, encoded, and adapted to mammalian airways with the ultimate goal of providing new ways to treat autonomic dysfunction.
Prescott earned her bachelor’s degree in molecular biology from Princeton University in 2008 followed by her PhD in developmental biology from Stanford University in 2016. Prior to joining MIT, she was a postdoc at Harvard Medical School and Howard Hughes Medical Institute. The Department of Biology welcomes Prescott as an assistant professor.
Alison Ringel is a T-cell immunologist with a background in biochemistry, biophysics, and structural biology. She investigates how environmental factors such as aging, metabolism, and diet impact tumor progress and the immune responses that cause tumor control. By mapping the environment around a tumor on a cellular level, she seeks to gain a molecular understanding of cancer risk factors.
Ringel received a bachelor’s degree in molecular biology, biochemistry, and physics from Wesleyan University, then a PhD in molecular biophysics from John Hopkins University School of Medicine. Previously, Ringel was a postdoc in the Department of Cell Biology at Harvard Medical School. She joins MIT as an assistant professor in the Department of Biology and a core member of the Ragon Institute of MGH, MIT and Harvard.
Francisco J. Sánchez-Rivera PhD ’16 investigates genetic variation with a focus on cancer. He integrates genome engineering technologies, genetically-engineered mouse models (GEMMs), and single cell lineage tracing and omics approaches in order to understand the mechanics of cancer development and evolution. With state-of-the-art technologies — including a CRISPR-based genome editing system he developed as a graduate student at MIT — he hopes to make discoveries in cancer genetics that will shed light on disease progression and pave the way for better therapeutic treatments.
Sánchez-Rivera received his bachelor’s degree in microbiology from the University of Puerto Rico at Mayagüez followed by a PhD in biology from MIT. He then pursued postdoctoral studies at Memorial Sloan Kettering Cancer Center supported by a HHMI Hanna Gray Fellowship. Sánchez-Rivera returns to MIT as an assistant professor in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research at MIT.
Nidhi Seethapathi builds predictive models to help understand human movement with a combination of theory, computational modeling, and experiments. Her research focuses on understanding the objectives that govern movement decisions, the strategies used to execute movement, and how new movements are learned. By studying movement in real-world contexts using creative approaches, Seethapathi aims to make discoveries and develop tools that could improve neuromotor rehabilitation.
Seethapathi earned her bachelor’s degree in mechanical engineering from the Veermata Jijabai Technological Institute followed by her PhD in mechanical engineering from Ohio State University. In 2018, she continued to the University of Pennsylvania where she was a postdoc. She joins MIT as an assistant professor in the Department of Brain and Cognitive Sciences with a shared appointment in the Department of Electrical Engineering and Computer Science at the MIT Schwarzman College of Computing.
Hernandez Moura Silva researches how the immune system supports tissue physiology. Silva focuses on macrophages, a type of immune cell involved in tissue homeostasis. He plans to establish new strategies to explore the effects and mechanisms of such immune-related pathways, his research ultimately leading to the development of therapeutic approaches to treat human diseases.
Silva earned a bachelor’s degree in biological sciences and a master’s degree in molecular biology from the University of Brasilia. He continued to complete a PhD in immunology at the University of São Paulo School of Medicine: Heart Institute. Most recently, he acted as the Bernard Levine Postdoctoral Fellow in immunology and immuno-metabolism at the New York University School of Medicine: Skirball Institute of Biomolecular Medicine. Silva joins MIT as an assistant professor in the Department of Biology and a core member of the Ragon Institute.
Yadira Soto-Feliciano PhD ’16 studies chromatin — the complex of DNA and proteins that make up chromosomes. She combines cancer biology and epigenetics to understand how certain proteins affect gene expression and, in turn, how they impact the development of cancer and other diseases. In decoding the chemical language of chromatin, Soto-Feliciano pursues a basic understanding of gene regulation that could improve the clinical management of diseases associated with their dysfunction.
Soto-Feliciano received her bachelor’s degree in chemistry from the University of Puerto Rico at Mayagüez followed by a PhD in biology from MIT, where she was also a research fellow with the Koch Institute. Most recently, she was the Damon Runyon-Sohn Pediatric Cancer Postdoctoral Fellow at The Rockefeller University. Soto-Feliciano returns to MIT as an assistant professor in the Department of Biology and a member of the Koch Institute.
Cocaine, opioids, and other drugs of abuse disrupt the brain’s reward system, often shifting users’ priorities to obtaining more drug above all else. For people battling addiction, this persistent craving is notoriously difficult to overcome—but new research from scientists at MIT’s McGovern Institute and collaborators points toward a therapeutic strategy that could help.
Researchers in MIT Institute Professor Ann Graybiel’s lab and collaborators at the University of Copenhagen and Vanderbilt University report in a January 25, 2022 online publication in the journal Addiction Biology that activating a signaling molecule in the brain known as muscarinic receptor 4 (M4) causes rodents to reduce cocaine self-administration and simultaneously choose a food treat over cocaine.
M4 receptors are found on the surface of neurons in the brain, where they alter signaling in response to the neurotransmitter acetylcholine. They are plentiful in the striatum, a brain region that Graybiel’s lab has shown is deeply involved in habit formation. They are of interest to addiction researchers because, along with a related receptor called M1, which is also abundant in the striatum, they often seem to act in opposition to the neurotransmitter dopamine.
Drugs of abuse stimulate the brain’s habit circuits by allowing dopamine to build up in the brain. With chronic use, that circuitry can become less sensitive to dopamine, so experiences that were once rewarding become less pleasurable and users are driven to seek higher doses of their drug. Attempts to directly block the dopamine system have not been found to be an effective way of treating addiction and can have unpleasant or dangerous side-effects, so researchers are seeking an alternative strategy to restore balance within the brain’s reward circuitry. “Another way to tweak that system is to activate these muscarinic receptors,” explains Jill Crittenden, a research scientist in the Graybiel lab.
New pathways to treatment
At the University of Copenhagen, neuroscientist Morgane Thomsen has found that activating the M1 receptor causes rodents to choose a food treat over cocaine. In the new work, she showed that a drug that selectively activates the M4 receptor has a similar effect.
When rats that have been trained to self-administer cocaine are given an M4-activating compound, they immediately reduce their drug use, actively choosing food instead. Thomsen found that this effect grew stronger over a seven-day course of treatment, with cocaine use declining day by day. When the M4-activating treatment was stopped, rats quickly resumed their prior cocaine-seeking behavior.
While Thomsen’s experiments have now shown that animals’ cocaine use can be reduced by activating either M1 or M4, it’s clear that the two muscarinic receptors don’t modulate cocaine use in the same way. M1 activation works on a different time scale, taking some time to kick in, but leaving some lasting effects even after the treatment has been discontinued.
Experiments with genetically modified mice developed in Graybiel’s lab confirm that the two receptors influence drug-seeking behavior via different molecular pathways. Previously, the team discovered that activating M1 has no effect on cocaine-seeking in mice that lack a signaling molecule called CalDAG-GEFI. M4 activation, however, reduces cocaine consumption regardless of whether CalDAG-GEFI is present. “The CalDAG-GEFI is completely essential for the M1 effect to happen, but doesn’t appear to play any role in the M4 effect,” Thomsen says. “So that really separates the pathways. In both the behavior and the neurobiology, it’s two different ways that we can modulate the cocaine effects.” The findings suggest that activating M4 could help people with substance abuse disorders overcome their addiction, and that such a strategy might be even more effective if combined with activation of the M1 receptor.
Graybiel’s lab first became interested in CalDAG-GEFI in the late 1990s, when they discovered that it was unusually abundant in the main compartment of the brain’s striatum. Their research revealed the protein to be important for controlling movement and even uncovered an essential role in blood clotting—but CalDAG-GEFI’s impacts on behavior remained elusive for a long time. Graybiel says it’s gratifying that this long-standing interest has now shed light on a potential therapeutic strategy for substance abuse disorder. Her lab will continue investigating the molecular pathways that underlie addiction as part of the McGovern Institute’s new addiction initiative.
When we read, information zips between language processing centers in different parts of the brain, traveling along neural highways in the white matter. This coordinated activity allows us to decipher words and comprehend their meaning. Many neuroscientists suspect that variations in white matter may underlie differences in reading ability, and hope that by determining which white matter tracts are involved, they will be able to guide the development of more effective interventions for children who struggle with reading skills.
In a January 14, 2022, online publication in the journal NeuroImage, scientists at MIT’s McGovern Institute report on the largest brain imaging study to date to evaluate the relationship between white matter structure and reading ability. Their findings suggest that if white matter deficiencies are a significant cause of reading disability, new strategies will be needed to pin them down.
White matter is composed of bundles of insulated nerve fibers. It can be thought of as the internet of the brain, says senior author John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology at MIT. “It’s the connectivity: the way that the brain communicates at some distance to orchestrate higher-level thoughts, and abilities like reading,” explains Gabrieli, who is also a professor of brain and cognitive sciences and an investigator at the McGovern Institute.
The left inferior cerebellar peduncle, a white matter tract that connects the cerebellum to the brainstem and spinal cord. Image: Steven Meisler
Long-distance connections
To visualize white matter and study its structure, neuroscientists use an imaging technique called diffusion-weighted imaging (DWI). Images are collected in an MRI scanner by tracking the movements of water molecules in the brain. A key measure used to interpret these images is fractional anisotropy (FA), which varies with many physical features of nerve fibers, such as their density, diameter, and degree of insulation. Although FA does not measure any of these properties directly, it is considered an indicator of structural integrity within white matter tracts.
Several studies have found the FA of one or more white matter tracts to be lower in children with low reading scores or dyslexia than in children with stronger reading abilities. But those studies are small—usually involving only a few dozen children—and their findings are inconsistent. So it has been difficult to attribute reading problems to poor connections between specific parts of the brain.
Hoping to glean more conclusive results, Gabrieli and Steven Meisler, a graduate student in the Harvard Program in Speech and Hearing Bioscience and Technology who is completing his doctoral work in the Gabrieli lab, turned to a large collection of high-quality brain images available through the Child Mind Institute’s Healthy Brain Network. Using DWI images collected from 686 children and state-of-the-art methods of analysis, they assessed the FA of 20 white matter tracts that are thought to be important for reading.
The children represented in the dataset had diverse reading abilities, but surprisingly, when they compared children with and without reading disability, Meisler and Gabrieli found no significant differences in the FA of any of the 20 tracts. Nor did they find any correlation between white matter FA and children’s overall reading scores.
More detailed analysis did link reading ability to the FA of two particular white matter tracts. The researchers only detected the correlation when they narrowed their analysis to children older than eight, who are usually reading to learn, rather than learning to read. Within this group, they found two white matter tracts whose FA was lower in children who struggled with a specific reading skill: reading “pseudowords.” The ability to read nonsense words is used to assess knowledge of the relationship between letters and sounds, since real words can be recognized instead through experience and memory.
The right superior longitudinal fasciculus, a white matter tract that connects frontal brain regions to parietal areas. The research team found that fractional anisotropy (FA) of the right superior longitudinal fasciculus and the left inferior cerebellar peduncles (shown above) correlated positively with pseudoword reading ability among children ages 9 and older. Image: Steven Meisler
The first of these tracts connects language processing centers in the frontal and parietal brain regions. The other contains fibers that connect that the brainstem with the cerebellum, and may help control the eye movements needed to see and track words. The FA differences that Meisler and Gabrieli linked to reading scores were small, and it’s not yet clear what they mean. Since less cohesive structure in these two tracts was linked to lower pseudoword-reading scores only in older children, it may be a consequence of living with a reading disability rather than a cause, Meisler says.
The findings don’t rule out a role for white matter structure in reading disability, but they do suggest that researchers will need a different approach to find relevant features. “Our results suggest that FA does not relate to reading abilities as much as previously thought,” Meisler says. In future studies, he says, researchers will likely need to take advantage of more advanced methods of image analysis to assess features that more directly reflect white matter’s ability to serve as a conduit of information.
MIT neuroscientist and McGovern Investigator Nancy Kanwisher. Photo: Jussi Puikkonen/KNAW
The National Academy of Sciences (NAS) has announced today that Nancy Kanwisher, the Walter A. Rosenblith Professor of Cognitive Neuroscience in MIT’s Department of Brain and Cognitive Sciences, has received the 2022 NAS Award in the Neurosciences for her “pioneering research into the functional organization of the human brain.” The $25,000 prize, established by the Fidia Research Foundation, is presented every three years to recognize “extraordinary contributions to the neuroscience fields.”
“I am deeply honored to receive this award from the NAS,” says Kanwisher, who is also an investigator in MIT’s McGovern Institute and a member of the Center for Brains, Minds and Machines. “It has been a profound privilege, and a total blast, to watch the human brain in action as these data began to reveal an initial picture of the organization of the human mind. But the biggest joy has been the opportunity to work with the incredible group of talented young scientists who actually did the work that this award recognizes.”
A window into the mind
Kanwisher is best known for her landmark insights into how humans recognize and process faces. Psychology had long-suggested that recognizing a face might be distinct from general object recognition. But Kanwisher galvanized the field in 1997 with her seminal discovery that the human brain contains a small region specialized to respond only to faces. The region, which Kanwisher termed the fusiform face area (FFA), became activated when subjects viewed images of faces in an MRI scanner, but not when they looked at scrambled faces or control stimuli.
Since her 1997 discovery (now the most highly cited manuscript in its area), Kanwisher and her students have applied similar methods to find brain specializations for the recognition of scenes, the mental states of others, language, and music. Taken together, her research provides a compelling glimpse into the architecture of the brain, and, ultimately, what makes us human.
“Nancy’s work over the past two decades has argued that many aspects of human cognition are supported by specialized neural circuitry, a conclusion that stands in contrast to our subjective sense of a singular mental experience,” says McGovern Institute Director Robert Desimone. “She has made profound contributions to the psychological and cognitive sciences and I am delighted that the National Academy of Sciences has recognized her outstanding achievements.”
One-in-a-million mentor
Beyond the lab, Kanwisher has a reputation as a tireless communicator and mentor who is actively engaged in the policy implications of brain research. The statistics speak for themselves: her 2014 TED talk, “A Neural portrait of the human mind” has been viewed over a million times online and her introductory MIT OCW course on the human brain has generated more than nine million views on YouTube.
Nancy Kanwisher works with researchers from her lab in MIT’s Martinos Imaging Center. Photo: Kris Brewer
Kanwisher also has an exceptional track record in training women scientists who have gone on to successful independent research careers, in many cases becoming prominent figures in their own right.
“Nancy is the one-in-a-million mentor, who is always skeptical of your ideas and your arguments, but immensely confident of your worth,” says Rebecca Saxe, John W. Jarve (1978) Professor of Brain and Cognitive Sciences, investigator at the McGovern Institute, and associate dean of MIT’s School of Science. Saxe was a graduate student in Kanwisher’s lab where she earned her PhD in cognitive neuroscience in 2003. “She has such authentic curiosity,” Saxe adds. “It’s infectious and sustaining. Working with Nancy was a constant reminder of why I wanted to be a scientist.”
The NAS will present Kanwisher with the award during its annual meeting on May 1, 2022 in Washington, DC. The event will be webcast live. Kanwisher plans to direct her prize funds to the non-profit organization Malengo, established by a former student and which provides quality undergraduate education to individuals who would otherwise not be able to afford it.
For people struggling with substance use disorders — and there are about 35 million of them worldwide — treatment options are limited. Even among those who seek help, relapse is common. In the United States, an epidemic of opioid addiction has been declared a public health emergency.
A 2019 survey found that 1.6 million people nationwide had an opioid use disorder, and the crisis has surged since the start of the COVID-19 pandemic. The Centers for Disease Control and Prevention estimates that more than 100,000 people died of drug overdose between April 2020 and April 2021 — nearly 30 percent more overdose deaths than occurred during the same period the previous year.
In the United States, an epidemic of opioid addiction has been declared a public health emergency.
A deeper understanding of what addiction does to the brain and body is urgently needed to pave the way to interventions that reliably release affected individuals from its grip. At the McGovern Institute, researchers are turning their attention to addiction’s driving force: the deep, recurring craving that makes people prioritize drug use over all other wants and needs.
McGovern Institute co-founder, Lore Harp McGovern.
“When you are in that state, then it seems nothing else matters,” says McGovern Investigator Fan Wang. “At that moment, you can discard everything: your relationship, your house, your job, everything. You only want the drug.”
With a new addiction initiative catalyzed by generous gifts from Institute co-founder Lore Harp McGovern and others, McGovern scientists with diverse expertise have come together to begin clarifying the neurobiology that underlies the craving state. They plan to dissect the neural transformations associated with craving at every level — from the drug-induced chemical changes that alter neuronal connections and activity to how these modifications impact signaling brain-wide. Ultimately, the McGovern team hopes not just to understand the craving state, but to find a way to relieve it — for good.
“If we can understand the craving state and correct it, or at least relieve a little bit of the pressure,” explains Wang, who will help lead the addiction initiative, “then maybe we can at least give people a chance to use their top-down control to not take the drug.”
The craving cycle
For individuals suffering from substance use disorders, craving fuels a cyclical pattern of escalating drug use. Following the euphoria induced by a drug like heroin or cocaine, depression sets in, accompanied by a drug craving motivated by the desire to relieve that suffering. And as addiction progresses, the peaks and valleys of this cycle dip lower: the pleasant feelings evoked by the drug become weaker, while the negative effects a person experiences in its absence worsen. The craving remains, and increasing use of the drug are required to relieve it.
By the time addiction sets in, the brain has been altered in ways that go beyond a drug’s immediate effects on neural signaling.
These insidious changes leave individuals susceptible to craving — and the vulnerable state endures. Long after the physical effects of withdrawal have subsided, people with substance use disorders can find their craving returns, triggered by exposure to a small amount of the drug, physical or social cues associated with previous drug use, or stress. So researchers will need to determine not only how different parts of the brain interact with one another during craving and how individual cells and the molecules within them are affected by the craving state — but also how things change as addiction develops and progresses.
Circuits, chemistry and connectivity
One clear starting point is the circuitry the brain uses to control motivation. Thanks in part to decades of research in the lab of McGovern Investigator Ann Graybiel, neuroscientists know a great deal about how these circuits learn which actions lead to pleasure and which lead to pain, and how they use that information to establish habits and evaluate the costs and benefits of complex decisions.
Graybiel’s work has shown that drugs of abuse strongly activate dopamine-responsive neurons in a part of the brain called the striatum, whose signals promote habit formation. By increasing the amount of dopamine that neurons release, these drugs motivate users to prioritize repeated drug use over other kinds of rewards, and to choose the drug in spite of pain or other negative effects. Her group continues to investigate the naturally occurring molecules that control these circuits, as well as how they are hijacked by drugs of abuse.
Distribution of opioid receptors targeted by morphine (shown in blue) in two regions in the dorsal striatum and nucleus accumbens of the mouse brain. Image: Ann Graybiel
In Fan Wang’s lab, work investigating the neural circuits that mediate the perception of physical pain has led her team to question the role of emotional pain in craving. As they investigated the source of pain sensations in the brain, they identified neurons in an emotion-regulating center called the central amygdala that appear to suppress physical pain in animals. Now, Wang wants to know whether it might be possible to modulate neurons involved in emotional pain to ameliorate the negative state that provokes drug craving.
These animal studies will be key to identifying the cellular and molecular changes that set the brain up for recurring cravings. And as McGovern scientists begin to investigate what happens in the brains of rodents that have been trained to self-administer addictive drugs like fentanyl or cocaine, they expect to encounter tremendous complexity.
McGovern Associate Investigator Polina Anikeeva, whose lab has pioneered new technologies that will help the team investigate the full spectrum of changes that underlie craving, says it will be important to consider impacts on the brain’s chemistry, firing patterns, and connectivity. To that end, multifunctional research probes developed in her lab will be critical to monitoring and manipulating neural circuits in animal models.
Imaging technology developed by investigator Ed Boyden will also enable nanoscale protein visualization brain-wide. An important goal will be to identify a neural signature of the craving state. With such a signal, researchers can begin to explore how to shut off that craving — possibly by directly modulating neural signaling.
Targeted treatments
“One of the reasons to study craving is because it’s a natural treatment point,” says McGovern Associate Investigator Alan Jasanoff. “And the dominant kind of approaches that people in our team think about are approaches that relate to neural circuits — to the specific connections between brain regions and how those could be changed.” The hope, he explains, is that it might be possible to identify a brain region whose activity is disrupted during the craving state, then use clinical brain stimulation methods to restore normal signaling — within that region, as well as in other connected parts of the brain.
To identify the right targets for such a treatment, it will be crucial to understand how the biology uncovered in laboratory animals reflects what’s happens in people with substance use disorders. Functional imaging in John Gabrieli’s lab can help bridge the gap between clinical and animal research by revealing patterns of brain activity associated with the craving state in both humans and rodents. A new technique developed in Jasanoff’s lab makes it possible to focus on the activity between specific regions of an animal’s brain. “By doing that, we hope to build up integrated models of how information passes around the brain in craving states, and of course also in control states where we’re not experiencing craving,” he explains.
In delving into the biology of the craving state, McGovern scientists are embarking on largely unexplored territory — and they do so with both optimism and urgency. “It’s hard to not appreciate just the size of the problem, and just how devastating addiction is,” says Anikeeva. “At this point, it just seems almost irresponsible to not work on it, especially when we do have the tools and we are interested in the general brain regions that are important for that problem. I would say that there’s almost a civic duty.”
New research from MIT neuroscientists suggest that natural soundscapes have shaped our sense of hearing, optimizing it for the kinds of sounds we most often encounter.
Mark Saddler, graduate fellow of the K. Lisa Yang Integrative Computational Neuroscience Center. Photo: Caitlin Cunningham
In a study reported December 14 in the journal Nature Communications, researchers led by McGovern Institute Associate Investigator Josh McDermott used computational modeling to explore factors that influence how humans hear pitch. Their model’s pitch perception closely resembled that of humans—but only when it was trained using music, voices, or other naturalistic sounds.
Humans’ ability to recognize pitch—essentially, the rate at which a sound repeats—gives melody to music and nuance to spoken language. Although this is arguably the best-studied aspect of human hearing, researchers are still debating which factors determine the properties of pitch perception, and why it is more acute for some types of sounds than others. McDermott, who is also an associate professor in MIT’s Department of Brain and Cognitive Sciences and an investigator with the Center for Brains Minds and Machines (CBMM), is particularly interested in understanding how our nervous system perceives pitch because cochlear implants, which send electrical signals about sound to the brain in people with profound deafness, don’t replicate this aspect of human hearing very well.
“Cochlear implants can do a pretty good job of helping people understand speech, especially if they’re in a quiet environment. But they really don’t reproduce the percept of pitch very well,” says Mark Saddler, a CBMM graduate student who co-led the project and an inaugural graduate fellow of the K. Lisa Yang Integrative Computational Neuroscience Center. “One of the reasons it’s important to understand the detailed basis of pitch perception in people with normal hearing is to try to get better insights into how we would reproduce that artificially in a prosthesis.”
Artificial hearing
Pitch perception begins in the cochlea, the snail-shaped structure in the inner ear where vibrations from sounds are transformed into electrical signals and relayed to the brain via the auditory nerve. The cochlea’s structure and function help determine how and what we hear. And although it hasn’t been possible to test this idea experimentally, McDermott’s team suspected our “auditory diet” might shape our hearing as well.
To explore how both our ears and our environment influence pitch perception, McDermott, Saddler and research assistant Ray Gonzalez built a computer model called a deep neural network. Neural networks are a type of machine learning model widely used in automatic speech recognition and other artificial intelligence applications. Although the structure of an artificial neural network coarsely resembles the connectivity of neurons in the brain, the models used in engineering applications don’t actually hear the same way humans do—so the team developed a new model to reproduce human pitch perception. Their approach combined an artificial neural network with an existing model of the mammalian ear, uniting the power of machine learning with insights from biology. “These new machine learning models are really the first that can be trained to do complex auditory tasks and actually do them well, at human levels of performance,” Saddler explains.
The researchers trained the neural network to estimate pitch by asking it to identify the repetition rate of sounds in a training set. This gave them the flexibility to change the parameters under which pitch perception developed. They could manipulate the types of sound they presented to the model, as well as the properties of the ear that processed those sounds before passing them on to the neural network.
When the model was trained using sounds that are important to humans, like speech and music, it learned to estimate pitch much as humans do. “We very nicely replicated many characteristics of human perception…suggesting that it’s using similar cues from the sounds and the cochlear representation to do the task,” Saddler says.
But when the model was trained using more artificial sounds or in the absence of any background noise, its behavior was very different. For example, Saddler says, “If you optimize for this idealized world where there’s never any competing sources of noise, you can learn a pitch strategy that seems to be very different from that of humans, which suggests that perhaps the human pitch system was really optimized to deal with cases where sometimes noise is obscuring parts of the sound.”
The team also found the timing of nerve signals initiated in the cochlea to be critical to pitch perception. In a healthy cochlea, McDermott explains, nerve cells fire precisely in time with the sound vibrations that reach the inner ear. When the researchers skewed this relationship in their model, so that the timing of nerve signals was less tightly correlated to vibrations produced by incoming sounds, pitch perception deviated from normal human hearing.
McDermott says it will be important to take this into account as researchers work to develop better cochlear implants. “It does very much suggest that for cochlear implants to produce normal pitch perception, there needs to be a way to reproduce the fine-grained timing information in the auditory nerve,” he says. “Right now, they don’t do that, and there are technical challenges to making that happen—but the modeling results really pretty clearly suggest that’s what you’ve got to do.”
by Robert Desimone, McGovern Institute | Nergis Mavalvala, MIT School of Science | Maria T. Zuber, MIT Office of the Vice President for Research |
Following is an open statement in response to “Is MIT’s Research Helping the Chinese Military?”, an opinion essay by Michelle Bethel posted by the Wall Street Journal on Dec. 10, 2021. This statement is jointly from Prof. Robert Desimone, director of the McGovern Institute for Brain Research at MIT, Prof. Nergis Mavalvala, dean of MIT’s School of Science, and Prof. Maria T. Zuber, vice president for research at MIT.
Ms. Bethel is absolutely right that research relationships with institutions in China require the most serious care and consideration. MIT brings a thorough and rigorous approach to these matters.
First let us be clear about the work of the MIT McGovern Institute for Brain Research. Of the dozens of research projects currently under way at the McGovern Institute, there is one active research collaboration with China. It involves better identifying and ultimately developing treatments for severe forms of autism or neurological disorders that often render individuals unable to speak and frequently require lifelong care. That project was thoroughly vetted and approved by the U.S. National Institutes of Health in 2019. MIT receives no funding from China for this research, and all findings will be published in peer-reviewed journals, meaning that they are open to medical researchers anywhere in the world. This is the collaboration with the Shenzhen Institute of Advanced Technology that Ms. Bethel referenced in vague terms.
This does not eliminate general concerns about how research may be conducted or used, however. That’s why MIT has strong processes for evaluating and managing the risks of research involving countries, including China, whose behavior affects U.S. national and economic security. Every proposed engagement that involves an organization or funding source from China, once it has been evaluated for compliance with U.S. law and regulation, is further reviewed by committees of senior administrators to consider risks related to national security, economic competitiveness, and civil and human rights. Projects have been variously turned down, modified, or approved under this process.
Ms. Bethel raises important points with respect to U.S.-China relations – but not with respect to the work of the McGovern Institute. We regret that Ms. Bethel felt it necessary to step away from the McGovern, but we respect her views and continue in conversation with her. We note that two other members of the McGovern family, including the McGovern Institute’s co-founder and another daughter, continue to proudly serve on the McGovern board. We are grateful to all three family members.
