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  • richardmitnick 2:14 pm on December 30, 2017 Permalink | Reply
    Tags: a new algorithm termed state-space multitaper time-frequency analysis (SS-MT), Electroencephalograms, Medical Engineering and Computational Neuroscience, , MIT researchers analyzed raw brain activity data, Picower Institute for Learning and Memory, Recalculating time, Spectrogram estimation is a standard analytic technique applied commonly in a number of problems, State-space modeling is a flexible paradigm which has been broadly applied to analyze data whose characteristics evolve over time   

    From MIT: “Recalculating time” 

    MIT News

    MIT Widget

    MIT News

    December 21, 2017
    Sara Cody | Brain and Cognitive Sciences

    1
    Using a novel analytical method they have developed, MIT researchers analyzed raw brain activity data (B). The spectrogram shows decreased noise and increased frequency resolution, or contrast (E and F) compared to standard spectral analysis methods (C and D). Image courtesy of Seong-Eun Kim et al.

    Whether it’s tracking brain activity in the operating room, seismic vibrations during an earthquake, or biodiversity in a single ecosystem over a million years, measuring the frequency of an occurrence over a period of time is a fundamental data analysis task that yields critical insight in many scientific fields. But when it comes to analyzing these time series data, researchers are limited to looking at pieces of the data at a time to assemble the big picture, instead of being able to look at the big picture all at once.

    In a new study, MIT researchers have developed a novel approach to analyzing time series data sets using a new algorithm, termed state-space multitaper time-frequency analysis (SS-MT). SS-MT provides a framework to analyze time series data in real-time, enabling researchers to work in a more informed way with large sets of data that are nonstationary, i.e. when their characteristics evolve over time. It allows researchers to not only quantify the shifting properties of data but also make formal statistical comparisons between arbitrary segments of the data.

    “The algorithm functions similarly to the way a GPS calculates your route when driving. If you stray away from your predicted route, the GPS triggers the recalculation to incorporate the new information,” says Emery Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience, a member of the Picower Institute for Learning and Memory, associate director of the Institute for Medical Engineering and Science, and senior author on the study.

    “This allows you to use what you have already computed to get a more accurate estimate of what you’re about to compute in the next time period,” Brown says. “Current approaches to analyses of long, nonstationary time series ignore what you have already calculated in the previous interval leading to an enormous information loss.”

    In the study, Brown and his colleagues combined the strengths of two existing statistical analysis paradigms: state-space modeling and multitaper methods. State-space modeling is a flexible paradigm, which has been broadly applied to analyze data whose characteristics evolve over time. Examples include GPS, tracking learning, and performing speech recognition. Multitaper methods are optimal for computing spectra on a finite interval. When combined, the two methods bring together the local optimality properties of the multitaper approach with the ability to combine information across intervals with the state-space framework to produce an analysis paradigm that provides increased frequency resolution, increased noise reduction and formal statistical inference.

    To test the SS-MT algorithm, Brown and colleagues first analyzed electroencephalogram (EEG) recordings measuring brain activity from patients receiving general anesthesia for surgery. The SS-MT algorithm provided a highly denoised spectrogram characterizing the changes in power across frequencies over time. In a second example, they used the SS-MT’s inference paradigm to compare different levels of unconsciousness in terms of the differences in the spectral properties of these behavioral states.

    “The SS-MT analysis produces cleaner, sharper spectrograms,” says Brown. “The more background noise we can remove from a spectrogram, the easier it is to carry out formal statistical analyses.”

    Going forward, Brown and his team will use this method to investigate in detail the nature of the brain’s dynamics under general anesthesia. He further notes that the algorithm could find broad use in other applications of time-series analyses.

    “Spectrogram estimation is a standard analytic technique applied commonly in a number of problems such as analyzing solar variations, seismic activity, stock market activity, neuronal dynamics and many other types of time series,” says Brown. “As use of sensor and recording technologies becomes more prevalent, we will need better, more efficient ways to process data in real time. Therefore, we anticipate that the SS-MT algorithm could find many new areas of application.”

    Seong-Eun Kim, Michael K. Behr, and Demba E. Ba are lead authors of the paper, which was published online the week of Dec. 18 in Proceedings of the National Academy of Sciences PLUS. This work was partially supported by a National Research Foundation of Korea Grant, Guggenheim Fellowships in Applied Mathematics, the National Institutes of Health including NIH Transformative Research Awards, funds from Massachusetts General Hospital, and funds from the Picower Institute for Learning and Memory.

    See the full article here .

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  • richardmitnick 12:16 pm on November 1, 2017 Permalink | Reply
    Tags: , , Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16, , Picower Institute for Learning and Memory, R-Baclofen treatment   

    From MIT: “Promise seen in possible treatment for autism spectrum disorder” 

    MIT News
    MIT Widget

    MIT News

    October 31, 2017
    Picower Institute for Learning and Memory

    1
    In searching for a potential therapeutic for autism spectrum disorder, researchers have found that R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice.

    Image courtesy of the Picower Institute for Learning and Memory.

    Studies in mice show improved social interaction and cognition from a potential therapeutic for a syndrome that often results in autism.

    Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16. This deletion is characterized by intellectual disability; impaired language, communication, and socialization skills; and autism spectrum disorder or ASD.

    Research from the laboratories of Mark Bear at MIT and Jacqueline Crawley at the University of California at Davis, has identified a potential therapeutic for ASD. Researchers found that R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice.

    The findings, published in the journal Neuropsychopharmacology, have the potential to treat humans with 16p11.2 deletion syndrome and ASD.

    “Our collaborative teams found that treatment with the drug R-baclofen improved scores on several learning and memory tasks, and on a standard assay of social behavior, in 16p11.2 mutant mice,” says Crawley, co-senior author of the paper along with Bear.

    “This unique corroboration of findings by two independent labs, using two distinct lines of mice with the same mutation, increases confidence that R-baclofen may be an effective pharmacological treatment for some of the symptoms of human 16p11.2 deletion syndrome, including intellectual impairment and autism,” she says.

    “These findings are particularly exciting on two fronts,” says Bear, who is the Picower Professor of Neuroscience at MIT. “First, the results show that diverse genetic causes of intellectual disability and autism may converge on a limited number of pathophysiological processes that can be ameliorated pharmacologically. Thus, a treatment for one genetically defined disorder may be beneficial for another with phenotypic overlap. Second, R-Baclofen has a well-understood safety profile and is well-tolerated in children and adults, making clinical studies feasible in the near future.”

    Growing knowledge about genetic mutations in people with autism is enabling researchers to evaluate hypothesis-driven pharmacological interventions in terms of their ability to reverse the biological and behavioral consequence of specific mutations that cause autism. One of the genes in the 16p11.2 deletion region regulates the inhibitory neurotransmitter GABA. Researchers tested the hypothesis that increasing GABA neurotransmission using R-baclofen, which binds to GABA-B receptors, could reverse analogous behavioral symptoms in a mouse model of 16p11.2 deletion syndrome.

    In the current paper, researchers report the results of animal model studies using two independently derived lines of mutant mice, each missing a chromosomal region analogous to human 16p11.2. Normal and mutant mice at both labs were tested after receiving R-baclofen in their drinking water on three tasks: novel object recognition, object location memory, and contextual recognition learning and memory. In addition, R-baclofen treated mutant mice scored better after treatment on each cognitive task than the untreated mutant mice. R-baclofen also increased scores on a standard assay of mouse social behaviors — male-female reciprocal social interactions — in the 16p11.2 mutant mice.

    This study suggests that R-baclofen should be explored for the treatment of cognitive phenotypes in affected humans.

    See the full article here .

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    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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  • richardmitnick 2:17 pm on July 11, 2017 Permalink | Reply
    Tags: Amygdala, Kay Tye, , Neurons, , Picower Institute for Learning and Memory,   

    From MIT Tech Review: Women in STEM – “How the Brain Seeks Pleasure and Avoids Pain” Kay Tye 

    MIT Technology Review
    M.I.T Technology Review

    June 27, 2017
    Amanda Schaffer

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    Neuroscientist Kay Tye

    As a child, Kay Tye was immersed in a life of science. “I grew up in my mom’s lab,” she says. At the age of five or six, she earned 25 cents a box for “restocking” bulk-ordered pipette tips into boxes for sterilization as her mother, an acclaimed biochemist at Cornell University, probed the genetics of yeast. (Tye’s father is a theoretical physicist known for his work on cosmic inflation and superstring theory.)

    Today, Tye runs her own neuroscience lab at MIT. Under large black lights reminiscent of a fashion shoot, she and her team at the Picower Institute for Learning and Memory can observe how mice behave when particular brain circuits are turned on or off. Nearby, they can record the mice’s neural activity as the animals move toward a particular stimulus, like sugar water, or away, if they’re crossing a floor that delivers mild electric shocks. Elsewhere, they create brain slices to test in vitro, since these samples retain their physiological activity, even outside the body, for up to eight hours.

    Tye has been at the forefront of efforts to pinpoint the sources of anxiety and other emotions in the brain by analyzing how groups of neurons work together in circuits to process information. In particular, her work has contributed to a profound shift in researchers’ understanding of the amygdala, a brain area that has been thought of as central to fear responses: she has found that signaling in the amygdala can in fact reduce anxiety as well as increase it. To gain such insights, she has also made crucial advances in a technique, called optogenetics, that allows researchers to activate or suppress particular neural circuits in lab animals using light. Optogenetics was developed by Stanford neuroscientist and psychiatrist Karl ­Deisseroth, and it represented a breakthrough in efforts to determine the role of specific parts of the brain. While Tye was working in his laboratory as a postdoc, she demonstrated, for the first time, that it was possible to pinpoint and control specific groups of neurons that were sending signals to specific target neurons.

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    No image caption or credit.

    This fine-grained approach is important because drugs that treat conditions like anxiety currently do not target specific circuits, let alone individual neurons; rather, they operate throughout the brain, which often leads to undesirable side effects. Tye’s research may eventually help open the door to drugs that affect only specific neural circuits, reducing anxiety with fewer side effects.

    Such work has earned formal accolades, including a Presidential Early Career Award for Scientists and Engineers from President Obama, a Freedman Prize for neuroscience, and a TR35 award, recognizing outstanding researchers under the age of 35. Tye has also won high praise from others in her field who admire the creative breadth of her ambition. “She’s not afraid to ask the most fundamental questions, the ones most other scientists shy away from,” says Sheena Josselyn of the University of Toronto and the Hospital for Sick Children Research Institute.

    The questions she takes on involve emotions and phenomena that loom large in human experience, such as reward-seeking, loneliness, and compulsive overeating. Her goal is to understand their neural basis—to bridge the gap between brain, as understood by neuroscientists, and the mind, as conceived more expansively by psychiatrists, psychologists, and other students of human behavior.

    Would-be novelist

    Though it might seem as if Tye was born to be a scientist, she says her choice of career was anything but inevitable. In high school, she was ambivalent about science and gravitated instead toward writing; she wrote plays, short stories, and poetry. “In my mind, I was going to be a novelist,” she recalls.

    Still, while applying to college, she included MIT on her list, partly to humor her parents, Bik-Kwoon Tye and Henry Tye, both of whom had earned PhDs there in 1974. And when she received an acceptance letter, her father found it hard to disguise his feelings as his eyes welled with tears. “I’d never in my life seen my dad cry,” she says. She decided that she ought to give scientific learning a more dedicated try. She also convinced herself (with parental encouragement) that focusing on the natural world would give her more to write about down the road.

    As a freshman at MIT, Tye joined the lab of Suzanne Corkin, who was working with H.M., one of the most famous patients in the history of neuroscience. H.M., whose name was revealed to be Henry Molaison upon his death in 2008, suffered from profound amnesia after a lobotomy to treat seizures; studying his condition allowed researchers to probe the neural underpinnings of memory. One of Tye’s roles in the group was to make H.M. a peanut butter and jelly sandwich for lunch. He would eat it and then, moments later, with crumbs still on his face, ask, “Did we have lunch yet?”

    3
    Researchers troubleshoot behavioral boxes in which mice learn to form positive and negative associations with sounds. No image credit.

    “It made me appreciate that these basic functions, like memory, that are so key to who we are have biological substrates in the brain,” she says. Neuroscience can be intimidating and filled with jargon, she adds. But the experience with H.M., along with an inspiring introductory psychology class taught by Steven Pinker, “made it seem worth it to slog through the all-nighters” to understand the biological mechanisms behind psychological constructs.

    Still, after graduation, Tye wanted to make sure she was “looking around,” thinking about who she was and who she wanted to be. So she spent a year backpacking in Australia, where she worked on a farm, lived in a yoga ashram, taught yoga, camped out on the beach, and worked on a novel. She found that writing was “hard and lonely.” She enjoyed teaching yoga but didn’t see it as a satisfying career path.

    “I came out of that year surprisingly ready to go to grad school,” she says. Diving back into the academic world, she initially struggled to find a lab that would accept her and almost dropped out after her first year. But she found a mentor in Patricia Janak, who became her advisor, and earned a PhD in neuroscience at the University of California, San Francisco, in 2008.

    A surprise in the amygdala

    In 2009, Tye joined Deisseroth’s lab at Stanford. Deisseroth had already developed optogenetics, which gave researchers a much more precise way to identify the contributions of individual neurons within a circuit. Along with others in the lab, Tye used optogenetics to probe the connection between two parts of the amygdala, an almond-shaped region that is crucial to anxiety and fear. She first identified neurons in one area (known as the basolateral amygdala) that formed connections to neurons in another amygdalar area (known as the central nucleus) by sending out projections of nerve fibers. When she stimulated those basolateral amygdala neurons, she was able to reduce anxiety in mice. That is, she could cause the animals to spend more time in open spaces and less time cowering to the side. This was surprising, because when researchers stimulated the amygdala as a whole, the mice’s behavior grew more anxious.

    At first, everyone asked, “Are you sure you’re using the tool right? What’s going on?” she recalls. But after meticulous validation, in 2011, Tye and the group published their results in Nature, showing that some circuitry within the amygdala helps to calm animals down. This paper also represented a breakthrough in optogenetic technique. For the first time, researchers were able to zero in on and manipulate a specific part of a brain circuit: particular groups of neurons communicating with known target neurons. The technique, known as optogenetic projection-specific manipulation, is now considered one of the key tools of neuroscience.

    In 2012, Tye came to MIT as an assistant professor of brain and cognitive sciences at the Picower, continuing her work on anxiety. While setting up her lab, she targeted neurons within the amygdala that seemed to have the opposite effect on mouse anxiety, causing it to increase. These brain cells are also located in the basolateral amygdala, but they send projections to a nearby region known as the ventral hippocampus. When Tye stimulated this circuit using optogenetics, the mice avoided open spaces, apparently suffering from anxiety. (When she inhibited the connections from forming, the animals hung out in the open again, their anxiety seemingly alleviated.) Tye proposed that neighboring neurons in the amygdala can have opposite effects on animals’ behavior, depending on the targets to which they send signals.

    4
    Tye lab grad students Chris Leppla and Caitlin Vander Weele and postdocs Praneeth Namburi and Stephen Allsop. No image credit.

    Threats and rewards

    At the time, most researchers studying the amygdala still tended to focus mainly on its role in fear. Yet Tye suspected that activity in this part of the brain might encode a stimulus as either rewarding or threatening, good or bad, helping individuals decide how to respond. “There are many stimuli we encounter in our daily lives that are ambiguous,” says Conor ­Liston of the Brain and Mind Research Institute at Weill Cornell. “A social interaction, for example, can be either threatening or rewarding, and we need brain circuits devoted to differentiating which is which.”

    By looking at the relative strength of the currents passing through two glutamate receptors known to indicate synaptic strength, Tye discovered that different neural connections in mice were reinforced depending on whether a particular stimulus was linked to a reward or a threat. When mice learned to associate a sound with a treat of sugar, she found stronger synaptic input to the neurons in the basolateral amygdala that were sending information to the nucleus accumbens, which is part of the brain’s reward circuitry. On the other hand, when mice learned to associate the sound with mild electric shocks to their feet, input signals grew stronger in circuits leading from the basolateral amygdala to the centromedial amygdala, which is involved in pain and fear. In addition, she demonstrated a trade-off: when one of these circuits grew more active, the other grew less so. In other words, she had found how the brain encodes information that allows mice to differentiate between stimuli that are rewarding and those that are potentially harmful. The results were published in Nature in 2015.

    In recent work, Tye also probed the circuitry involved in making split-second decisions when both threatening and rewarding cues are present at the same time. She and her team focused this time on connections between the amygdala and the prefrontal cortex, an area responsible for higher-order thinking. (Specifically, they examined interactions between the basolateral amygdala and the prelimbic medial prefrontal cortex.) Using optogenetics and other techniques, they showed that this circuitry was active when the animals were simultaneously exposed to a potential sugar treat and a potential electric shock and had to make a decision about how to behave. Her results, which appeared in April in Nature Neuroscience, help illuminate how animals figure out what to do in the face of complex and sometimes contradictory cues.

    5
    Grad student Caitlin Vander Weele examines magnified images of brain slices to verify that a calcium sensor is targeting a specific type of neuron. No image credit.

    Cravings and compulsions

    As a graduate student, Tye had worked with researchers focused on addiction, but she was more interested in natural rewards, like sugar, than in substances that are regularly abused. In 2012, New York City mayor Michael Bloomberg announced a plan to limit the portion size of sodas sold in movie theaters, stadiums, and fast-food restaurants. Tye found herself wondering what exactly, at a brain level, causes people to crave sugary treats, above and beyond the normal drive to satisfy hunger.

    So she delved into the neural circuitry. In a paper published in 2015 in Cell, she and her team focused on neurons in the lateral hypothalamus (LH), a brain area involved in drives like hunger, and studied their projections into another region, called the ventral tegmental area (VTA), known to play a role in both motivation and addiction. Using optogenetics, she and her team showed that turning on specific LH-VTA connections caused the mice to gorge on sugar, while turning them off reduced the compulsive overeating.

    On her desktop, Tye loads a video demonstration featuring a mouse with a cable for light transmission attached to its brain. The video shows the mouse moving around, casually at first. Then, when the laser light is turned on to activate specific neurons in the LH-VTA circuit, the animal becomes frantic, running and licking the floor. Soon after, it brings its empty paws up to its mouth and does a pantomime of tasting and nibbling. “It engages in this complicated motor sequence and pretends to eat, which is crazy because there’s no food,” says Tye. In other words, turning the circuit on causes the animal to behave compulsively. Turning it off has the opposite effect.

    Crucially, though, while switching off this circuit prevents compulsive behavior, it does not affect normal eating. That is, it is possible to define a brain-based difference between at least some healthy and unhealthy drives to eat. This suggests that it might be possible to develop targeted drugs or even some form of biofeedback that might someday help people reduce unhealthy cravings without blocking ordinary hunger.

    Another recent finding, about loneliness, arose serendipitously from a project that postdoc Gillian Matthews had begun as a graduate student at Imperial College London with Mark Ungless. ­Matthews noticed that mice that had been isolated for 24 hours during experiments displayed stronger neural signaling in the brain’s dorsal raphe nucleus, which participates in reward signaling—and actively sought out the company of other mice. After she moved to Tye’s lab at MIT, Matthews and Tye developed the theory that the animals were craving interaction. In further experiments, they used optogenetics to turn off the signaling pathway in the dorsal raphe nucleus. Mice subjected to this treatment did not seem to seek out additional social interaction following time by themselves.

    Ultimately, Tye hopes that she and her team can speak to fundamental human questions, like why some people prefer to spend more time alone while others crave greater social contact.

    A lab without drama

    Though Tye’s lab is interested in the origins of phenomena like fear and compulsion, it is notable for its own lack of tension and conflict. Stephen Allsop, a postdoc who has worked with her for five years (several of which were spent as a graduate student), says that she stresses close collaboration among team members and oversees an upbeat, supportive culture: “It’s amazing how little drama we have in this lab.”

    “Along with scientific integrity, I make the positive, collaborative, open culture of my research group—and the happiness of the individuals within it—my top priority,” says Tye. “Scientific excellence is a close second.” Strong relationships with professors and mentors are part of the draw of science, she adds.

    Indeed, she says, they are second only to the bonds between parents and children. In 2013, Tye and her husband, Jim Wagner, a software developer, had a daughter, Keeva, who has already accompanied her to conferences around the world. Their son, Jet, was born last year. And the children have found a place in her lab, much as she found a niche in her mother’s (though they have yet to earn paid positions). As she told Nature when Keeva was still an infant: “If my daughter all of a sudden needs to be picked up, I bring her to my lab meeting or meet with people while I bounce her. If she has a total meltdown, then sometimes I have to bail and follow up later.”

    But while she may be easygoing as a parent and a lab leader, Tye finds plenty of drama in neuroscience itself, and she keeps returning to its central questions because they are so enticing. Though she says she reads fewer novels now than she used to, she still seems compelled by the kinds of mysteries a writer might probe: Why does a hero set out on a journey? Why does the chatter in his or her head go awry and lead to gloomy soliloquizing or anxious self-sabotage? Like a novelist, she exhibits tremendous creative breadth. “There is something special about science,” she says. “Your new work is based on what you did previously. And if you’re lucky, you can help shape the future.”

    See the full article here .

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