Now, researchers have tapped into how the flicker may work. They discovered in the lab that the exposure to light pulsing at 40 hertz – 40 beats per second – causes brains to release a surge of signaling chemicals that may help fight the disease.

Though conducted on healthy mice, this new study is directly connected to human trials, in which Alzheimer’s patients are exposed to 40 Hz light and sound. Insights gained in mice at the Georgia Institute of Technology are informing the human trials in collaboration with Emory University.

“I’ll be running samples from mice in the lab, and around the same time, a colleague will be doing a strikingly similar analysis on patient fluid samples,” said Kristie Garza, the study’s first author. Garza is a graduate research assistant in the lab of Annabelle Singer at Georgia Tech and also a member of Emory’s neuroscience program.

One of the surging signaling molecules in the new study on mice is strongly associated with the activation of brain immune cells called microglia, which purge an Alzheimer’s hallmark – amyloid beta plaque, junk protein that accumulates between brain cells.

Immune signaling

In 2016, researchers discovered that light flickering at 40 Hz mobilized microglia in mice afflicted with Alzheimer’s to clean up that junk.  The new study looked for brain chemistry that connects the flicker with microglial and other immune activation in mice and exposed a surge of 20 cytokines – small proteins secreted externally by cells and which signal to other cells. Accompanying the cytokine release, internal cell chemistry – the activation of proteins by phosphate groups – left behind a strong calling card.

“The phosphoproteins showed up first. It looked as though they were leading, and our hypothesis is that they triggered the release of the cytokines,” said Singer, who co-led the new study and is an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

“Beyond cytokines that may be signaling to microglia, a number of factors that we identified have the potential to support neural health,” said Levi Wood, who co-led the study with Singer and is an assistant professor in Georgia Tech’s George W. Woodruff School of Mechanical Engineering.

The team published its findings in the Journal of Neuroscience on February 5, 2020. The research was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, and by the Packard Foundation.

Singer was co-first author on the original 2016 study at the Massachusetts Institute of Technology, in which the therapeutic effects of 40 Hz were first discovered in mice.

Sci-fi surrealness

Alzheimer’s strikes, with few exceptions, late in life. It destroys up to 30% of a brain’s mass, carving out ravines and depositing piles of amyloid plaque, which builds up outside of neurons. Inside neurons, phosphorylated tau protein forms similar junk known as neurofibrillary tangles suspected of destroying mental functions and neurons. 

After many decades of failed Alzheimer’s drug trials costing billions, flickering light as a potentially successful Alzheimer’s therapy seems surreal even to the researchers.

“Sometimes it does feel like science fiction,” Singer said.

The 40 Hz frequency stems from the observation that brains of Alzheimer’s patients suffer early on from a lack of what is called gamma, moments of gentle, constant brain waves acting like a dance beat for neuron activity. Its most common frequency is right around 40 Hz, and exposing mice to light flickering at that frequency restored gamma and also appears to have prevented heavy Alzheimer’s brain damage.

Adding to the surrealness, gamma has also been associated with esoteric mind expansion practices, in which practitioners perform light and sound meditation. Then, in 2016, research connected gamma to working memory, a function key to train of thought.

Cytokine bonanza

In the current study, the surging cytokines hinted at a connection with microglial activity, and in particular, the cytokine Macrophage Colony-Stimulating Factor (M-CSF).

“M-CSF was the thing that yelled, ‘Microglia activation!’” Singer said.

The researchers will look for a causal connection to microglia activation in an upcoming study, but the overall surge of cytokines was a good sign in general, they said.

“The vast majority of cytokines went up, some anti-inflammatory and some inflammatory, and it was a transient response,” Wood said. “Often, a transient inflammatory response can promote pathogen clearance; it can promote repair.”

“Generally, you think of an inflammatory response as being bad if it’s chronic, and this was rapid and then dropped off, so we think that was probably beneficial,” Singer added.

Chemical timing

The 40 Hz stimulation did not need long to trigger the cytokine surge.

“We found an increase in cytokines after an hour of stimulation,” Garza said. “We saw phosphoprotein signals after about 15 minutes of flickering.”

Perhaps about 15 minutes was enough to start processes inside of cells and about 45 more minutes were needed for the cells to secrete cytokines. It is too early to know.

20 Hz bombshell

As controls, the researchers applied three additional light stimuli, and to their astonishment, all three had some effect on cytokines. But stimulating with 20 Hz stole the show.

“At 20 Hz, cytokine levels were way down. That could be useful, too. There may be circumstances where you want to suppress cytokines,” Singer said. “We’re thinking different kinds of stimulation could potentially become a platform of tools in a variety of contexts like Parkinson’s or schizophrenia. Many neurological disorders are associated with immune response.”

The research team warns against people improvising light therapies on their own, since more data is needed to thoroughly establish effects on humans, and getting frequencies wrong could possibly even do damage.

Also read:  A family coping with Alzheimer’s leads you through our fight against it 

Also read: Why Alzheimer’s research probably needs to shift focus 

Lu Zhang and Ben Borron from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University co-authored the study. The research was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (grants NIH R01-NS109226 and R01-NS109226-01S1), by the Packard Foundation, the Friends and Alumni of Georgia Tech, and by the Lane family. Any findings, conclusions, and recommendations are those of the authors and not necessarily of the sponsors.

Writer & Media Representative: Ben Brumfield (404-272-2780), email: ben.brumfield@comm.gatech.edu

Georgia Institute of Technology

Election of new NAE members, the culmination of a yearlong process, recognizes individuals who have made outstanding contributions to "engineering research, practice, or education, including, where appropriate, significant contributions to the engineering literature" and to "the pioneering of new and developing fields of technology, making major advancements in traditional fields of engineering, or developing/implementing innovative approaches to engineering education."  

“It’s the honor of a lifetime to be recognized by the National Academy of Engineering for the impact we’ve have on understanding lung injuries in the critical care unit and traumatic brain injuries in children,” said Margulies, chair of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and, with Brown, one of just three women on the Georgia Tech faculty accorded NAE membership – one of the highest professional distinctions an engineer can receive.

“Our work is deeply collaborative, and I am grateful to the engineers, scientists, physicians, and patients who are partners in our journey,” Margulies added.

Margulies, a researcher in the Petit Institute for Bioengineering and Bioscience at Tech and a Georgia Research Alliance Eminent Scholar in Injury Biomechanics at Emory, was elected, “for elaborating the traumatic injury thresholds of brain and lung in terms of structure-function mechanisms,” according to the NAE announcement.

Using an integrated biomechanics approach, Margulies’ research program spans the micro-to-macro scales in two distinct areas, traumatic brain injury and ventilator-induced lung injury. Her work has generated new knowledge about the structural and functional responses of the brain and lungs to their mechanical environment. Margulies came to Georgia Tech in 2017 from the University of Pennsylvania, where she’d been a professor of bioengineering, and had earned her Master of Science in Engineering and Ph.D. in Bioengineering.

Brown, a Regents and Brook Byers Professor of Sustainable Systems in the School of Public Policy, was co-recipient of the Nobel Peace Prize in 2007 (for co-authorship of the Intergovernmental Panel on Climate Change Working Group III Assessment Report on Mitigation of Climate Change, Chapter 6). 

She joined Georgia Tech in 2006 after a career at the U.S. Department of Energy's Oak Ridge National Laboratory, where she led several national climate change mitigation studies and became a leader in the analysis and interpretation of energy futures in the United States. Her research at Tech focuses on the design and impact of policies aimed at accelerating the development and deployment of sustainable energy technologies, emphasizing the electric utility industry. She was elected to NAE “for bridging engineering, social and behavioral sciences, and policy studies to achieve cleaner electric energy.” 
 
Brown, who earned her Ph.D. at the Ohio State University, co-founded and chaired the Southeast Energy Efficiency Alliance, served two terms as a presidential appointee on the board of the Tennessee Valley Authority – the nation’s largest public power provider – and also served two terms on the U.S. Department of Energy’s Electricity Advisory Committee, where she led the Smart Grid Subcommittee. 

“The most rewarding feature of my career has been working toward solutions with colleagues across disciplines,” Brown said.

Shapiro is the Russell Chandler III Chair and professor in the H. Milton Stewart School of Industrial and Systems Engineering, where his research is focused on stochastic programming, risk analysis, simulation-based optimization, and multivariate statistical analysis.

In 2013, he was awarded the INFORMS Khachiyan Prize for lifetime achievements in optimization. He received the 2018 Dantzig Prize from the Mathematical Optimization Society and the Society for Industrial and Applied Mathematics.

Since earning his Ph.D. in applied mathematics-statistics from Israel’s Ben-Gurion University of the Negev in 1981, Shapiro has made substantial contributions to the fields of optimization and large-scale, stochastic programming, and he was elected to NAE “for contributions to the theory, computation, and application of stochastic programming.” 

Kurfess is professor and HUSCO/Ramirez Distinguished Chair in Fluid Power and Motion Control in the George W. Woodruff School of Mechanical Engineering, where he has helped guide the evolution of technology as a pioneer in the digital transformation of manufacturing. 

Improving manufacturing technology is a pursuit that has roots in his childhood. “I grew up in my father’s machine shop,” said Kurfess, who has a special fondness for mom-and-pop operations. He was elected by the NAE “for development and implementation of innovative digital manufacturing technologies and system architectures.”

“I’m proud that the work we do has a positive impact on small and medium-sized enterprises, which are about 99% of the manufacturing operations, as well as large operations,” said Kurfess, who earned all of his degrees at MIT. “Our work targets people who are implementing the digital thread in manufacturing, and what the digital thread will do is make sure those smaller enterprises, those mom and pops, can have access to the latest and greatest technologies.”

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Media Relations Contact: John Toon (404-894-6986) (jtoon@gatech.edu).

Writer: Jerry Grillo

Cerebral palsy (CP) is the most common cause of physical disability in children in most developed countries, and spastic CP is the most common form of the disorder. For these patients (and others), spasticity can be severely debilitating, negatively impacting their movement, speech, gait, and overall quality of life.

The lab of Lena Ting, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and in the Division of Physical Therapy in Emory’s Department of Rehabilitation Medicine, is tackling the problem, shedding new light on issues underlying spasticity.

Ting’s lab is part of an international collaborative effort with a recently published research article in the open access scientific journal, PLOS One. She is corresponding author of, “Interaction between muscle tone, short-range stiffness and increased sensory feedback

gains explains key kinematic features of the pendulum test in spastic cerebral palsy: A

simulation study.”

The pendulum test is a sensitive clinical assessment of spasticity in which the lower leg is

dropped from the horizontal position and the features of leg motion are recorded. “This problem actually arose out of a homework problem for my Computational Neuromechanics class, where we simulate the leg as a pendulum,” said Ting.

In typically-developed people, the swinging leg behaves like a damped pendulum, with the angle of leg swing decreasing as it oscillates several times before coming to rest. In children with spastic CP, three key differences in the leg motion are observed: Reduced angle of leg swing in the first oscillation,  fewer oscillations, and the coming to rest at a less vertical angle.

Overall, the decrease in the first swing has been found to be the best predictor of spasticity severity, but why this is the case is has not been clear. Ting’s team hypothesized that increased muscle tone– the continual contraction of muscles while at rest­–accounts for both the reduced leg swing and the non-vertical resting leg angle. This idea contrasts with the clinical explanation of spasticity as an abnormal increase in the activation of reflexes as the leg is stretched with higher velocities. 

 “We were stumped because the clinical explanation of increased velocity-dependent reflexes didn’t generate realistic motion,” Ting said. “But we happened to be working on a different research project studying an interesting property of muscles called short-range stiffness, which increases when muscles are activated. We wanted to know if this very rapid rise and drop of resistive force in muscles when they are stretched could explain the parts of the pendulum test that were giving us a hard time in the simulation.”

So the researchers developed and tested a physiologically-plausible computer simulation of how muscle tone and reflexes would interact to reproduce key features of the pendulum test for spasticity across a range of severity levels. Their new model helps to explain a whole range of pendulum test kinematics in people with and without CP.

“Increased muscle tone plays a primary role in generating a key feature of the leg motion that is most closely related to the level of spasticity,” Ting explained. “Even when reflexes are increased,  can only account for pendulum test results across the spectrum of spasticity severity if we also increase muscle tone and short-range stiffness. This is exciting because the pendulum test is more objective than a clinician’s subjective assessment of leg stiffness. And with our model we can now begin to understand how multiple mechanisms of spasticity might interact to cause abnormal body motion, not just in the pendulum test, but in everyday movements.”

Lead author of the paper was Friedl De Groote, assistant professor in the Department of Movement Sciences at KU Leuven in Belgium. Other authors were both researchers from Ting’s lab, Kyle Blum and Brian Horslen.

But a team of researchers at the Georgia Institute of Technology wants develop intelligent closed-loop algorithms for turning measurements into precise actions in real time – kind of like those used in technologies such as self-driving cars and robotics.

"Intelligent algorithms for interacting with the brain holds promise to help us alleviate diseases with no current treatments, as well as better understanding the basis of human intelligence,” says Chris Rozell, professor in Georgia Tech’s School of Electrical and Computer Engineering, who is leading the study with Garrett Stanley, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. Both are researchers in the the Petit Institute for Bioengineering and Bioscience at Georgia Tech, where Rozell also is a member of the Center for Machine Learning and Stanley is co-director of the Neural Engineering Center.

Their project just received a $1.6 million, five-year award from the National Institutes of Health (NIH)/National Institutes of Neurological Disorders and stroke (NINDS) through a long-standing and innovative NSF/NIH partnership in the Collaborative Research in Computational Neuroscience (CRCNS) program. The project leverages neurotechnology and engineering advances to pioneer a nascent field, closed-loop computational neuroscience.

"There has been an explosion of remarkable advances in both neuroengineering and machine learning, making the intersection of these fields one of the most exciting frontiers I can imagine,” adds Rozell. “I am excited that this collaborative project will allow us to pioneer these interactive neurotechnology advances.”

Rather than just analyzing data after an experiment, the team’s integrative approach will develop real-time algorithms that operate as a type of autopilot for a neural circuit, “where we can lock in a precise response, regardless of surrounding activity,” Rozell says.

The five-year project, called “Closed-Loop Computational Neuroscience for Causally Dissecting Circuits,” will build on the theory, methods, and findings of engineering,  computer science, neuroscience, and other disciplines (machine learning and genetics, for example). Through the CRCNS program, the National Science Foundation and National Institutes of Health (along with several international partners) support collaborative activities designed to advance understanding of nervous system structure and function, the mechanisms underlying nervous system disorders, and the computational strategies used by the nervous system.

“The advances in tools that we and others have made in precisely measuring and manipulating neurons and neural circuits now make it possible to read and write brain activity at the same time, and communicate with the brain in the fast timescale on which it operates,” says Stanley, professor in the Wallace H. Coulter Department of Biomedical Engineering. “We think this is a game-changer, experimentally and computationally.”

“This year’s awardees reflect the cutting–edge research being done at every career stage across neurology and neuroscience,” said David M. Holtzman, MD, president of the ANA and Andrew B. and Gretchen P. Jones Professor and Chairman, Dept. of Neurology at the Washington University School of Medicine. “The pace of advances we’re seeing in translational neuroscience and the neurobiology of disease are extraordinary. We hope the gains will inspire the new generation of physician scientists to pursue careers that combine research and teaching with clinical practice. There has never been a more exciting time to work in academic neurology.”

Each year, the ANA Annual Meeting convenes more than 900 of the nation's top academic neurologists and neuroscientists to share updates and late-breaking research on the diseases that affect more than 100 million Americans each year including stroke, Alzheimer’s disease, Parkinson’s disease, neuromuscular disorders, headache, traumatic brain and spinal cord injuries, epilepsy, multiple sclerosis and more.

Derek Denny-Brown Young Neurological Scholars

The Derek Denny-Brown Young Neurological Awards are clinical awards given each year during the Annual Meeting to new members of the association who have achieved significant stature in neurological research, and who show promise and will continue making major contributions to the field of neurology.

The Derek Denny-Brown Young Neurological Scholar Award in Neuroscience went to Cassie S. Mitchell, Ph.D., Georgia Institute of Technology. Her presentation title: Literature-based discovery facilitates predictive medicine for neurological disease.

Full list of ANA 2019 winners.

But, they see well enough to quickly detect visual stimuli throughout their visual fields.  Bilal Haider says this makes mice an excellent model system, “for studying how neural circuits mediate rapid visual behaviors – mice are a very good model for studying what can happen in humans making fast decisions about visual information.”

Haider, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and his colleagues prove the value of mice while demonstrating how the brain visually detects and perceives visual stimuli in their latest research, entitled “Cortical State Fluctuations across Layers of V1 during Visual Spatial Perception,” published recently in the journal Cell Reports.

“This paper shows that mice can detect a small, faint object appearing very briefly and unpredictably in the visual field, and they can respond to this stimuli in less than half a second, and make a precise motor response,” explains Haider, corresponding author of the paper, whose co-researchers on the project were lead authors Anderson Speed and co-author Joseph Del Rosario, grad students in his lab, and Christopher P. Burgess, a researcher at Google DeepMind in the UK.

“Actually, mice have a very fast visual system to produce actions, not that much slower than ours,” Haider adds.

In the paper, the authors explain that behavioral factors like sleep, wakefulness, and movement have strong effects on the state of cortical activity. And while Haider and others have previous established that cortical states have profound effects on sensory responses, there remain unresolved questions about cortical states and their effects on the speed and accuracy of sensory perception.

So, to address the questions they trained mice to detect visual stimuli appearing in discrete portions of the visual field. And they simultaneously measured local field potentials (an electrophysiological signal generated by the electric current flowing from large populations of neurons) and excitatory and inhibitory neuron populations across layers of the primary visual cortex that receives visual information.

Through their experiments, Haider’s team showed that changes in cortical activity states exert strong, widespread effects in a mouse’s primary visual cortex, and can play a prominent role for visual spatial behavior.  Haider’s team could use this neural activity to “mind read” and accurately predict perceptual outcomes.

Basically, the team figured out, Haider says, “that the properties of the visual system in mice, especially the way they use vision for behavior, and the neural activity that we see in their visual system, is remarkably similar to what’s seen in primates and humans.  This will allow us to use the mouse as a platform for studying neural circuits underlying visual dysfunctions in models of neurological diseases.”

In receiving their fellowships, Eva Dyer and Chethan Pandarinath, assistant professors in the Coulter Department, are ranked among “the best young scientists working today,” according to Adam F. Falk, president of the Sloan Foundation.

“Sloan Fellows stand out for their creativity, for their hard work, for the importance of the issues they tackle and the energy and innovation with which they tackle them,” Falk said. “To be a Sloan Fellow is to be in the vanguard of 21^st-century science.”

Past Sloan Research Fellows include many towering figures in the history of science, including physicists Richard Feynman and Murray Gell-Mann, and game theorist John Nash. Forty-seven fellows have received a Nobel Prize in their respective field, 17 have won the Fields Medal in mathematics, 69 have received the National Medal of Science and 18 have won the John Bates Clark Medal in economics, including every winner since 2007.

“It is truly remarkable for one department to have two Sloan Research Fellowship winners in the same year,” said Susan Margulies, Coulter Department Chair. “Last year, Bilal Haider from BME won a Sloan Fellowship, and Annabelle Singer was awarded a Packard Fellowship. Three Sloan awards and a Packard Fellowship in just two years are evidence of the brilliance and thought leadership of our early-stage neuro-engineering faculty.”

Dyer’s research interests lie at the intersection of machine learning, optimization and neuroscience. Her lab develops computational methods for discovering principles that govern the organization and structure of the brain, as well as methods for integrating multi-modal datasets to reveal the link between neural structure and function.

Pandarinath, who is also an assistant professor in Emory’s Department of Neurosurgery as well as the Emory Neuromodulation Technology Innovation Center, leads the Emory and Georgia Tech Systems Neural Engineering Lab. He’s part of an interdisciplinary team at Emory and Georgia Tech working to better understand how large networks of neurons in the brain encode information and control behavior. Pandarinath’s team hopes to design new brain-machine interface technologies to help restore movement to people who are paralyzed, including those affected by spinal cord injury and stroke, and by Parkinson’s disease and ALS.

Valued not only for their prestige, Sloan Research Fellowships are a highly flexible source of research support. Funds may be spent in any way a fellow deems will best advance his or her work. Drawn this year from 57 colleges and universities in the United States and Canada, the 2019 Sloan Research Fellows represent a diverse array of research interests.

Open to scholars in eight scientific and technical fields — chemistry, computer science, economics, mathematics, computational and evolutionary molecular biology, neuroscience, ocean sciences and physics — the Sloan Research Fellowships are awarded in close coordination with the scientific community. Candidates must be nominated by their fellow scientists, and winning fellows are selected by independent panels of senior scholars on the basis of a candidate’s research accomplishments, creativity and potential to become a leader in his or her field. Winners receive a two-year, $70,000 fellowship to further their research.

The Alfred P. Sloan Foundation is a philanthropic, not-for-profit grant making institution based in New York City. Established in 1934 by Alfred Pritchard Sloan Jr., then-president and CEO of the General Motors Corporation, the Foundation makes grants in support of original research and education in science, technology, engineering, mathematics and economics.

The grant, entitled “A novel brain-machine interface for rehabilitation,” aims to develop new strategies to help restore movement to people who are paralyzed, including those affected by spinal cord injury and stroke. Brain-machine interface systems interface directly with the brain to allow people with paralysis to control external assistive devices, such as robotic arms or exoskeletons, or to control the movement of their own limbs through direct electrical stimulation of muscles.

In previous work at Stanford, Pandarinath and colleagues developed brain-machine interfaces that focused on a particular portion of the brain known as the motor cortex. In the current study, Pandarinath, in collaboration with colleagues in the departments of Neurosurgery and Neurology at Emory, hopes to test whether multiple areas of the brain, which each control different aspects of movement, might provide complementary signals for controlling brain-machine interfaces.

The mission of the Interdisciplinary Rehabilitation Engineering Career Development program is to recruit and train scholars with engineering and other quantitative backgrounds to become successful rehabilitation scientists in basic, translational, and/or clinical research. These rehabilitation scientists will have the ability to integrate knowledge from the various disciplines involved in Movement and Rehabilitation Science (MRS) research, including engineering, quantitative neuroscience and physiology, and affiliated clinical sciences.

The program is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number K12HD073945.

A team of researchers from Georgia Tech and other local universities would study this problem with a grant up to $2 million, dependent on successful completion of milestones, from the Defense Advanced Research Projects Agency’s (DARPA) Lifelong Learning Machines (L2M) program managed by Dr. Hava Siegelmann. DARPA’s goal would be to develop new machine learning approaches that enable systems to learn continually while they operate and apply prior knowledge to new situations.

School of Computer Science Professor Constantine Dovrolis, Georgia Tech Research Institute Senior Research Scientist Zsolt Kira, Georgia State University neuroscience Professor Sarah Pallas, and Emory biology Associate Professor Astrid Prinz are collaborating on the two-year project.

Bringing neural networks to the 21^st century

The concept of modeling a computational neural network based on the brain first arose in the 1950s, but it hasn’t evolved much since.

“Obviously, since the ‘50s there’s been a lot of progress in neuroscience, but not a lot of it has translated to machine learning,” Kira said. “Supervised machine learning through neural networks is fundamentally a computer scientist’s translation of a high-level understanding of the brain from the past. But I think there’s a lot we can learn from contemporary neuroscience.”

One of the fundamental problems of machine learning that neuroscience could alleviate is what Dovrolis calls “catastrophic forgetting.” When the artificial neural network learns a new task, it often forgets the previous one.

“Deep learning networks are very different from the brain, both in terms of structure (architecture) and function (dynamics),” Dovrolis said.

Take the brain of a baby. Within the first few years of life, it not only has the ability to learn but also to generalize with very little supervision. Dovrolis believes that machine learning can achieve the same goal but only through a major departure from the currently established machine learning paradigms.

“The brain is really the only example of general intelligence we have,” Dovrolis said. “It makes sense to take that example, identify its fundamental principles, and transfer them to the computational domain.”

Bridging the gap between neuro and computer science

It may make sense, but it’s also controversial. Many computer scientists see the brain as mere hardware, and they prefer to focus instead on more statistical machine learning approaches. This is why this project is so unique: It brings together different ideas from network science, machine learning, evolutionary computing, computational neuroscience, and systems neuroscience — fields that should’ve been working together from the start.

“It’s easier for each field to work by themselves because it’s very comfortable,” Kira said. “But there’s a lot of potential if you actually make the effort to bring people together.”

Yet working with neuroscientists doesn’t just benefit computer scientists. Many neuroscientists believe computing could help with better modeling of biological networks, and ultimately, a deeper understanding of how the brain works.

“Neuroscience can in turn be guided by results from machine learning research that can inform new experiments to deepen our understanding of the brain,” Prinz said.

One of these examples is the flexibility of the brain.

"Neural circuits in the developing brain are highly flexible and adaptable to environmental changes, which endows them with an ability to learn rapidly and to self-repair after damage,” Pallas said.

Adult brains are much less plastic, so one of the neuroscientists’ goals is to uncover the neuronal mechanism that regulates the level of plasticity versus stability in brain circuits. With this, they can harness the mechanism for medical purposes and design machines that can continue learning without forgetting.

Approaching the research

The project should attempt to address five goals of the L2M program:

• Continual learning: The building block of the cortex is a largely invariant structure referred to as a “cortical column.” The function of cortical columns is not known yet, but it seems that they act as associative memories and predictors. The structure of cortical columns suggests that recurrent neural networks could learn incrementally and in an unsupervised manner simply by interacting with the environment.

• Adaptation to new tasks/environments: These cortical columns could interconnect through deep brain-wide hierarchies and nested feedback loops that interact and inform each other, enabling the brain to adapt to different environments with minimal need for re-training.

• Goal-driven perception: At any time, the brain is receiving data from many sensory sources. Hierarchical neural networks could use task-driven inputs to adjust low-level sensory processing and integration dynamically, depending on top-down goal-related signals.

• Selective plasticity: The project should be investigating how the connections and weights between (artificial) neurons could be adjusted when a new task is encountered, without catastrophically forgetting previous tasks. Neuromodulator-driven plasticity and homeostatic plasticity are two biological mechanisms that could be transferred in machine learning to address this problem.

• Monitoring and safety: Researchers would also investigate how to ensure stability and safety, based on the organization of the brain’s autonomic nervous system. Additionally, the safety concern could be further addressed through an “artificial impulse control” system, operating on the same prediction principles as the corresponding cortical system.

This research could allow machine learning to become increasingly adaptive and continually learn, which could have vast applications. A self-driving car could be programmed in the summer, but with these principles, it could learn how to drive in previously untested winter conditions. Siri could be next.

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“We can record the electrical activity of a single neuron, and large groups of neurons, as animals learn and perform skilled behaviors,” says Samuel Sober, an associate professor of biology at Emory University who studies the brain and nervous system. “What’s missing,” he adds, “is the technology to precisely record the electrical signals of the muscles that ultimately control that movement.”

The Sober lab is now developing that technology through a collaboration with the lab of Muhannad Bakir, a professor in Georgia Tech’s School of Electrical and Computer Engineering. The researchers recently received a $200,000 Technological Innovations in Neuroscience Award from the McKnight Foundation to create a device that can record electrical action potentials, or “spikes” within muscles of songbirds and rodents. The technology will be used to help understand the neural control of many different skilled behaviors to potentially gain insights into neurological disorders that affect motor control.

“Our device will be the first that lets you record populations of spikes from all of the muscles involved in controlling a complex behavior,” Sober says. “This technique will offer unprecedented access to the neural signals that control muscles, allowing previously impossible investigations into how the brain controls the body.”

“By combining expertise in the life sciences at Emory with the engineering expertise of Georgia Tech, we are able to enter new scientific territory,” Bakir says. “The ultimate goal is to make discoveries that improve the quality of life of people.”

The Sober lab previously developed a prototype device — electrodes attached to flexible wires — to measure electrical activity in a breathing muscle used by Bengalese finches to sing. The way birds control their song has a lot in common with human speech, both in how it is learned early in life and how it is produced in adulthood. The neural pathways for birdsong are also well known, and restricted to that one activity, making birds a good model system for studying nervous system function.

“In experiments using our prototype, we discovered that, just like in brain cells, precise spike timing patterns in muscle cells are critical for controlling behavior — in this case breathing,” Sober says.  

The prototype device, however, is basic. Its 16 electrodes can only record activity from a single muscle — not the entire ensemble of muscles involved in birdsong. In order to gain a fuller picture of how neural signals control movement, neuroscientists need a much more sophisticated device.

The McKnight funding allowed Sober to team up with Bakir. Their goal is to create a micro-scale electromyography (EMG) sensor array, containing more than 1,000 electrodes, to record single-cellular data across many muscles.

The engineering challenges are formidable. The arrays need to be flexible enough to fit the shape of small muscles used in fine motor skills, and to change shape as the muscles contract. The entire device must also be tiny enough not to impede the movement of a small animal.

“Our first step is to build a flexible substrate on the micro-scale that can support high-density electrodes,” Bakir says. “And we will need to use microchips that work in parallel with 1,000 electrodes, and then attach them to that substrate.”

To meet that challenge, the Bakir lab will create a 3D integrated circuit. “Essentially, it’s building a miniature skyscraper of electrical circuits stacked vertically atop one another,” Bakir says. This vertical design will allow the researchers to minimize the size of the flexible substrate.

“To our knowledge, no one has done what we are trying to do in this project,” Bakir says. “That makes it more difficult, but also exciting because we are entering new space.”

The Sober lab will use the new device to expand its songbird vocalization studies. And it will explore how the nervous system controls the muscles involved when a mouse performs skilled movements with its forelimbs.

An early version of the technology will also be shared with collaborators of the Sober lab at three different universities. These collaborators will further test the arrays, while also gathering data across more species.

“We know so little about how the brain organizes skilled behaviors,” Sober says. “Once we perfect this technology, we will make it available to researchers in this field around the world, to advance knowledge as rapidly as possible.”

The mission of the McKnight Foundation’s Technological Innovations in Neuroscience Award, as described on its website, is “to bring science closer to the day when diseases of the brain and behavior can be accurately diagnosed, prevented and treated.” 

Lena Ting explores the unanswered questions in her quest to use engineering principles to understand how people move. Her approach integrates research and education in the fields of neuroscience, biomechanics, engineering, rehabilitation, robotics, neurology and physiology, to ultimately benefit those suffering from movement disorders.

“I love that I get to probe interesting and unanswered questions and work at the intersection of a lot of fields,” she said.

Ting says she is not building the better device or machine to advance mobility; she is finding the answers to help others build new technologies to impact people and how they move.

She is changing the way engineers develop technologies for rehabilitation and health care and helping develop autonomous cooperative robots to enhance, assist and improve impairments in gait and balance.

Ting, a professor and educator at the the Department of Rehabilitation Medicine at Emory University School of Medicine and the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech, is the 2018 Health Care Hero Award winner in the Allied Health Professional category [by the Atlanta Business Chronicle].

Ting brings a unique blend of science, engineering and robotics to improve rehabilitation for individuals with movement disorders and those who have experienced stroke, spinal cord injury or lower limb loss. Her research focuses on the brain and body interactions that impact walking, standing and balance.

“The way I think about how people move is how I learned about how machines work,” she said. “When a machine breaks down, you find the root cause. You can describe what is happening but you can’t identify the key part that is loose and if I could just tweak it, the symptoms would go away and be resolved. With movement disorders, we have to figure out what causes it.”

“Lena’s research is a perfect example of how biomedical engineering links medicine and engineering to benefit patients,” said Susan Margulies, chair of the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “She has made critical discoveries about the connections between signals in the brain and the way our bodies coordinate movement and balance. When injury or disease interrupts these signals, peoples’ lives are impacted very negatively. Technology and engineering can influence these circuits in a positive way.”

Ting has won multiple teaching awards.

“If my research is not fun, I can’t do it well,” she said. “I like to look at problems that are intellectually challenging and come up with new, out-of-the-box ideas — that is exciting to me.”

In one such study, Ting and a Georgia Tech colleague discovered an energy-saving mechanism that helps flamingos balance on one leg while asleep, and that could one day be used to develop novel prosthetic devices. In another, she and her colleagues found that a program called “adapted tango” improved balance-correcting muscle activity that is impaired in people with Parkinson’s disease.

Tonya Layman
Contributing Writer
Atlanta Business Chronicle

The National Neurotrauma Society seeks to accelerate research that will provide answers for clinicians and ultimately improve the treatments available to patients. The society promotes excellence in the field by providing opportunities for scientists, establishing standards in both basic and clinical research, encouraging and supporting research, and promoting liaisons with other organizations that influence the care and cure of neurotrauma victims.

LaPlaca earned a Ph.D. in bioengineering (1996) and completed her postdoctoral training in neurosurgery while at the University of Pennsylvania. Her research interests surround translational research in traumatic brain injury (TBI) and concussion. Her research goals are to better understand acute injury mechanisms and mechanotransduction, identify novel TBI biomarkers, and develop multimodal concussion assessment tools. She has won numerous awards for her research and currently serves as vice chair of the Brain Injury Association of Georgia.

Arvanitis (also an assistant professor in the Woodruff School of Mechanical Engineering) and his fellow researchers received a grant designed to support research that addresses demanding, urgent, and consequential challenges for advancing America’s prosperity, health and infrastructure.

For more information on the team’s work and the grant, read the story here.

“The blood-brain barrier is a challenge in the treatment of brain malignancies,” said Costas Arvanitis, an assistant professor at the Georgia Institute of Technology in the George W. Woodruff School of Mechanical Engineering. “Even when a drug reaches the brain’s circulation, abnormal blood vessels in and around tumors lead to non-uniform drug delivery with low concentrations in some areas of the tumor.”

If a drug does make it through the distorted blood vessels, then dense tumorous tissue often blocks the drug’s path to the malignant cells. Arvanitis co-led the new study with Dr. Vasileios Askoxylakis at Massachusetts General Hospital to explore the effectiveness of ultrasound that is focused on affected brain areas to buzz the drugs through these barriers and into the cancer.

Already, the method had proven effective enough in fighting tumors to make it to phase I clinical trials, but until now, it was not well observed how it actually worked. 

Beaming tumors

Arvanitis, also an assistant professor in the Wallace E. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and his collaborators sought to determine tissue-level mechanisms behind the new ultrasound treatment’s improved drug delivery throughout brain tumors. The findings will help researchers and clinicians fine-tune this potential treatment against cancers in the brain.

The team, which included researchers from the University of Edinburgh, and Brigham and Women’s Hospital, published its findings in the journal Proceedings of the National Academy of Sciences on August 27, 2018. The research was funded by the National Institutes of Health, the German Research Foundation, the Solidar-Immun Foundation, the Harvard Ludwig Cancer Center, and the National Foundation for Cancer Research. 

The therapy is minimally invasive, focusing multiple beams of ultrasound energy onto a cancerous spot, where microbubbles, tiny lipid bubbles in the bloodstream that vibrate in response to ultrasound signals, can temporarily breach the blood-brain barrier at the target site. That creates an opening for drugs to get through. The microbubbles are injected intravenously before ultrasound is applied.

Observing success

The team studied the new method on mice with metastasized breast cancer cells in the brain. In lab experiments, the researchers observed improved delivery of two cancer therapies, the common chemotherapy drug doxorubicin, and the targeted drug T-DM1.

“We established that we were able to get more of both drugs across blood vessel walls,” said Yutong Guo, a graduate student in Arvanitis’s lab and coauthor of the study. “The doxorubicin molecule is small, and it got the bigger boost, but altogether, the therapy distributed more of both drugs to more tumor tissue.”

Also, the fluid that surrounds cells, interstitial fluid, which can serve as a conduit for drugs, was seen flowing more freely between cells of a tumor in high-resolution images taken following ultrasound treatment. The drugs appeared to make it through significant barriers to reach tumors.

“Evidence of increased cellular transmembrane transport and uptake of doxorubicin by focused ultrasound was largely unknown until now,” Askoxylakis said.

The improved delivery dissipated five days after treatment, suggesting that the higher T-DM1 accumulation indeed had resulted from the ultrasound method better permeating blood vessels and tumor tissue.

Optimizing treatment

The researchers quantified the changes in tissues and in cellular drug transport properties using mathematical modeling and used this to devise parameters for optimal drug delivery, which may prove useful in the design of new rounds of clinical trials.

“By explaining and underscoring the potential of combining focused ultrasound with different drugs for the treatment of brain metastases, our findings provide important scientific principles for the optimal clinical use of the technology,” said Rakesh Jain, who collaborated on the study and is a professor of radiation oncology at Harvard Medical School.

The study may also stimulate a broader discussion on how some cancer drugs should be administered, perhaps in some cases as a slow infusion rather than a quicker injection. The researchers would like to explore tuning the new method to optimize delivery of varying drugs or engineered immune cells to fight an array of tumors occurring in the brain.

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Also READ: Punching Cancer with RNA Knuckles

These researchers co-authored the study: Meenal Datta, Jonas Kloepper, Gino Ferraro, and Dai Fukumura of Steele Labs, Mass Gen Radiation Oncology; Miguel Bernabeu of the University of Edinburgh; and Nathan McDannold of Brigham and Women’s Hospital. The research was funded by the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (grant R00 EB016971) and the National Heart, Blood, and Lung Institute (F31 HL126449), the German Research Foundation (grant AS 422-2/1) and grants from the Solidar-Immun Foundation, the Harvard Ludwig Cancer Center, and the National Foundation for Cancer Research. Findings, opinions, and conclusions are those of the authors and not necessarily of the funding agencies. 

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Media relations assistance: Ben Brumfield (404) 660-1408, ben.brumfield@comm.gatech.edu

Writer: Ben Brumfield

The NSF has awarded a team of researchers $1 million over three years to understand how networks of neurons work together to perceive the world and to generate the control signals needed to produce coordinated movement. Their project is titled “Discovering dynamics in massive-scale neural datasets using machine learning.”

The team includes Chethan Pandarinath, PhD, a researcher in the Petit Institute for Bioengineering and Bioscience and assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University; Lee Miller, PhD at Northwestern; and Matthew Kaufman, PhD at the University of Chicago.

Conventional neuroscientific experiments monitor the activity of just a small fraction of the neurons in any given brain area, and for just a few hours. Here the scientists anticipate being able to create massive datasets using new brain-interfacing technologies. In one set of studies, they aim to monitor much larger numbers of neurons -- up to 10,000 neurons at a time -- using two-photon imaging techniques. In another, the team will monitor for much longer time periods -- over the course of many weeks to months -- as animals go about normal, natural behaviors.

However, collecting the data is just half the challenge. Being able to analyze and interpret such massive datasets requires innovative new algorithms, which build on "deep learning"-based techniques recently developed in Pandarinath's lab. Analyzing the data will guide engineers in developing technologies that could help paralyzed people move their limbs, or improve the treatment of people with Parkinson’s and other diseases via deep brain stimulation, Pandarinath says.

“We anticipate that this project will provide windows into the brain's control of motor behavior that have never before been possible,” says Pandarinath, principal investigator of the Systems Neural Engineering Lab. “The framework developed here can be extended from motor behaviors to higher level problems of error processing, decision making, and learning.”

The award is one of 18 NSF-supported grants announced this week, which are part of the federal government’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative.

It’s the latest breakthrough in a saga that began several years ago in the Pathology Dynamics Lab that Mitchell runs as an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

“We work in the realm of predictive medicine, in which we use data to try and predict what we call the three big C’s – causes, cures, and care,” says Mitchell, a researcher in the Petit Institute for Bioengineering and Bioscience at Georgia Tech. “We wanted to research Alzheimer’s disease, so I asked my students to go into the published literature and examine the most prevalent data that was out there.”

She was shocked by what they ultimately came back with. Their findings showed a minor correlation between amyloid-beta and Alzheimer’s disease. Mitchell says she nearly panicked. “I thought we were going to have so many eggs thrown at us for going against the dogma in the field.”

So they followed that up with further data analysis of the cumulative evidence, which showed that plaque from amyloid-beta protein may be an accomplice, but the chief offender is another bad protein, phosphorylated tau (p-tau). Mitchell’s team published their study, funded by the National Institutes of Health (NIH), last November in the Journal of Alzheimer’s Disease.

“In that study we found out, with a more advanced mouse model this time, that amyloid-beta plaque has only a minimal impact in cognitive decline – it’s more like a side effect of the disease,” Mitchell says. “By the time the plaque forms, cognitive decline is already happening, so targeting the plaque happens too late in the disease process. In that same paper, we were able to show that p-tau, on the other hand, was more strongly tied to cognitive decline. So, long story short, you’re probably not going to have a solo target in Alzheimer’s.”

And that’s what led Mitchell to submitting an application with the Alzheimer’s Association International Research Grant Program for her research, entitled, “Quilting Disparate Data Patches to Elucidate Alzheimer’s Disease.”

“I figured, we’re data scientists, why don’t we just take in all of the data? Instead of just going after one target, we should rank all of the potential contributing factors and their different interactions,” Mitchell says.

The challenge is, rather than trying to mine data from mere hundreds or a few thousand Alzheimer’s research papers, this time the Mitchell team is sifting through a much bigger data set – the more than 130,000 Alzheimer’s papers in the National Library of Medicine’s PubMed database. Her lab is creating algorithms to sift through and aggregate the data, “like putting together a puzzle,” Mitchell says.

“This award is testament to the innovation and creativity in the project – the best of the best Alzheimer’s researchers apply for these grants, so we’re honored,” she adds. “The hope is that there will be spinoff projects and NIH R01 grants to follow. But there is a lot of work to be done. We can’t just throw standard data mining techniques at this. It’s going to take some ingenuity.”

Singer, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, received a R01 grant from the NIH for her a grant proposal entitled, “Non-Invasive Methods to Drive Neural Activity with Millisecond Precision and to Recruit the Brain’s Immune Cells,” which will draw almost $2 million over five years from the NIH.

“This is really gratifying and it validates the work we’re doing,” says Singer, a researcher in the Petit Institute for Bioengineering and Bioscience at Tech. “The NIH doesn’t take big risks, so it shows that they believe we can execute on this project, and the grant lasts long enough for us to really make some headway.”

Singer’s lab recently discovered that flickering sound or a combination of lights and sound at gamma frequency drives neural activity in the deep brain structures, while also rallying microglia (the main form of immune defense in the central nervous system) to engulf pathogenic proteins in mouse models of Alzheimer’s disease.

The goal of the group’s R01 project is to develop sensory flicker as a non-invasive sensory tool that will translate to humans and spur new research with wide-ranging impact and therapies for multiple neurological diseases.

“This is important because current stimulation methods are invasive and usually don’t reach deep brain structures,” Singer says. “There’s been some work in this area, but there aren’t a lot of options – they’re not very fast, they don’t have millisecond precision. This novel approach would spur new possible therapeutic approaches to Alzheimer’s and other neurological diseases and galvanize new basic science research with wide-ranging impact.”

Dyer, who is an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, was awarded through NSF’s CRII program – the Computer and Information Science and Engineering Research Initiative. Sometimes referred to as the “Mini CAREER Award,” the program encourages research independence early in a faculty member’s career.

The aim of her project, entitled “Using Large-Scale Neuroanatomy Datasets to Quantify the Mesoscale Architecture of the Brain,” is to develop new computational approaches for modeling the connectivity of the mouse brain, in order to reveal principles of wiring and information routing.

As Dyer explains, “Methods for revealing the global connections of the brain typically start by tracing a small number of neurons at a time. It is through performing many experiments, in different brain areas and across many brains, that information can be aggregated and consolidated to produce detailed maps of the brain’s global networks and architecture.”

Her project will leverage whole-brain imaging datasets from the Allen Institute for Brain Science. Each dataset provides a small piece of the puzzle. But, when combined, they can yield a picture of whole-brain connectivity.

“The outcomes of this research will be new maps of the global connectivity of the mouse brain, and a framework for studying the impact of disease and aging on whole-brain networks,” Dyer says.

Heaps of plaque formed from amyloid-beta that accumulate in afflicted brains are what stick out under the microscope in tissue samples from Alzheimer’s sufferers, and that eye-catching junk has long seemed an obvious culprit in the disease. But data analysis of the cumulative evidence doesn’t support giving so much attention to that usual suspect, according to a new study from the Georgia Institute of Technology.

Though the bad amyloid-beta protein does appear to be an accomplice in the disease, the study has pointed to a seemingly more likely red-handed offender, another protein-gone-bad called phosphorylated tau (p-tau). What’s more, the Georgia Tech data analysis of multiple studies done on mice also turned up signs that multiple biochemical actors work together in Alzheimer’s to tear down neurons, the cells that the brain uses to do its work.

Suspect line-up: P-tau implicated, plaque not so much

And the corrupted amyloid-beta that appeared more directly in cahoots with p-tau in the sabotage of brain function was not tied up in that plaque. In the line-up of the biochemical suspects examined, principal investigator Cassie Mitchell, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, said the data pointed to a pecking order of culpability.

“The most important one would be the level of phosphorylated tau present. It had the strongest connection with cognitive decline,” Mitchell said. “The correlation with amyloid plaque was there but very weak; not nearly as strong as the correlation between p-tau and cognitive decline.”

Mitchell, a biomedical informaticist, and first author Colin Huber statistically analyzed data gleaned from 51 existing lab studies in mice genetically augmented with a human form of Alzheimer’s. They published their analysis in the current edition of the Journal of Alzheimer’s Disease. The research was funded by the National Institutes of Health.

The crime: Eviscerating the brain

One look at an image of an Alzheimer’s afflicted brain is unflinching testimony to the disease’s cruelty: It destroys of up to 30 percent of a brain’s mass, carving out ravines and depositing piles of molecular junk, most visibly amyloid plaque.

The plaque builds up outside of neurons, while inside neurons, p-tau forms similar junk known as neurofibrillary tangles that many researchers believe push the cells to their demise. But many biochemical machinations behind Alzheimer’s are still unknown, and the fight to uncover them has vexed researchers for decades.

Since the first patient was diagnosed by Dr. Aloysius Alzheimer between 1901 and 1906, little medical progress has been made. Though some available medications may mitigate symptoms somewhat, none significantly slow disease progression, let alone stop it.

Alzheimer’s mostly strikes late in life. Longer lifespans in industrialized countries have ballooned the caseload, advancing the disease to a major cause of death.

Meet the syndicate: Assassin, accomplices, stooges

Even though p-tau showed the strongest correlation with cognitive decline, and amyloid-beta only a slight correlation, that doesn’t mean that p-tau is committing the crime inside cells all by itself while amyloid loiters in spaces outside of cells in large gangs, creating a distraction. Mitchell’s data analysis has pointed to dynamics more enmeshed than that.

“Though the study had clear trends, it also had a good bit of variance that would indicate multiple factors influencing outcomes,” Mitchell said. And a particular manifestation of amyloid-beta has piqued the researchers’ ire.

Little pieces are water soluble, that is, not tied up in clumps of plaque. The data has shown that these tiny amyloids may be up to no good. After p-tau levels, the study revealed that those of soluble amyloid-beta had the second-strongest correlation with cognitive decline.

“Lumpy amyloid-beta, the stuff we see, ironically doesn’t correlate as well with cognitive decline as the soluble amyloid,” Mitchell said. “The amyloid you don’t see is like the sugar in your tea that dissolves and hits your taste buds versus the insoluble amyloid, which is more like the sugar that doesn’t dissolve and stays at the bottom of the cup.”

Some Alzheimer’s researchers have cited evidence indicating that free-floating amyloid helps produce the corrupted p-tau via a chain of reactions that centers around GSK3 (Glycogen synthase kinase 3), an enzyme that arms tau with phosphorous, turning it into a potential biochemical assassin.

Incidentally, Mitchell’s study also looked at un-phosphorylated tau and found its levels do not correlate with cognitive decline. “That makes sense,” Mitchell said. “Regular tau is the backbone of our neurons, so it has to be there.”

Also, p-tau is a normal part of healthy cells, but in Alzheimer’s it is wildly overproduced.

Massive dataset: 528 mice rat out p-tau

One advantage of data mining 51 existing studies versus doing one new lab experiment, is that the cumulative analysis adds the sample sizes of so many studies together for a whopping grand total. Mitchell’s analysis encompassed results from past experiments carried out on, all totaled, 528 Alzheimer’s mice.

A previous study Mitchell led had already indicated that amyloid-beta plaque levels may not be the most productive target for drug development. Separate reports by other researchers on failed human trials of drugs that fought plaque would seem to corroborate this.

Mitchell’s prior analysis examined lab studies that used an Alzheimer’s lab mouse model that did not allow for the study of p-tau. Mitchell’s current analysis covered studies involving a different mouse model that did allow for the observation of p-tau.

Mitchell’s latest findings have corroborated the prior study’s findings on amyloid, and also added p-tau as a key suspect in cognitive decline.

Principal investigator: My take on possible treatments

To arrive at the 51 studies with data suitable for inclusion in their analysis, Mitchell’s research team sifted through hundreds of Alzheimer’s research papers, and over time, Mitchell has examined a few thousand herself. She has gained some impressions of how biomedical research may need to tackle the disease’s slippery biochemical labyrinth.

“When we see multifactorial diseases, we tend to think we’ll need multifactorial treatments,” Mitchell said. “That seems to be working well with cancer, where they combine chemotherapy with things like immunotherapy.”

Also, Alzheimer’s diagnosticians might be wise to their adopt cancer colleagues’ early detection stance, she said, as Alzheimer’s disease appears to start long before amyloid-beta plaque appears and cognitive decline sets in.

Above all, basic research should cast a broader net.

“I think p-tau is going to have to be a big part,” she said. “And it may be time to not latch onto amyloid-beta plaque so much like the field has for a few decades.”

Did you know? Cassie Mitchell is also an Olympic medalist! Watch her video here.

Also READ: Our feature on Alzheimer’s research – Killing the Mind First

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Georgia Tech’s Connor Yee, Taylor May, and Apoorva Dhanala coauthored the study. Funding was provided by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (grants NS069616, NS098228, and NS081426). Any findings or conclusions are those of the authors and not necessarily of the sponsor.

The fellowships, awarded by the Alfred P. Sloan Foundation since 1955, honor early-career scholars who, “represent the very best science has to offer,” says Sloan President Adam Falk. “The brightest minds, tackling the hardest problems, and succeeding brilliantly—Fellows are quite literally the future of twenty-first century science.”

He is one of three Georgia Tech researchers so honored. The others are Vinayak Agarwal, assistant professor in the School of Chemistry, and Lutz Warnke, assistant professor in the School of Mathematics.

Haider’s research goal is to identify cellular and circuit mechanisms that modulate neural responsiveness in the cerebral cortex, using a variety of advanced electrical and optical techniques to record, stimulate, and the interpret the activity of specific neuronal sub-types.

But the two-year, $65,000 Sloan award doesn’t support a specific research project effort, according to Haider. It supports the individual.

“It’s very exciting because it’s different from a traditional kind of grant. This is more about the research direction you have envisioned as a young investigator,” says Haider, who is a researcher in the Petit Institute for Bioengineering and Bioscience. “This is about funding the person. It’s a real vote of confidence.”

Available to tenure track faculty in eight scientific fields, the Fellowships are awarded at a key moment in a researcher’s career. Past Sloan Research Fellows include towering figures in the history of science, including physicists Richard Feynman and Murray Gell-Mann, and game theorist John Nash. Forty-five fellows have received a Nobel Prize in their respective field, 16 have won the Fields Medal in mathematics, 69 have received the National Medal of Science, and 17 have won the John Bates Clark Medal in economics, including every winner since 2007.

Drawn this year from 53 colleges and universities in the U.S. and Canada, the 2018 Sloan Research Fellows represent a diverse array of institutions and backgrounds. This year’s Fellows include:

• A molecular biologist who studies how birds perceive color;
• A chemist who has developed molecular “printing” techniques that can make flexible solar cells that are twice as efficient as current models;
• A computer scientist who is constructing robots for the home that users can program themselves;
• An environmental economist who is exposing the hidden costs of pollution;
• A mathematician who is trying to explain the remarkable success of neural networks in performing complicated tasks like recognizing faces;
• A neuroscientist whose work is revealing that best friends don’t just think alike; they have similar brains;
• An ocean scientist that has shown how warming currents are leading many marine species to breed early, bringing them out of sync with the plankton blooms on which they feed;
• A physicist who says the structure of the outer solar system makes sense only if there is an undiscovered ninth planet.

Open to scholars in eight scientific and technical fields—chemistry, computer science, economics, mathematics, computational and evolutionary molecular biology, neuroscience, ocean sciences, and physics—the Sloan Research Fellowships are awarded in close coordination with the scientific community. Candidates must be nominated by their fellow scientists and winning fellows are selected by an independent panel of senior scholars in their field on the basis of a candidate’s research accomplishments, creativity, and potential to become a leader in his or her field.

Additional 2018 Winners at Georgia Tech: Agarwal, Warnke Named 2018 Sloan Research Fellows

###

The Alfred P. Sloan Foundation is a philanthropic, not-for-profit grant making institution based in New York City. Established in 1934 by Alfred Pritchard Sloan Jr., then-President and Chief Executive Officer of the General Motors Corporation, the Foundation makes grants in support of original research and education in science, technology, engineering, mathematics, and economics.

The grant is also a collaboration with professor Stuart Factor, director of the Movement Disorders Clinic at the Emory Brain Health Center, Madeleine Hackney, a research health scientist in the Atlanta VA and the Department of Medicine at Emory, and Erin Buckley and Lucas McKay, both assistant professors in Coulter Department of Biomedical Engineering.

Ting’s research will use combined experimental and computational approaches to systematically isolate the causal linkages and interactions between muscle rigidity, muscle activity, and balance ability in Parkinson’s disease. Her goals are to identify the causal role of rigidity on impaired balance in PD, to validate novel optically-based and clinically-feasible methods to measure muscle rigidity during standing, and to establish a computational model of neuromechanical balance to simulate how multiple mechanisms interact to cause balance impairments. This research will facilitate the identification of treatment targets for the rational development of rehabilitation and other therapies for balance impairments across a variety of neurological movement disorders.

“It was surprising to me that the effects of muscle rigidity on balance is so poorly understood,” said Ting. “People with Parkinson’s disease have both muscle rigidity and postural instability, yet the effects of muscle rigidity have not been considered as contributing to balance impairments. One reason is that we can’t yet measure low levels of muscle activity reliably, nor predict how it would alter movement. In our research, we will address both of these problems.”

The Neuromechanics Lab based at Emory and directed by Ting, uses a broad range of techniques from neuroscience, biomechanics, rehabilitation, robotics, and physiology to discover new principles of human movement. Her lab’s basic science findings have facilitated advances in understanding movement disorders and in identifying mechanisms of rehabilitation. In 2016, The American Institute for Medical and Biological Engineering (AIMBE) inducted Ting into its College of Fellows. The College of Fellows is comprised of the top two percent of medical and biological engineers in the country.

Media Contacts:

Walter Rich

Communications Manager

Wallace H. Coulter Department of Biomedical Engineering

at Georgia Tech and Emory

The research road ahead feels endless, many neuroscientists say, and comprehending how the brain generates the human psyche may be decades beyond the horizon. But neuroscience is in a forward lunge powered by sweeping national funding programs such as the BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies), which is tapping into the brain to understand it and support well-being.

You can find the Research Horizons feature story here.

“I’m very honored by it,” Nichols says. “It’s unusual because you have to be a physical therapist to be a regular member. I am not a physical therapist, I’m a basic scientist.”  

Nichols' research areas of interest include motor control, sensory feedback, spinal cord injury, muscle physiology, and limb mechanics. In addition to his research in the School of Biological Sciences, Nichols is also a professor in the Wallace H. Coulter Department of Biomedical Engineering, a partnership between Georgia Tech’s College of Engineering and Emory School of Medicine.

Nichols was chair of the School of Applied Physiology until 2016, when it joined the School of Biology to form the School of Biological Sciences.  

APTA cites Nichols as “an internationally recognized scholar whose research has contributed to the advancement of scientific knowledge related to the control of movement.” APTA also calls Nichols a “stalwart advisor” who has done exemplary work to help train future physical therapists and advanced physical therapist clinicians.

APTA’s approximately 95,000 members include physical therapists, their assistants, and those who are studying to become therapists. The organization represents their interests in the legislative and regulatory arenas. 

Since the new degree program was approved by the Board of Regents on Valentine’s Day 2017, nearly 200 students clamored to sign on.

This enthusiastic response was surprising — but then again, not, says Tim Cope, chair of the Undergraduate Neuroscience Curriculum Committee and professor in the School of Biological Sciences and the Wallace H. Coulter Department of Biomedical Engineering.

“Hardly a day goes by that there’s not something in the news — a health concern or a recent breakthrough or societal challenge — that doesn’t involve neuroscience,” he says. “It’s a growing field with so many opportunities, and it’s inspired a lot of interest from our students.”

One of them is Yeseul Heo.

“I got really excited when I learned about the new major,” the rising second-year student says. “I think I was one of the first to turn in my paper to switch.”

Heo’s original major was psychology — and she is keeping that as a minor, along with a double major in international affairs — but she sees neuroscience as a way to put her studies on a more quantitative footing.

“Along with psychology, I wanted to focus more on hard research, specifically on brain activity, and working with quantitative data,” she says.

Heo has gotten a taste of neuroscience already as a student assistant in the lab of Associate Professor of Psychology Eric Schumacher, whose research uses functional magnetic resonance imaging (fMRI) and other experimental techniques to investigate the neural mechanisms for vision, attention, memory, learning, and cognitive control.

A Research Community

Schumacher is one of more than 50 faculty members from disciplines across Georgia Tech who are involved in neuroscience research — and have been for years. But however collaborative, widespread, and even world-renowned these neuroscience efforts have been, what they have lacked, Cope suggests, is “community.”

He and many others anticipate this new undergraduate degree will build that necessary component, for both faculty and students. “It’s a very important, symbolic event in the development of neuroscience on this campus,” he says.

Neuroscience is “the perfect incarnation of an interdisciplinary subject,” says College of Sciences Dean and Sutherland Chair Paul M. Goldbart. 

“It’s also a subject of deep intellectual interest. Who couldn't be curious about how the brain and nervous systems work at the most basic level?”

Goldbart “couldn’t be more excited” about the new degree, because “It opens up a marvelous new channel to a wide variety of career paths and will make Georgia Tech even more appealing to prospective undergraduates in the sciences.”

“I am grateful to everyone who worked so hard to create a program that defines 21^st-century neuroscience education for a 21^st-century technological research university.” 

NeuroX Factor

Getting from neuroscience activity to neuroscience community at Georgia Tech has been something of a journey, starting with the formation of a “NeuroX” committee back in 2014 and ending with Board of Regents approval for the new undergraduate degree in February 2017.

To reach this place, certain boxes had to be checked. It was not enough that faculty were engaged in neuroscience and students wanted it, although that was clearly the case.

Every time the Institute offered a neuroscience course, it maxed out, and professors were constantly asked if there would be more courses, or if they could open up another section.

Still, Cope points out, “It’s a legitimate thing for the administration to think about these things exceedingly carefully. No university can be everything — there’s a limit to resources and we have to be strategic with our planning.”

Basically, the key questions were: Is there a demand for this major from employers? Is there a demand for this degree from students? How would a neuroscience degree program advance Georgia Tech’s strategic plan? And would the program be redundant within the University System of Georgia?

This last question sent Cope over to Georgia State University — the only other USG school with an undergraduate neuroscience degree — to meet with the leadership of their Neuroscience Institute.

“I said, ‘Here’s what we’re planning to do,’” Cope recalls.

“They said, ‘Oh, this is fantastic, with Georgia Tech’s traditions and resources, you bring something unique to the table,’ and they wrote a letter for me right on the spot — they endorsed our plan 100 percent.”

'Kind of Pulsing'

While every neuroscience program has its “multiplication tables,” as Cope terms them — certain facts every neuroscientist has to know — the bigger challenge is, where do students take it from there?

Heo eventually wants to take her neuroscience focus into the study of first impressions. “You develop this first impression within two seconds in your brain, and you don’t control that, ever,” she says.

“So, I want to figure what’s the reason behind it, and if we learn the reason, is there a way to, not eliminate it, but maybe try to understand each other better, avoid racism and discrimination, and bring about more peace.”

As a neuroscience undergraduate, Heo will learn what Cope calls “the three flavors of neuroscience” — cell and molecular, behavioral, and systems.

Beyond these basics, Heo can branch out into one of 10 different specializations — biochemistry, biology, chemistry, computer science, engineering, health and medical, physics, physiology, or psychology.

In her case, completing the psychology specialization will qualify her for a minor in that field.

Students are coming into the program from disciplines all over campus, and all these areas can and do intersect with neuroscience, notes Cope. “To have a degree in neuroscience means you have to be conversant in wide-ranging concepts,” he says.

“In my mind’s eye, I have the sense of neuroscience kind of pulsing — it borrows concepts and technologies from all the fields, but it doesn’t only take, it gives back.”

The undergraduate neuroscience degree will — as with all Georgia Tech disciplines — culminate in a senior research or capstone project.

“We want to leave our students with an experience that really gets their creative juices going and gives them a tantalizing view of what they might do next,” Cope says.

The program website lists 50 occupations for which neuroscience can serve as preparation or grad school foundation, and then, of course, there’s entrepreneurship.

Among the many other student startup and business incubators in and around Georgia Tech, there’s even one called NeuroLaunch, which introduces itself as “the world’s first neuroscience startup accelerator.”

Proving It

Georgia Tech’s Bachelor of Science in Neuroscience launched this fall.

As the community builds and the degree program gains visibility, Cope expects Georgia Tech to carve its niche among neuroscience programs as only Georgia Tech can.

“We’re especially mindful of active learning here, of inquiry-based education, where the students are led to discovery, not just have the discovery dumped in their laps,” he says.

“What we’d like to bring to neuroscience is the strong analytical, deep understanding of concepts and methods that Tech brings to its curriculum in all fields.”

Down the road, Cope sees the undergraduate degree program leading to more and bigger grants for neuroscience research at Tech, and ultimately a Ph.D. program.

In the meantime, he says, there’s much to learn and do, quoting a fortune cookie slip he’s kept in his wallet for more than 25 years now: “It says, ‘You are respectable, you are intelligent, you are creative — prove it.’

I think that applies here. We’ve got a lot of what we need to do some really great things in neuroscience. Now we’ve got to prove it.”

Neuroscience Research in the College of Sciences

Neuroscience is “the perfect incarnation of an interdisciplinary subject,” says College of Sciences Dean and Sutherland Chair Paul M. Goldbart. “It’s also a subject of deep intellectual interest. Who couldn’t be curious about how the brain and nervous systems work at the most basic level?”

Neuroscience majors interested in research have a broad array of options. Researchers at Tech seek to understand the mechanics of brain function and the emergence of normal, aberrant, or developmental behavior from the components of the nervous system at multiple scales of complexity.

The details of every faculty member’s research are diverse, but they all aim to address one or more of the following overarching questions:

1. How does the brain perceive the world, learn new information, express emotions, and produce behaviors?
2. How does the nervous system cooperate with the body it lives in?
3. How does the brain compute responses and commands?
4. How do behaviors emerge from molecules, cells, and systems?
5. How can genetic and environmental factors impact neural functions?

Here are examples of research led by College of Sciences faculty members.

The Reorganization Problem of Neurons: Addressing the neurotoxicity of chemotherapy

By A. Maureen Rouhi

Even as a child, Tim Cope was fascinated by how physically disabled people move. Why can’t they move normally? That fascination led to scientific curiosity about why it can be so difficult to recover normal movement after disease or damage.

One path of inquiry Cope has pursued is the organization of sensory signals to the spinal cord. Over more than two decades of research, he and others have shown that sensory signals can be restored to normal when damaged sensory nerves regenerate and reconnect with muscle; however, their connections in the central nervous system reorganize.  

Central reorganization changes the flow of sensory information, so some neurons completely lose sensory signals, while others receive twice as much input. Thus, regeneration is not synonymous to recovery, says Cope, a professor in the School of Biological Sciences and in the Wallace H. Coulter Department of Biomedical Engineering and member of the Parker H. Petit Institute for Bioengineering and Bioscience (IBB).

Another condition that may cause peripheral nerve damage, and subsequent reorganization is chemotherapy. “We have peripheral nerve regeneration after chemo, but we don’t regain normal function,” Cope says. “Maybe it’s this reorganization problem again.”

To explore this possibility, researchers in Cope’s lab recorded sensory signals of rats after chemotherapy. In this case, the sensory signal itself showed long-lasting abnormality. However, they also found that even when nerves are not structurally damaged by chemotherapy, the sensory signal remains atypical.

These puzzling findings led to the discovery that chemotherapy affects cellular mechanisms responsible for translating mechanical stimuli — for example, muscle stretch — into sensory signals. As with peripheral nerve trauma, sensory information changes, but for a very different reason. 

Cope relishes this unexpected turn of the research. “Our chemo studies led us to a way of restoring the signals to normal, and I think our findings may have some translation to humans,” he says. “We believe if we can fix the signal, then we can improve the daily movement activity in patients who otherwise might experience disability long after chemotherapy is discontinued.”

Fixing the signal means restoring the damaged proteins, or just bypassing them. Cope’s team has identified a drug to do the latter. “But a better solution is to find out exactly what protein is damaged and restore it through genetic therapy or other molecular techniques.”

Next, Cope hopes to do genetic screening to try to get a comprehensive list of the proteins damaged by chemotherapeutic neurotoxicity, particularly those involved in generating sensory signals. This work would be in collaboration with John McDonald, a cancer expert, professor in the School of Biological Sciences and member of IBB.

Meanwhile, other work goes on in the Cope lab. “If you’re interested in how we generate movement and how sensory information is required to generate that movement, and what goes wrong in various disease and damage situations, then whether you’re a chemist, an engineer, or interested in behavioral science, there is an entry level for you in my lab to study those things,” he says.

Memory, Emotion, and Aging: Exploring “memory clutter” and the neuroscience of human cognition

By Renay San Miguel

Forget where you parked your car? Misplaced your keys? Can’t remember what a restaurant dinner companion just said to you? All signs of early-onset dementia, right?

Not quite, says Audrey Duarte, associate professor in the School of Psychology and principal investigator in Georgia Tech’s Memory and Aging Lab. “There are memory changes we think of as being associated with dementia, and that’s very concerning, but that’s not really what we’re talking about,” Duarte says. “Just by getting older, we experience more memory impairment.”

Take that restaurant dinner, for example. When you’re younger, people coming in and out of the dining room, nearby conversations, and any other distractions are easier to tune out. “As we get older and we have that impaired ability to ignore distracting information, it gets incorporated into our memories,” Duarte says. “That information is there even at the subconscious level, and that creates what we call memory clutter.”

That clutter gums up the brain and forces older adults to work harder than before to recreate that restaurant experience in their minds in the hopes of remembering information.

Duarte’s 2016 study on memory clutter is the latest example of her focus on human cognition. How does the brain process new information, and how is that tied to emotions and behaviors?

“I’m a memory person, so I always think memory is the most important thing,” she says. The information we take into our brains has to be processed by our sensory systems — what we see, hear, etc. — and then filtered through our past experiences. “Those memories have emotional associations with them, some positive, some negative. If it comes down to why a particular emotion is stronger than others, we don’t really understand why the brain is organized that way.”

Duarte’s research involves exploring which areas of the brain are necessary for emotional processing. She and her team in the Memory and Aging Lab use electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to determine which parts of the brain make those connections between memory and emotion.

It’s known that the amygdala, located within the brain’s medial temporal lobes, is associated with processing emotions. Duarte says her research shows that “if you see something that’s negative, the amygdala is sensitive to that.” But she emphasizes that other brain regions also seem to process stimuli associated with bad emotions such as disgust, sadness, anger, etc.

Duarte is determined to discover how disease, injury and aging effect all aspects of human cognition. She believes the future of her field will bring an interdisciplinary focus, folding in computational modeling, biology, genetics and biomedical engineering.

The research tools she’s using now are noninvasive. “We’re not implanting electrodes in people.” But to get a complete picture of neural communications — how that supports human cognition and what happens when that communication breaks down — “we’re going to have to drill down to the neuron level itself.”

Protective Responses: Neurons linked to itch and bronchoconstriction

By A. Maureen Rouhi

Itch. Just seeing the word makes you feel itchy. The sensation that makes you want to scratch your skin does the same to other mammals, amphibians, reptiles and birds. “Itch sensation is an evolutionarily conserved way used by many animals to sense environmental irritations and respond accordingly,” says Liang Han, an assistant professor in the School of Biological Sciences. 

Han’s laboratory strives to understand how the nervous system receives, transmits, and interprets stimuli to induce responses. In particular, she is interested in the mechanisms of nocifensive — or protective — responses. She wants to know how alterations in neural pathways that mediate these responses lead to chronic disease. For now, she’s focusing on two protective responses: itch and constriction of the lungs’ airways, or bronchoconstriction.

“Everyone experiences itchy feelings — when they get a mosquito bite or are wearing a prickly wool sweater.” Han says. In these cases, the itch is relieved by scratching. But imagine if the itchiness goes on and on!

“Chronic itch accompanying disease can be devastating,” Han says. More than 40 percent of patients receiving dialysis for end-stage renal disease suffer from severe itching, as do 60 to 70 percent of patients with advanced liver disease, according to Han. Persistent itching can lead to sleep deprivation and depression. Despite the clinical importance of itch sensation, Han says, the mechanisms governing it are largely unknown.

A long-standing question is whether itch-sensing neurons are itch specific or also signal other sensations such as pain. In earlier work using molecular genetic approaches, Han discovered a subpopulation of sensory neurons specifically linked to itch sensation. When those neurons are removed from experimental mice, the animals do not sense itch from multiple stimuli, but they continue to sense pain or pressure. Conversely, when these neurons are activated by painful stimuli, they elicit itch, not pain. “The data demonstrate the existence of the dedicated itch-sensing neurons,” Han says, “and advances our understanding of the cellular mechanisms of itch sensation.”

Now at Georgia Tech, Han aims to discover the mechanisms of chronic itch and find therapeutic targets for treatment, while also advancing understanding of bronchoconstriction.

The lungs’ sensory nerves help regulate the respiratory system, for example, by controlling breathing patterns and evoking airway-protective behavior such as coughing, airway constriction, and mucus secretion. Han’s lab recently discovered a subpopulation of sensory neurons that, when stimulated, induce bronchoconstriction and airway hyperresponsiveness, both of which are hallmarks of asthma.

“Current investigations of the pathogenesis of asthma have largely focused on immune responses,” Han says. “However, anti-inflammatory treatment only partially controls asthma symptoms. We need to understand the involvement of non-immune systems in the disease.”

Recent studies, including Han’s, indicate an important role for the nervous system in the pathogenesis of asthma. “We are currently using molecular genetic tools to investigate whether blocking those neurons can inhibit asthma in a mouse model,” she says. “We hope to obtain insights into the neural mechanisms of asthma and identify neuronal targets for management of asthma symptoms.”

Muscle-Neuron Connections: Maintaining contact as aging occurs

By A. Maureen Rouhi

Young C. Jang aspires to understand the aging process, particularly as it relates to muscle loss. An assistant professor in the School of Biological Sciences and the Wallace H. Coulter Department of Biomedical Engineering, and member of the Parker H. Petit Institute for Bioengineering and Bioscience, Jang hopes that therapeutic interventions could be developed to treat muscle loss, whether from aging or disease.

In considering scientific questions, Jang’s approach is to look at the forest. “You can be interested in muscle,” he says, “but you can’t just work on muscle to understand the whole biological process.”

Motor neurons connect muscles to the nervous system; however, the muscle-neuron connection can be severed by injury or disease. When the muscle is restored to function, the junction can be reconnected.

With age, the reconnection between muscle and neuron becomes increasingly difficult. When contact disappears, Jang explains, “muscles cannot communicate with the spinal cord and brain, and they start to degenerate.” Jang studies how to keep these connections going in hopes of developing ways to prevent or treat muscle loss. 

Aging and disease have some common pathways, Jang says. One is oxidative stress. When the body has an excess of reactive, oxidizable species, aging occurs faster than usual.

Jang’s work has shown that oxidative stress contributes to disconnection of the muscle-neuron junction. Oxidative stress is a well-accepted theory of aging, Jang says. It posits that when the body’s balance of antioxidant enzyme and oxidizing free radicals tilts in favor of free radicals, aging accelerates.

Jang’s early work showed that, in mice, removing the antioxidant enzyme — which increases reactive oxygen species — promotes severance of the muscle-neuron junction. In humans, Jang notes, genetic mutation of the same enzyme leads to amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, a motor neuron disease.

“We’ve found one mechanism that promotes detachment,” Jang says. “Can we reverse the process or slow it down?” Looking for ways to halt or reverse muscle-neuron detachment has taken Jang to multiple paths of inquiry, including caloric restriction, parabiosis, and organs-on-a-chip.

Jang’s caloric restriction research showed that mice receiving only 60 percent of the normal caloric requirement form fewer reactive oxygen species, and the treatment promotes muscle-neuron attachment. Furthermore, caloric restriction rejuvenates muscle stem cells, which help restore the function of muscles degenerated by aging or disease. With aging, these stem cells’ number and viability diminish, thus making muscle more prone to damage, a trend that slows with caloric restriction. 

In physiological research, parabiosis is the physical joining of two individuals. Jang turned to this approach because blood is a way for cells, tissues, and organs to communicate. When Jang joined a young mouse to an old one so that they share the same circulating blood, he found that the muscle-neuron junction in the old animal is rejuvenated. However, “if you put two old animals together, that junction detaches,” Jang says. “Something in young blood is helping preserve the muscle-neuron junction.”

Indeed, Jang has reported a circulating protein in the blood that seems to be an important factor in connecting the muscle-neuron junction. However, this protein “is not the only one,” Jang says. “We need more research.”

Meanwhile, how could parabiosis be applied to humans? “Obviously, we can’t put two humans together,” Jang says. But it is possible to faithfully mimic parabiosis of organs on microfluidic chips. Jang is collaborating with YongTae (Tony) Kim, an assistant professor in the George W. Woodruff School of Mechanical Engineering, to design organ-on-a-chip systems for parabiosis of human organs.

Sensory Input, Neural Networks, and Locomotion: Creating a new rehabilitation paradigm

By A. Maureen Rouhi

So you think walking across a room is easy, peasy? Think again.

“Walking across the room is one of the most complicated things we do,” says T. Richard Nichols, a professor in the School of Biological Sciences and the Wallace H. Coulter Department of Biomedical Engineering and a member of the Parker H. Petit Institute for Bioengineering and Bioscience. Locomotion is complex, he says, the result of networks of nerve cells communicating, processing information, and integrating myriad sensory signals.

In studying how sensory information from muscles helps regulate movement, Nichols has focused on the Golgi tendon organs (GTOs). These sensory receptors in the muscle tell the central nervous system — which consists of the brain and the spinal cord — the amount of force generated by muscles. The spinal cord then distributes the information to different muscles in the limb. The feedback of muscular forces is thought to help determine how the body responds to obstacles or unexpected circumstances.

So far, what we know about GTOs comes from research on animal subjects. Injury to the spinal cord disrupts communication between the central nervous system and the muscles and causes malfunctioning of the spinal cord’s neural circuits, Nichols says. “Muscle weakness or paralysis can result, as well as loss of balance and stability.”

Working with Dena Howland at the University of Louisville, Nichols has discovered a link between the disruption of the force-regulating system and motor disorders from partial spinal cord injury in animal models. They recently started two projects based on the GTO research.

One project, funded by the National Institutes of Health (NIH), aims to discover how the brain stem controls the GTO-generated neural circuits in the spinal cord to meet the needs of different movement tasks. The other project, funded by the Department of Veterans Affairs, will help define the extent to which malfunction in the force-regulating system contributes to motor dysfunction in partial spinal cord injury. It will also test the efficacy of a potential new treatment for spinal cord injury in humans that would not require special equipment.

The potential new treatment is based on the force-regulating neural networks of cats walking up — or down — hill. Researchers in the Nichols lab have shown that these networks are organized for propulsion when cats walk uphill and for suspension and braking when cats walk downhill.

“It turns out that in spinal cord injury, the downhill pathway becomes extreme” Nichols says. “Animals with spinal cord injury tend to crouch; it’s like an exaggeration of walking downhill.”

Suppose animals with spinal cord injury are rehabilitated by exercising under downhill-walking conditions? The idea is counterintuitive but, Nichols thought, “maybe the central nervous system has some internal wisdom that will say, okay, now we need to repair this injury.” Could training in this particular way promote recovery from partial spinal cord injury?

Nichols and Howland proposed this rehabilitation treatment to Veterans Affairs and received funding. “At the same time, because of our work at Tech, we can find whether the same exercise causes a change in the neural networks of the spinal cord,” Nichols says. Through the NIH grant funding, Howland and Nichols aim to mechanistically connect the recovery with restoration of normal function in the spinal network.

Biomechanics of Locomotion: Toward next-generation artificial limbs

By A. Maureen Rouhi

Research in the lab of Boris I. Prilutsky aims to understand the biomechanics and control of locomotion, which comprises the movements that take two- and four-footed animals from place to place.

During locomotion, sensations from the limbs (called sensory feedback) inform the nervous system about the state of the movement. Prilutsky studies how this sensory feedback affects locomotion. In particular, he investigates feedback from foot pressure and limb motion.

Disrupting the feedback, through injury for example, can lead to instability and falls during locomotion. “We modify sensory pathways in experimental animals and in computational models and observe the effects on locomotion,” says Prilutsky, a professor in the School of Biological Sciences and a member of the Parker H. Petit Institute for Bioengineering and Bioscience.

A key research tool is a neuromechanical model the Prilutsky group developed in collaboration with the group of Ilya A. Rybak, at Drexel University. This model accurately reproduces the walking mechanics and muscle activity of cats. Computational experiments have pinpointed the sensory feedback pathways that produce mild and severe locomotion defects when interrupted. These predictions have been experimentally tested.

In a recent study, for example, Prilutsky’s team injected local anesthetic to the paw pads on one side of a cat to block the sense of touch. Under this condition, the animal loses the symmetry of its gait and becomes less stable. The effect can be reversed, however, by electrically stimulating the nerves that convey the sense of touch to the central nervous system. When that happens, the cat’s walk becomes symmetric and stable again.  

In other experiments, they removed muscle stretch feedback – or stretch reflex – from selected muscles and investigated the effects. “We found that this feedback is task- and muscle-dependent,” Prilutsky says. For example, loss of feedback from certain muscles of the ankle causes problems only in downslope walking. More recently, they found that removing the stretch reflex from hip flexors causes profound changes in locomotion, as predicted and explained by their computational model.

“From our experimental and computational studies, we gain insight into how spinal circuits cooperate with the moving body segments during locomotion,” Prilutsky says.

Those insights are now propelling Prilutsky and others toward prosthetic devices that behave like natural limbs. For example, Prilutsky is applying discoveries about sensory pathways, feedback loops, and natural control signals from the nervous system in the field of osseointegrated — or bone-anchored — limb prostheses. In this approach to attaching prosthetic devices, the artificial limb is directly anchored to the bone through a titanium rod, similar to a dental implant. Potentially this implant can be used as a neural interface between the prosthesis and nerves in the stump.

Although used in Europe, bone-anchored limb prostheses are not approved in the U.S. because of the high rate of skin infections, which develop when skin fails to form a close connection with the bone implant. However, Prilutsky and others have shown that, in rats, use of porous titanium allows skin to grow into the implant, thereby reducing infections. Recently they experimented with cats to test this implant in natural walking conditions to see whether it forms a tight bond with skin and bone and whether and how the animals use a bone-anchored prosthesis for walking. “It works,” Prilutsky says.

Now the stage is set for the next phase: using the implant as a neural interface between the prosthetic device and the nerves in the residual limb so that the nerves and prosthesis talk to each other, and the prosthesis is controlled naturally without the person’s attention. If the promise of this approach is fulfilled, it could revolutionize prosthetics.

Moving in a Complex World: How do insects do it?

By A. Maureen Rouhi

How do animals navigate their environments? That question motivates the research of Simon Sponberg. An assistant professor in the School of Physics with a joint appointment in the School of Biological Sciences, Sponberg studies animals to discover how they move around in a complex world.

“Perceiving and then navigating the irregular terrain of Earth requires sophisticated processing by the brain,” says Sponberg, who received a National Science Foundation Early-Career Award in 2016 in recognition of his promise as a teacher-scholar and is a member of the Parker H. Petit Institute for Bioengineering and Bioscience. “It also demands that the brain work in conjunction with an animal’s body and the environment surrounding it.”

Animals have evolved to negotiate almost every environment on this planet. To do this, Sponberg says, their nervous systems acquire, process, and act upon information. “Yet their brains must operate through the mechanics of the body’s sensors and actuators to both perceive and act upon the environment,” he adds.

In Sponberg’s lab, researchers are studying how muscles operate as soft, living matter. They’re trying to understand the physics of moving animal bodies and the computational principles implemented in the sensors — such as eyes or antennae — of animals in motion.

“Our research investigates how physics and physiology enable animals in motion to achieve the remarkable stability and maneuverability we see in biological systems,” Sponberg says. “We explore how animals fly and run stably even in the face of repeated perturbations, how the multifunctionality of muscles arises from their physiological properties, and how the tiny brains of insects organize and execute movement. We study how the grace and agility of animal movement arises from the synthesis of its parts. Among these is the brain — a crucial part, but not the only one.”

The hawkmoth is a frequent subject of Sponberg’s investigations. The swift-flying insect typically imbibes nectar while hovering over a flower. Feeding usually takes place at dusk, when light is limited. It’s hard enough to see in dim light and even more when it gets dimmer with time. Yet hawkmoths also hover in air while following a flower that’s swaying with the wind. How do they do it?

Sponberg’s group has shown that hawkmoths slow their brain down to improve vision in dim light, much like increasing the exposure on a camera.  However, this adjustment can cause their motion to blur, so they only slow down to the point where they can still track the wind-blown motions of the flowers they prefer in nature. The behavior demonstrates that their neural circuits adapt exquisitely to the environment.

More recent work on three hawkmoth species tracking the group’s “roboflowers” suggests that simple models of neuronal processing can account for interspecies differences in adapting to different light intensities, and the moths actually use touch sensors on their proboscis to help feel the flower’s movements.

“Behavior, especially movement, arises from the context in which the brain acts,” Sponberg says. “We start by asking questions like, “If we know something about the biophysics of how muscles works, how might the brain activate and control muscle to enable an animal to be most agile and versatile?

“What we are finding is that how brains process sensory input and program motor output is intimately coupled to the physics of the surrounding systems and the features of the environment the animal most cares about. Figuring out these coupling principles is a huge task but one that we are confident will help us better understand how we think and act.”

Intent and Action: Unpacking a little-understood aspect of skilled movement

By A. Maureen Rouhi

Lewis A. Wheaton wishes to play golf like a pro. He could raise his game by watching videos of star players like Rory McIlroy. But Wheaton knows from experience — and his research — that observation alone doesn’t always help motor learning.

Research in Wheaton’s lab is explaining why observing people who are highly skilled at motor tasks may not be helpful to those who are far less proficient. Wheaton is interested in unpacking how the brain integrates information to effect motor behavior, particularly highly skilled tasks that involve hands and tools. His findings underscore the importance of intent.

Consider an array of objects on a table: pens, paper, mug, stapler. “You need intent to use things together,” Wheaton says. “If you decide to write a note, you’ll focus attention on the pen and paper.”

That’s obvious, yet some people with certain neurological injuries have trouble understanding what they need to do to write a note. “It’s not automatic that you can string the information together,” Wheaton says. “Part of our work is understanding the relationship between intent and action and how that falls apart in case of neurological injury.”

Using brain-imaging techniques, Wheaton identifies neural signals that capture intent.

Recently he conducted an experiment with people with sound limbs wearing artificial limbs. The participants were asked to learn how to use the prosthetic limbs by watching a video of another prosthetic-device user.

“The norm in prosthetic limb rehabilitation is to let people figure it out themselves, with help from physical therapists,” Wheaton says. “But most physical therapists have two hands. They don’t know what it’s like to be an amputee.”

The study showed that people who watched other prosthetic-device users became more efficient than those who watched people with sound limbs. 

Another tool is eye-tracking, based on the well-known correlation of eye and arm movements. “Particularly in tasks that involve reaching, the eyes precede the hand,” Wheaton says. Can we see intent from what the eyes are doing?

New research suggests that a key to rehabilitation gains might be rooted in visual strategies that capture specific action intent. The eyes see differently when observing different people do the same task, like bringing an object from one side of a barrier to the other side. When watching a person with sound limbs, the prosthetic-device user’s eyes look only at the task itself: The object starts on one side and ends on the other, Wheaton says.

When watching another prosthetic-device user, the subject’s eyes go over the barrier and are paying attention to the shoulders, which power the prosthetic limb. “They are paying attention to the motor intent instead of just the task,” Wheaton says. “Instead of training execution, which we do a lot in rehabilitation, perhaps we should be training intent.”

Back to golf, Wheaton suggests, “Its’ hard to understand the intent of a professional when you are an amateur, until you develop more skill. Instead of watching Rory, take a different approach. You may be more like Joe, who will help you progress to the next step. Then you’ll meet Mary, who’s a bit better than Joe. She’ll take you farther.”

When to Make a Decision: Accumulating and evaluating evidence

By A. Maureen Rouhi

What was your dinner last night? How about the previous night? How about the week before?

Mark E. Wheeler is interested in memories and what happens in the brain that allows us to remember. Part of what he studies is how we make decisions about the accuracy of what we retrieve. “You can’t remember immediately what you had for dinner a week before because you lack information,” he says. “If you think about it a bit more, you may remember. How can you evaluate the accuracy of your memory? What is happening in the brain when we decide whether our memories are accurate or not?”

Memory is difficult to study, however. “People are often not good at describing how they remember,” says Wheeler, a professor in the School of Psychology. “Some retrieved information may not be easy to communicate, people may ignore some memories, or they may be unaware of other memories.”

To get at memory, Wheeler studies perception, which is easier to manipulate and measure. The hope is that understanding how we evaluate evidence in making decisions based on perception can help us understand what happens when retrieving memories.

When viewed from the brain’s perspective, even simple tasks — such as deciding whether an object is green or yellow — consist of a sequence of processing stages, Wheeler says. These stages can be represented by different patterns of brain activity. “If we understand the process as a system,” Wheeler says, “then we can ask: What parts of this system are involved when things break down or don’t function well?” 

Central to Wheeler’s work is the concept of an accumulation-to-boundary mechanism. “In the midst of gathering evidence, you reach some threshold of evidence: Okay, now I’m going to decide,” Wheeler explains. “The idea is that brain activity that is thought to reflect evidence builds up, and when it crosses that threshold, that is the signal that you have enough information to commit to a decision. We don’t understand precisely how that works, which is why we’re studying it, but there’s a lot of data that this happens at the neural level.”

Instead of asking experimental subjects to remember what they had for dinner, Wheeler asks them to lie still while being scanned by a functional MRI (fMRI) machine at the Georgia State University/Georgia Tech Center for Advanced Brain Imaging. Amid the constant beeping of the scanner, participants receive visual stimuli and make decisions about what they see.

Brain activity data reveal how much evidence participants accumulate before they decide. The basis for this approach was developed a decade ago, when Wheeler and others showed that fMRI allows identification of distinct neural processes that work together when people make decisions based on perception.

Currently Wheeler is interested in how aging affects the way decision-making evidence accumulates and how that manifests in brain activity. His recent work, funded by the National Science Foundation and Georgia Tech, examines how noise — anything that degrades information — affects the accumulation of evidence and decision-making as we get older.

“Perception and decision-making,” Wheeler says, “can involve a series of stages, where you take in sensory information, analyze the information, and accumulate evidence, until you can make a decision. Suppose that aging affects the first stage most significantly, but the latter two are fine. You could target interventions more precisely, if you know where the problem lies.”

The experimental approach, Wheeler notes, can apply to other conditions, such as drug addiction or alcoholism. If one can deconstruct how the brain of an alcoholic takes in and processes information, it may be possible to develop better ways to train alcoholics to avoid that first drink.

“Anytime I go to the zoo, I always hear a kid ask why or how they do that,” says Young-Hui Chang, a professor in the School of Biological Sciences who studies locomotion in animals from both a neurological and a biomechanical lens. “It’s a natural question.”

Because science has yet to provide a definitive answer, Chang and fellow researcher Lena Ting investigated how flamingos are able to stand and sleep on one leg so easily for so long. Ting is a professor in the Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Tech who studies balance control in humans and mammals.

Their findings, published this week in Biology Letters, suggest a reason that differs from most previous suggestions: it’s about reducing muscular effort.

Potential applications stretch from better robotics, orthopedic braces, and artificial limbs, to more focused treatments for neurological or balance problems.

But Chang argues that simply providing clarity to long-standing questions about long-standing flamingos has great value as well.

“There’s something to be said for just scientific curiosity and learning how nature works,” he says. Flamingos aren’t the only birds that stand on one leg, he adds, but “the extreme example is the flamingo. It’s precisely from these extreme examples in nature where you can really gain a lot of insight.”

A firmer foundation for flamingos

Surprisingly, Chang says, given how long the question about flamingos has been around, “there hasn’t been a whole lot of research done.” Others have suggested that the birds engage in this behavior to avoid muscle fatigue or to conserve body heat.

Chang and Ting studied live birds at the Zoo Atlanta flock, one of the largest breeding flocks of Chilean flamingos in the U.S. They also used two cadaver birds from the Birmingham Zoo and flamingo skeletons from the University of California at Berkeley’s Museum of Paleontology. 

Zoo Atlanta and Georgia Tech Institutional Animal Care and Use Committees (IACUCs) approved all procedures using live animals. No animal was killed or harmed for the purposes of the study.

Their research shows that a “passively engaged gravitational stay apparatus” helps the birds support their weight and maintain balance while on one reed-thin leg. The bird’s specialized anatomy, clever posture, and gravity combine to give the flamingo this ability, which does not involve bones locking into position. Chang says it’s more like a hammock or sling than a lock, but it does require the unique anatomy of flamingos.

“The biomechanics are such that when they stand on one leg, they become very stable and are able to maintain that posture without activating muscle,” Ting says. “If they deviate from that posture to two legs, that no longer holds. It’s very posture-specific, a one-legged posture that can support their body weight.”

The “passively engaged” part of the flamingo’s gravitational stay apparatus is exactly as it sounds: It requires minuscule, if any, active muscular or nerve control, Chang adds.

Those who marvel at a large, fluffy pink lump of flamingo body held up by one slender leg may be surprised to learn that the “joint” in the middle of that leg is actually an ankle, not a knee. “Most people don’t realize that knee and hip joints are not actually in view in most birds,” Chang says. “They’re near the body, kind of behind the wing. The flamingo thigh is almost perfectly horizontal.”

All that contributes to biomechanics that might actually require greater muscular effort if not for the flamingo’s ability to “stay” in a pose, which flamingos can get out of easily in flight-or-fight situations.

Giving robots - and people – stronger legs to stand on

A one-legged standing test, actually termed a “flamingo test,” is used to diagnose human balance disorders with the help of pressure plates, instruments that measure balance, force, and other data. Humans are usually more than willing to stand on pressure plates. But flamingos? They tend to squawk at things foreign in their environment.

“The zoo didn’t want us to interact with the adult flamingos because they don’t handle change in their environment very well,” Ting says. But zoo workers could handle juvenile flamingos and placed them near the plates after they were fed, hoping that postprandial sleepiness would yield measurable data.

The cadaver birds actually provided a eureka moment for Chang. After putting one into the one-legged pose, “I don’t know what made me do it, but I just kind of grabbed the leg and picked it up,” he says. The bird maintained its posture. “Here we have a non-living animal able to stand on one leg. Obviously, if it’s not alive, then the muscles are not activated.”

Can flamingo biomechanics help treat human movement and balance disorders?

“If we know how much is passive mechanics and how much the nervous system has to control, it puts researchers in a better position to treat people,” Chang says. Flamingo biomechanics can mean better wearable artificial limbs and longer battery life for stability supports.

Robots could also benefit. Getting robots to balance can be difficult; sensing the environment and making adjustments is how they currently do it. “But if you design the biomechanics of a robot in the right way, not so much sensing but a sort of feedback control,” Ting says, “then they would have this passive ability, and they would be more robust in uncertain environments.”

J. Lucas McKay, Ph.D., MSCR, assistant professor (research) in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, was awarded a four-year, $500,000 Mentored Quantitative Research Career Development Award from the National Center for Medical Rehabilitation Research (NCMRR), a sub–institute of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) entitled "Neural mechanisms of balance deficits, falls, and freezing of gait in Parkinson's disease."

The grant will allow McKay to apply his engineering background to help improve clinical outcomes for Parkinson's patients, working with faculty mentors, including Thomas Wichmann, M.D., director of Emory's Morris K. Udall Center of Excellence for Parkinson's Disease Research, to better understand the scientific mechanisms of Parkinson's disease, and Stewart Factor, DO, director of the Emory Movement Disorders Clinic, to understand how recent advances in human movement science can be applied to the clinical management of Parkinson's disease.

McKay will work with Lena Ting, Ph.D., professor of rehabilitation medicine at Emory and professor of biomedical engineering at Georgia Tech and Emory, to conduct laboratory-based movement studies in people with Parkinson's disease to identify new physiologic markers of fall risk.

Ting was recently awarded a $1.7 million Collaborative Research Grant from the NICHD/NCMRR to develop computer simulations of how sensory signals are generated within the muscles for balance control. Tim Cope, Ph.D., a neuroscientist in the Coulter Department at Georgia Tech and Emory, and in the School of Applied Physiology at Georgia Tech, is co-principal investigator of the grant, along with Ken Campbell, Ph.D., a muscle physiologist at the University of Kentucky.

The research is aimed at developing a fundamental understanding of how muscle spindle proprioceptive organs provide sensory awareness during movement. Proprioceptors feed information to the brain about the position and length of joints and muscles and the position of limbs in space, allowing people to maintain balance and move their limbs effectively.

"We plan to predict changes in sensory function associated with chemotherapy-based sensory loss and other sensory neuropathies," explains Ting. "The establishment of this new model will provide a new basis for understanding and treating other sensorimotor disorders such as spasticity seen in stroke and spinal cord injury, rigidity in Parkinson's disease, and abnormal muscle contractions in dystonia."

The awards follow a recent scientific paper by McKay, Ting, and collaborator Madeleine Hackney, PhD, research health scientist at the Atlanta VA Center for Visual and Neurocognitive Rehabilitation and assistant professor (research) in the division of general medicine/geriatrics at Emory. The paper describes changes in mechanisms of balance control in individuals with Parkinson's disease after dance-based rehabilitation. The work is published online and will be in the October issue of the Journal of Neurologic Physical Therapy.

Emory Contact:
Holly Korschun
404-727-3990
hkorsch@emory.edu

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Walter Rich
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Wallace H. Coulter Department of Biomedical Engineering
Georgia Institute of Technology

The brain’s ability to quickly focus on life-or-death, yes-or-no decisions, then immediately shift to detailed analytical processing, is believed to be the work of the thalamus, a small section of the midbrain through which most sensory inputs from the body flow. When cells in the thalamus detect something that requires urgent attention from the rest of the brain, they begin “bursting” – many cells firing off simultaneous signals to get the attention of the cortex. Once the threat passes, the cells quickly switch back to quieter activity.

Using optogenetics and other technology, researchers have for the first time precisely manipulated this bursting activity of the thalamus, tying it to the sense of touch. The work, done in animal models, was reported January 14th in the journal Cell Reports. The research is supported by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke.

“If you clap your hands once, that’s loud,” explained Garrett Stanley, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “But if you clap your hands several times in a row, that’s louder. And if you and your friends all clap together and at the same time, that’s even stronger. That is what these cells do, and the idea is that this mechanism produces bursts synchronized across many cells to send out a very strong signal about a stimulus in the outside world.”

Neuroscientists have long believed that such coordinated spikes of activity serve to focus the brain’s attention on issues requiring immediate attention. Stanley and graduate student Clarissa Whitmire – working with researchers Cornelius Schwarz and Christian Waiblinger from the University of Tübingen in Germany – used optogenetics techniques to study bursting activity in the thalamus of rats. Their findings could lead to a better understanding of how cells in this walnut-sized portion of the human brain perform a variety of sensory and motor control tasks, switching from one mode to another as needed.

“Clarissa was able to get into the mechanism of synchronized thalamic bursting so we can manipulate it and look at it not only from within individual cells, but also across cells, recording from multiple cells simultaneously,” said Stanley, who has been studying the thalamus for more than a decade. “We can now begin to provide a coherent story about how information gets from the outside world to the brain machinery that’s in the cortex.”

The researchers studied the connection between the rats’ whiskers and cells in their thalamus. By stimulating the whiskers in many different ways, they were able to induce signals – including bursting – in the thalamus. The researchers used light-sensitive proteins introduced into the thalamic cells – a technology known as optogenetics – to establish optical control of the bursting activity.

“We were able to turn the bursting mechanism on or off at will,” explained Stanley, who is the Carol Ann and David D. Flanagan Professor in the Coulter Department. “This is really the first time we have been able to readily control this, turning the knob in one direction to eliminate the bursting activity and then turning it the other way to make the cells produce these bursts in rapid succession.”

The control extended not just to turning the bursting on or off, but also allowed the researchers to create a continuum of cell activity.

“Clarissa could make them act very ‘bursty’ and very synchronized, or she could turn the knob and move them very smoothly to the opposite end of the spectrum,” Stanley said. “There is a range of activity that people had speculated would be there, but nobody had actually done the experiments to show it existed.”

The cellular bursting mechanism likely developed very early in mammalian evolution to help creatures survive threats posed by predators. The brain’s cortex is always busy with higher-level activity, and the thalamic bursting serves to let it know that critical outside activities need its urgent attention.

Other sensory inputs such as vision can initiate bursting, but Stanley’s group chose to study sense of touch in this work. In rats, the whiskers are embedded in follicles that have specialized cells whose function is similar to that of human sensory cells. Thus, these whiskers serve many of the same “touch” functions as human fingers.

“When you reach out with your hand and touch a surface, you are mechanically deforming the skin, stretching the sensors that are in the skin and sending signals to tell the brain about the surface you are touching,” Stanley noted. “In the rats, we moved the whiskers, recorded the activity, and identified the presence of a burst.”

As a next step, Stanley and his research team plan to connect what they’ve learned about bursting activity of the thalamus to behavior in an effort to fully confirm the theory. “The next step is to take this to behavior and work with animals that are trained to detect and discriminate between different kinds of inputs,” he said.

With the optogenetics and other advanced technology, researchers are beginning to see the big picture of how sensory inputs affect brain activity.

“These thalamic cells are somewhere in between the outside world and the cognitive machinery of the brain, and they have a job that changes rapidly,” Stanley said. “In some cases, they are saying ‘yes’ or ‘no’ about something in the outside world, and in some cases they are discriminating between the final details of objects in the outside world.”

This work was supported by US-German Collaborative Research in Computational Neuroscience grant (US: NSF CRCNS IOS-1131948; German: BMBF CRCNS 01GQ1113) and NIH National Institute of Neurological Disorders and Stroke grants R01NS048285 and R01NS085447. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CITATION: Clarissa Whitmire, Christian Waiblinger, Cornelius Schwarz, Garrett Stanley, “Information Coding Through Adaptive Gating of Synchronized Thalamic Bursting, (Cell Reports, 2016).

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A ballet dancer’s grace is not just because the dancer constantly practices moving with poise. New research published in the Journal of Neurophysiology reports that professional ballet dancers’ years of physical training have enabled their nervous systems to coordinate their muscles when they move more precisely than individuals who have no dance training.

The nervous system is comprised of the brain, spinal cord and nerves throughout the body. It allows the body’s systems to communicate and coordinate with each other, such as the brain controlling movement of the leg muscles.

Rather than controlling muscles individually, the nervous system initiates movement by activating muscles in groups. The groups of muscles are called "motor modules," and the nervous system combines different motor modules to achieve a wide range of motion.

In this study, a research team at Emory University and Georgia Institute of Technology examined whether long-term training to enhance physical coordination, such as dance training, affects how motor modules are recruited when moving.

"This study helps us understand how long-term training in an activity such as dance affects how we do everyday tasks," says study author Lena Ting, Ph.D. "We found that years of ballet training change how the nervous system coordinates muscles for walking and balancing behaviors overall. This may also have implications for how training through rehabilitation helps people with impaired mobility." Ting is professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory and in the Department of Rehabilitation Medicine at Emory University School of Medicine. 

The researchers compared the movements of professional ballet dancers with 10 or more years of ballet training to individuals with no dance or gymnastics training. Gait and activity of muscles in the legs and torso were tracked as the subjects walked across the floor, across a wide beam and across a challenging narrow beam.

Ballet dancers and untrained individuals had similar gait patterns when they walked across the floor or the beam. However, when walking across the narrow beam, ballet dancers showed better balance by walking across farther. Ballet dancers recruited more motor modules and did so more consistently than untrained individuals, indicating that ballet dancers used their muscles more effectively and efficiently, the researchers stated. The ballet dancers also used more of the same motor modules when walking across a floor as when walking across the beam compared with untrained individuals, supporting that training can affect control of every-day movements.

According to the researchers, the results show that years of ballet training changed how the nervous system coordinated muscles for walking and balancing behaviors.

The article "Long-term training modifies the modular structure and organization of walking balance control" is published ahead-of-print in Journal of Neurophysiology.

CONTACT:

Walter Rich
Communications Manager
Wallace H. Coulter Department of Biomedical Engineering
Georgia Institute of Technology

Christine Payne and Garrett Stanley, both faculty members of the Petit Institute for Bioengineering and Bioscience, are among the 131 investigators working at 125 institutions in the U.S. and eight other countries receiving 67 new awards, totaling more than $38 million. 

Payne, Stanley and their collaborators are part of a new round of projects for visualizing the brain in action. It’s all part of the initiative launched by President Obama in 2014 as a wide-spread effort to equip researchers with fundamental insights for treating a range of brain disorders, like Alzheimer’s, schizophrenia, autism, epilepsy and traumatic brain injury.

Stanley and Dieter Jaeger, professor in Emory University’s Department of Biology, are principal investigators of a project titled, “Multiscale Analysis of Sensory-Motor Cortical Gating in Behaving Mice.” 

Their overall goal is better understand and capture the flow of information as we sense and perceive the outside world, “so that we can take action,” says Stanley, professor in the Wallace H. Coulter Department of Biomedical Engineering (BME), a joint department of Emory and Georgia Tech.  

The Stanley lab provides expertise on tactile sensing and information processing, while the Jaeger lab provides expertise on motor/muscle coordination and control.

“We are developing approaches to using genetically expressed voltage sensors to optically image brain activity during a sensory-motor task,” Stanley says.

The new technology would let the researchers monitor brain activity at high spatial and temporal resolution over long periods of time.

“It allows us to address questions related to the circuits involved in coordinating the relationship between sensing and action for the first time,” Stanley says. 

The project grew out of another collaboration between Jaeger and Stanley. They are co-principal investigators of an NIH-sponsored training grant in computational neuroscience, which targets a new generation of scientists bound together through questions about how the brain computes. 

“Through this interaction, Dieter and I got to know each other better, started to talk more science, and eventually cooked up this project,” Stanley says.  “The research is relevant to public health because it provides an impactful and innovative study of the circuitry underlying the output from the basal ganglia to the motor cortex and the integration of basal ganglia output with sensory information.”

Debilitating and difficult to treat neurological disorders like Parkinson’s disease, Huntington’s disease and dystonia are caused by dysfunction of this circuitry.

“The proposed research is expected to provide basic insights into motor circuit function and may reveal new possibilities for treatment of these diseases as well as a better understanding of deep brain stimulation treatments already in use,” says Stanley, who was part of the first round of BRAIN Initiative funding last year with fellow Georgia Tech researcher Craig Forest.

Peter Borden, a Ph.D. student in Stanley’s lab, and Christian Waiblinger, a postdoctoral researcher in Stanley’s lab, will also be contributing to the research.

Meanwhile, Payne is principal investigator for a project titled, “Conducting polymer nanowires for neural modulation.” She’s collaborating with Bret Flanders, a professor at Kansas State whose lab is working on new ways to insulate nanowires. Georgia Tech students Scott Thourson (a Bioengineering Ph.D. candidate) and Rohan Kadambi (undergrad in Chemical and Biomolecular Engineering) are helping to lead the effort.

“Understanding how the brain functions requires fundamentally new tools to probe individual neurons without damaging the surrounding tissue,” says Payne, associate professor in the School of Chemistry and Biochemistry. 

“This research will develop a prototype device that uses biocompatible conducting polymer nanowires to interface with individual neurons,” says Payne. “The use of flexible conducting polymers in place of traditional metal, silicon, and carbon electrodes is expected to minimize disruption to the surrounding tissue.”    

The new round of funding brings the NIH investment for BRAIN Initiative research to $85 million in fiscal year 2015. Last year NIH awarded $46 million to the effort, designed to ultimately catalyze new treatments and cures for devastating brain disorders and diseases that are estimated by the World Health Organization to affect more than one billion people on the planet. 

“Georgia Tech is proud to play a role in this important global effort,” says Steve Cross, Tech's executive vice president for research. “These grants are further evidence of Tech’s reputation for conducting world-class bioengineering and bioscience research.” 

CONTACT:

Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience 

With the support of a five-year, $2.9 million grant from the National Science Foundation National Research Traineeship program, this faculty team will create new bachelor’s, master’s, and doctoral degree programs and concentrations in healthcare robotics – the first degree programs in this area in the United States.

Led by Ayanna M. Howard, the Linda J. and Mark C. Smith Chair Professor in the Georgia Tech School of Electrical and Computer Engineering (ECE), this initiative will blend Emory’s medical and clinical expertise and Tech’s robotics and engineering know-how to train engineering students in robotics, physiology, neuroscience, rehabilitation, and psychology. The program also aims to increase the appeal of STEM fields to a wide range of people, including women, underrepresented minorities, and people with disabilities.

The U.S. population is living longer and is becoming older and more racially and ethnically diverse. In addition, the number of younger people living with a lifelong disability is also increasing, including 52,351 post-9/11 military veterans with combat injuries and 6.4 million children with developmental disorders or delays. Fifty million people are also diagnosed annually with neurological/neurodegenerative diseases. “Providing innovative solutions to help improve an individual’s quality of life continues to emerge as a growing need,” said Howard, who leads the Human-Automation Systems Lab in ECE. “Keeping this need in mind, we will train engineers not only to develop robotics technologies, but also learn how to work with and listen to the needs of the technology end users – patients, caregivers, and healthcare professionals.”

Three faculty join Howard’s leadership team. Charlie Kemp, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering (BME) at Georgia Tech and Emory University and director of the Healthcare Robotics Lab in BME, focuses on intelligent mobile robots for physical assistance in the context of healthcare. Lena H. Ting, a BME professor with an appointment in Emory School of Medicine’s Department of Rehabilitation Medicine, Division of Physical Therapy, and co-director of the Neural Engineering Center, will integrate human needs related to accessibility and rehabilitation to inform the design of robotics solutions.

Randy D. Trumbower, an assistant professor in both BME and Physical Therapy and the director of research within Rehabilitation Medicine at Emory, will work on interfacing robotics and physical therapy techniques.

Additional faculty will serve as student advisors, including Wendy Rogers, professor in Tech’s School of Psychology; Jun Ueda, an associate professor from Tech’s George W. Woodruff School of Mechanical Engineering; Steven L. Wolf, a professor in Emory’s Division of Physical Therapy; and Minoru Shinohara, an associate professor in Tech’s School of Applied Physiology.

The team will focus first on developing the doctoral and master’s programs, with the goal of having a mini-cohort of Ph.D. students in spring 2016 and starting the official graduate degree programs next fall. The undergraduate degree will combine the five-year, B.S./M.S. degree program and undergraduate thesis option, allowing students to build a foundation for an eventual M.S. thesis. The graduate program will build on the highly successful multidisciplinary robotics Ph.D. program at Georgia Tech. “We’re excited about this opportunity to further enhance and grow our world-class educational programs in robotics,” said Kemp, who has served on the robotics Ph.D. program’s leadership team since its inception in 2007.

A sampling of these courses include:

•        Interfacing Engineering and Rehabilitation, taught by Trumbower, engages both engineering and clinical students. They will learn equally from clinical experts about their target demographics and the issues they face and from engineering faculty about how robotics can address these challenges. Members from collaborating medical organizations and non-profit agencies will regularly visit the class to talk with students. Discussion points and group projects will be derived from real case studies using persons with physical challenges as technology consumers and consultants.

“In order for clinicians to play a more active role in the development, evaluation, and implementation of robotics technologies in rehabilitation, they must first more comfortably engage engineers who develop and test these technologies,” said Trumbower. “Mutually, in order for engineers to play a more active role in the development, evaluation, and implementation of rehabilitation technologies, they must first more comfortably engage clinicians who evaluate and treat patients. This course provides a novel learning approach for this type of collaborative interaction.”

•        A course on ethics, privacy, and regulations in medicine and biomedical robotics will be offered, where students learn about considerations that must be addressed when designing and deploying robotic systems for health. “While engineering students at Tech are required to take ethics courses, certain areas like privacy or statistical analysis have different nuances in the healthcare arena,” said Howard. “For instance, what does ‘good’ mean as a healthcare roboticist vs. a traditional roboticist? How do you manage privacy and share information from doctor to doctor, and is there a correlation to a robot in the doctor’s office doing the same thing with a robot in a patient’s home?”

•        Interdisciplinary research training will provide students with hands-on, healthcare experience during their first summer in the program. Matched with mentors in both engineering and healthcare, students will do one week of clinical rotations, where they will observe medical practices and learn about current problems in healthcare.

Students will then conduct eight weeks of research using robotics to address healthcare issues discovered during rotations. Clinical partners with which students may work include Emory Medical School, Shepherd Center, Children’s Healthcare of Atlanta, Emory ALS Center, Atlanta Area Agency on Aging, and the Veterans Administration.

Additional components of the healthcare robotics degree programs are required communications training and availability of entrepreneurship activities for interested students. All students will receive communications training, so that they can interact effectively with different audiences. Examples include academic and professional communications; talking to patients or patient groups about their work; giving media interviews, writing press releases, and producing short videos about their work; and communicating with the general public. Trainees interested in entrepreneurship will be able to participate in a Georgia Tech student incubator during their second summer in the program, or they may intern at a medical startup company in the Atlanta area.

Working with engineering students to think about and design their technologies for the benefit of their target populations will be an exciting challenge, according to Howard. “Working in healthcare robotics will be a learning process, where there is no equation in the book that can be derived. It will require looking at a problem, working and talking with others, and developing a solution by being creative and thinking outside of the box,” said Howard. “This will be a different way of thinking for engineers, and when our students graduate, they will be exceptional because of that.” 

Sources for statistics: National Center for Education Statistics, Congressional Research Service/U.S. Department of Defense, and the National Institute of Neurological Disorders and Stroke.

An engineering example of closed-loop control is a simple thermostat used to maintain a steady temperature in the home. Without it, heating or air conditioning would run without reacting to changes in outside conditions, allowing inside temperatures to vary dramatically.

Optogenetics technology places genes that express light-sensitive proteins into mammalian cells that normally lack such proteins. When the proteins are illuminated with specific wavelengths of light, they change the behavior of the cells, introducing certain types of ions or pushing ions out of the cells to alter electrical activity. But without a feedback loop, scientists could only assume that the optical signals were having the effects desired – or try to confirm at the end of the experiment that this had happened.

To address that shortcoming, researchers have created an open-source technology called the optoclamp which closes the loop in optogenetic systems. The technique uses a computer to acquire and process the neuronal response to the optical stimulus in real-time and then vary the light input to maintain a desired firing rate. By providing this feedback control, the optoclamp could facilitate research into new therapies for epilepsy, Parkinson’s disease, chronic pain – and even depression.

“Our work establishes a versatile test bed for creating the responsive neurotherapeutic tools of the future,” said Steve Potter, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Neural modulation therapies of the future, whether they be targeted drug delivery, electrical stimulation or even light-plus-optogenetics through fiber optics, will all be closed loop. That means they will be responsive to the moment-to-moment needs of the nervous system.”

The research, supported by the National Institutes of Health and the National Science Foundation, was recently published in the open-access journal eLife. Feedback control already exists for neural stimulation systems based on electrical inputs, but the optoclamp is the first system to provide similar closed-loop control for optical stimulation.

Optoclamp provides continuous, real-time adjustments of optical stimulation to lock neural spiking activity to specified targets over time scales ranging from seconds to days. By providing precise optical control of firing in neuronal populations, the technology will help scientists disentangle causally related variables of circuit activation.

Researchers in Potter’s lab studied the effects of open-loop optical stimulation on neural systems, and found considerable variation in the responses of neuronal networks grown on multi-electrode arrays and in the neurons of animal models.

“The same stimulus pattern can produce highly variable levels of activity,” said Jon Newman, who built the optoclamp while a Ph.D. student in Georgia Tech’s Laboratory for Neuroengineering. Newman is now a postdoctoral researcher at MIT. “The amount of optical stimulation needed to achieve the same level of activity varied by orders of magnitude, depending on the population that was being controlled, or even in the same type of cells and preparation, but within different subjects.”

In a cultured cortical network, the optoclamp records activity from as many as 200 cells, using them to measure activity in the larger culture population, which can include as many as a million cells.

“Because we have all those electrodes, we can process the data in real-time and then compare the amount of activity being expressed by the culture to a target rate, then use the difference between those two signals to inform our optical stimulator to vary the intensities of different wavelengths of light,” Newman explained.

The optoclamp can be used to control cell cultures grown atop electrode arrays, as well as in living animal models in which electrodes have been implanted.

In research conducted with colleagues at Emory University, the optoclamp’s ability to maintain a steady neural firing state allowed researchers to study a key control issue in homeostatic plasticity, a phenomenon that results from a lack of neural stimulation. Scientists had believed that the effect was controlled by the firing rate of cells, but the optoclamp allowed a team of researchers from Georgia Tech and Emory University to clamp firing at normal levels during the addition of a drug that inhibits neurotransmission. This showed that neurotransmission levels, not firing activity, governed a key form of homeostatic plasticity.

“Effectively, we were able to decouple two things that are normally very closely related,” said Newman. “This is potentially a very big deal in terms of developing therapies for aberrant forms of synaptic plasticity.” Potential applications include chronic pain, epilepsy, tinnitus, phantom limb syndrome and other nervous systems disorders where the brain has over-reacted to the loss of normal inputs.

That work, recently published in the journal Nature Communications, was a collaboration with Emory University Professor Pete Wenner and former graduate student Ming-fai Fong, demonstrating the value of bringing biological scientists together with engineers. Newman, an engineer by training, says concepts common in engineering can be useful in the life sciences.

“Closed-loop control is a concept that is woven through all engineered systems, but it’s often hard to find in the biological sciences,” he said. “Any time you can introduce feedback control into an experiment, it almost always produces better control of the variables of interest. Feedback control is an extremely important concept for the life sciences.”

Scientists are already using the optoclamp in its current form, but the researchers hope to improve spatial differentiation of the optical signals, allowing experiments to focus stimulation on specific areas of the brain or brain cell cultures. The light signals now affect an entire culture or brain region.

“We want to precisely control where photons are being sent to activate different cells,” Newman said. “Optogenetics allows genetic specification of which cells express these proteins, and that gives you some level of spatial control. But I don’t believe that’s as precise as what will be required to speak the language of the brain.”

In addition to those already mentioned, the research team included Professor Garrett Stanley from the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and graduate students Daniel C. Millard and Clarissa J. Whitmire, also from the Coulter Department.

This research was supported by the National Science Foundation under Collaborative Research in Computational Neuroscience grant IOS-1131948 and Emerging Frontiers in Research and Innovation grant 1238097, and by the National Institutes of Health National Institute of Neurological Disorders and Stroke grant 2R01NS048285 and National Institute of Neurological Disorders grant 1R01NS079757-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Science Foundation or National Institutes of Health.

CITATIONS:
Newman, J. P., Fong, M-f, Millard, D. C., Whitmire, C. J., Stanley, G. B., & Potter, S. M., “Optogenetic feedback control of neural activity,” (eLife, 2015). http://dx.doi.org/10.7554/eLife.07192.

Ming-fai Fong, et al, “Upward synaptic scaling is dependent on neurotransmission rather than spiking,” (Nature Communications, 2015). http://dx.doi.org/10.1038/ncomms7339.

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Media Relations Contact: John Toon (jtoon@gatech.edu) (404-894-6986).
Writer: John Toon

The electromagnetically shielded in vivo extracellular electrophysiology rig is constructed with various elements, including Zesis surgical microscopes, a 128-channel Tucker Davis Technologies data acquisition system (RZ2), Kopf stereotaxic frames, and DC temperature controllers to enable stable, reliable and high-quality recordings. Also, a complete LED driver system (Thorlabs) was equipped to this rig to facilitate optogenetic in vivo experiments.
Automatic patch clamping devices (autopatchers) are also attached to both in vitro and in vivo patch clamping rigs to obtain high yield and high quality whole cell recordings.  

Forest and Stanley, professor in the Wallace H. Coulter Department of Biomedical Engineering (BME), were awarded BRAIN Initiative funding from the NIH for their project entitled, “In-vivo circuit activity measurement at single cell, sub-threshold resolution,” research that could only happen with the best tools available.

“We can use these tools not only to record what’s happening in cells, at the level of a single cell, but also in cells that are in two different brain regions simultaneously,” says Forest. “In each region we can record activity within a single cell, at the sub-threshold resolution of a single cell. No one’s been able to do that before. We can record cells talking to each other in a living brain.”

CONTACT:

Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience

CONTACT:

Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience

The Atlanta-based team was awarded for development of iDETECT (integrated Display Enhanced TEsting for Cognitive Impairment and mTBI), a rapidly deployable, easily administered, comprehensive system designed to improve neurologic assessment following mild traumatic brain injury, such as concussion sustained in athletic events and military conflict.

A total of seven winners of Head Health Challenge II were announced November 13, 2014. The winning teams, selected from more than 500 submissions, will receive $500,000 each for development of new innovations and technologies intended to identify, measure and mitigate brain injury. The first round of winners will be eligible for an additional $1 million after a second phase of judging.

iDETECT addresses feasibility and reliability drawbacks associated with current concussion screening tools. It is an easy-to-administer, portable, and immersive system that integrates multiple concussion tests within one platform. The next generation iDETECT system will be further tested in a clinical study comparing iDETECT outcomes against other traditional separate mTBI screening tools.

“Our team is excited and honored to be selected as a winner in the NFL-GE-UA Head Health Challenge II competition,” says Tamara Espinoza, assistant professor of emergency medicine at Emory University School of Medicine and principal investigator of the Head Health Challenge award. “A tremendous amount of research and effort has gone into the development of iDETECT, and we believe it may become an essential tool in assessing sports-related concussion.”

Of the 1.7 million traumatic brain injuries in the United States each year, more than 750,000 are considered “mild,” and over 173,000 are related to recreational and sports activity. In the last decade, emergency department visits for mild traumatic brain injury (mTBI) among highly vulnerable populations, such as children and developing youth, have increased by more than 60 percent.

“Adequately assessing mTBI using individual, single-pathway screening methods is extremely difficult, given the complexities of neurologic injury,” says Shean Phelps, principal research scientist at Georgia Tech Research Institute (GTRI). “With this additional funding from the Head Health Challenge II, our team can more fully pursue the long-term vision of iDETECT as a multi-modal device that addresses sports-related, mild traumatic brain injury.”

The DETECT project was the brainchild of David Wright, director of Emergency Neurosciences at Emory University School of Medicine and Michelle LaPlaca, associate professor of biomedical engineering at Georgia Tech and Emory University. In 2011, the project evolved from a single neurocognitive approach for detection of concussions to an extended, multi-modal platform when the partnership broadened to include the Georgia Tech Research Institute. GTRI added critical systems engineering, human factors and military medical operational expertise.

“Mild traumatic brain injuries in youth, college and professional sports have the potential for life-changing, long-term consequences,” says Wright. “The iDETECT system integrates multiple concussion testing capabilities within one platform and allows rapid and reliable assessment at the location where the injury occurred.” This comprehensive approach enhances the ability to validate the on-field assessment platform and more accurately screen for traumatic injury.

Phelps, a retired U.S. Army lieutenant colonel adds, “mTBI assessments in the military is an area that needs new approaches such as those provided by iDETECT.”

Partner institutions forming the iDETECT team include Georgia Tech, Emory and the University of Rochester. The Department of Defense and the Wallace H. Coulter Foundation provided financial support for development of iDETECT.

In addition to Espinoza, Wright, LaPlaca and Phelps, team members include Brian Liu, Georgia Tech Research Institute (GTRI) research engineer; Stephen Smith, research engineer, Russell Gore, sports neurologist; John Brumfield, biomedical engineer; Jeff Bazarian, associate professor of emergency medicine, University of Rochester; and Courtney Crooks, GTRI senior research scientist.
Written by Emory University

A new study found that neural circuits in the brain rapidly multitask between detecting and discriminating sensory input, such as headlights in the distance. That’s different from how electronic circuits work, where one circuit performs a very specific task. The brain, the study found, is wired in way that allows a single pathway to perform multiple tasks.

“We showed that circuits in the brain change or adapt from situations when you need to detect something versus when you need to discriminate fine details,” said Garrett Stanley, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, whose lab performed the research. “One of the things the brain is good at is doing multiple things. Engineers have trouble with that.”

The research findings were published online in the journal NEURON on March 5. The research was funded by the National Institutes of Health (NIH) and the National Science Foundation (NSF).

“Every day we are bombarded with sensations and the brain automatically chooses which ones to detect. This study may help scientists answer fundamental questions about how neurological disorders may disrupt the brain circuits that make those choices,” said Jim Gnadt, Ph.D., program director at the National Institute of Neurological Disorders and Stroke, part of NIH. “Insights into sensory perception may help design new therapies, including prosthetic devices for amputees that recreate human touch.”

The distance at which a person can discern two headlights from a single light is controlled by the acuity of the body’s sensory pathway. For decades neuroscientists have assumed that the level of one’s acuity is controlled by the distance between areas in the brain that are triggered by the sensory input. If these two areas of the brain closely overlap, then two sensory inputs — two headlights in the distance — will appear as one, the thinking went. The new study, for the first time, used animal models and optical imaging to directly assess how acuity is controlled in the brain, and how acuity can adapt to the task at hand. One neuronal circuit can do different things and do them in a robust way, the study found.

“The general problem that is not well understood is how information about the outside world makes its way into our brain, into these patterns of electrical activity that ultimately let us perceive the outside world,” Stanley said. “This paper squarely goes after that link between what the brain is doing, how it’s activated and what that means for perception.”

Sensory information is encoded in the brain, much like gene sequences in DNA code for some physical representation. The brain has corresponding codes for when the visual pathway detects an object, like a coffee cup. There’s a representation in the brain to transform that input into sensation.

Researchers had yet to adequately quantify the link between discerning whether an object exists and discriminating finer details about what that object is, Stanley said.

“Surprisingly, we don’t understand neural coding problems very well, either in normal physiology or in disease states,” Stanley said. “I think it’s great to be an engineer that works on this because engineers tend to love and think about very complicated systems.”

To learn about the details of the brain’s acuity, the researchers studied an animal with a high level of acuity — the rat. Rats are nocturnal animals that use their whiskers to sense the outside world. Their whiskers are arranged in rows, and chunks of brain tissue correspond to those individual whiskers. That’s similar to how a human’s body surface is mapped onto the brain surface. When a rat’s whisker touches something, a specific part of the brain becomes activated. When a person’s finger touches something, a specific part of the brain becomes activated.

“When we image the brain, we can move a whisker on the side of the face and on the opposite side of the brain there’s a little hotspot that you can image in real time,” Stanley said.
The researchers deflected rats’ whiskers and then used optical imaging technology to observe the areas of the brain that were activated and measured the overlap between those areas. Rats were also trained to perform a specific task depending on which whisker was deflected.

The researchers found that pathways in the brain have the ability to switch between doing different kinds of tasks, such as detecting a sensory input and deciding what to do with that information.

“Same circuit, same cells, but doing something different in two different contexts,” Stanley said.

When engineers want a circuit to do something, they build a circuit specific for that task. When they want a circuit to do something else, they build a different circuit. But in the brain, a pathway adaptively changes between being good at detecting something to being good at discriminating something, the study showed.

“As an engineer, I can’t design a circuit that would do that,” Stanley said. “This is where the brain jumps out and says, ‘I’m better than you are at this.’”

Learning more about how circuits in the brain multitask could lead to a better understanding of disease, therapeutic applications or to potentially improving how the brain functions. Stanley said that down the road engineers might be able to experimentally manipulate brain circuits to perform a desired task.

“Can we make individuals better at doing something? Can we have them detect things more rapidly or discriminate between things with better acuity?” Stanley said. “Using modern techniques, we believe that we can actually influence the circuit and have it selectively grab one kind of information from the outside world versus another.”

This research is supported by the National Institutes of Health (NIH) under award number R01NS48285, and by the National Science Foundation (NSF) Collaborative Research in Computational Neuroscience (CRCNS) program under award number IOS-1131948. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

CITATION: Douglas Ollerenshaw, et al., “The adaptive trade-off between detection and discrimination in cortical representations and behavior,” (NEURON, March 2014). (http://dx.doi.org/10.1016/j.neuron.2014.01.025).

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Writer: Brett Israel

Scientists and engineers at the Georgia Institute of Technology are applying their expertise, tools and techniques to address questions like these – and to explore on a fundamental level how the brain works.

Because the human brain is immensely complex, the researchers are pursuing many levels of inquiry – from molecules to cells to circuits to the mystery of the mind itself – and also studying brain disorders and development, along with daily feats of brain activity, such as vision, speech, movement and memory.

Georgia Tech researchers are also developing better interventions for brain injuries and disorders. They are designing tools to help neuroscientists better probe and record the activity of neurons in tissue samples and living animals. And they are using brain imaging techniques, such as magnetic resonance imaging (MRI) and electroencephalography (EEG), to peek inside the skull and examine how the brain reacts differently when cognitive tasks are completed by the young and the old, or the healthy and those with injuries.

This article provides a snapshot of Georgia Tech’s research in the biology of the brain.

Developing Better Interventions for Brain Disorders and Injuries

Reducing Epileptic Seizures -- Researchers at Georgia Tech and Emory University are investigating the use of electrical stimulation to reduce or eliminate seizures associated with epilepsy, a disorder that affects approximately 2 million people in the United States. Seizures are temporary disturbances in brain function in which groups of nerve cells in the brain fire abnormally and excessively.

To perform their studies, the researchers have created an animal model for temporal lobe epilepsy. Using this model, they can examine different approaches for preventing seizures associated with epilepsy. For one approach, they are implanting tiny electrodes in the animal’s brain that can be used to stimulate neurons and record their activity. The team is also trying to utilize the field of optogenetics – a mix of optical and genetic techniques – to stop the seizures by stimulating the brain with light.

“Our goal is to better understand what causes epileptic seizures and try to find a way to respond to those bursts in activity with stimulation and reduce the number of seizures an individual experiences,” said Steve Potter, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The stimulation techniques could be a possible alternative for individuals who do not respond to drug therapies and may therefore require surgical resection of the portion of the brain causing the seizures.

Potter is collaborating on this project with Robert Gross, an associate professor in the Departments of Neurosurgery and Neurology at Emory University, and a member of the program faculty in the Coulter Department. Their graduate students, Sharanya Desai and Neal Laxpati, are developing and testing these new brain stimulation therapies in the epileptic rat model. This work has been funded in part by the Wallace H. Coulter Foundation, the National Institutes of Health, Citizens United for Research in Epilepsy (CURE) and the American Epilepsy Society.

Improving Recovery from Spinal Cord Injuries -- Following an injury to the brain or spinal cord, a glial scar begins to form. While the scar signifies the beginning of the healing process, neuron extensions – called axons – cannot regenerate through the glial scar, thus preventing repair and recovery.

The inhibitory characteristics of the scar have been attributed to an increase in proteins known as chondroitin sulfate proteoglycans at the injury site. This family of proteins prevents regeneration of damaged nerve endings.

In a recent study, a research team led by Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, examined the influence on central nervous system recovery of a chondroitin sulfate proteoglycan called chondroitin sulfate-4,6 (CS-E). The researchers found that expression of CS-E increased following a central nervous system injury. In cell culture experiments, CS-E inhibited the growth of neurons, and when researchers reduced the amount of CS-E, the inhibition of neuron growth was significantly alleviated.

“Our findings showed that CS-E is a big player in inhibiting nerve growth following an injury, and its expression needs to be reduced as much as possible,” said Bellamkonda.

One strategy to overcome the inhibitory effects of proteins like chondroitin sulfate-4,6 is to enzymatically digest them. In 2009, Bellamkonda developed an improved version of an enzyme capable of digesting chondroitin sulfate proteoglycans.

The researchers eliminated the thermal sensitivity of the enzyme – called chrondroitinase ABC (chABC) – and developed a delivery system that allowed the enzyme to be active for weeks without implanted catheters and pumps. In animal studies, when the thermostabilized enzyme was delivered, the scar at the injury site was significantly degraded for at least six weeks, and enhanced axonal sprouting and recovery of nerve function at the injury site were observed.

“These results brought us a step closer to repairing spinal cord injuries, which require multiple steps including minimizing the extent of secondary injury, bridging the lesion, overcoming inhibition due to scar, and stimulating nerve growth,” said Bellamkonda, who is also the Carol Ann and David D. Flanagan Chair in Biomedical Engineering and a Georgia Cancer Coalition Distinguished Cancer Scholar.

Robert McKeon, an associate professor in cell biology at Emory University, Georgia Tech senior research scientist Lohitash Karumbaiah and graduate student Hyun-Jung Lee also contributed to this work, which was supported by the National Institutes of Health and the Wallace H. Coulter Foundation.

Uncovering the Neural Basis of Rapid Brain Adaptation -- Your brain is able to quickly switch from detecting an object flying toward you to determining what the object is through a phenomenon called adaptation.

Garrett Stanley, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, published a study in the journal Nature Neuroscience that detailed the biological basis for rapid adaptation: neurons located at the beginning of the brain’s sensory information pathway that change their level of simultaneous firing. This modification in neuron firing alters the nature of the information being relayed, which enhances the brain’s ability to discriminate between different sensations – at the expense of degrading its ability to detect the sensations themselves.

“Previous studies have focused on how brain adaptation influences how much information from the outside world is being transmitted by the thalamus to the cortex, but we showed that it is also important to focus on what information is being transmitted,” said Stanley.

Recording how neurons in different parts of the brain simultaneously communicate with each other in different situations is a big step in the neuroscience field. The researchers plan to use the techniques from this study to probe the effects of brain injury, which can change the degree of synchronization of neurons in the brain, resulting in harmful effects.

In addition to Stanley, Coulter Department research scientist Qi Wang and Harvard University researchers contributed to this work, which is supported by the National Institutes of Health.

Filling the Neuroscience Toolbox

Device for Probing Neurons in Tissue Samples -- Axion BioSystems, a startup company based on intellectual property developed at Georgia Tech, offers neural interfacing technologies for basic science, and for pharmaceutical and clinical research applications. The company has developed microelectrode arrays (MEAs) that allow simultaneous stimulation and recording of neural tissue, and include low-power chips that can  service hundreds of channels.

“Our objective has been to develop devices that can precisely manipulate and monitor electrically active cells and tissues of many types – including brain, spinal, muscle and cardiac – and provide real-time access to complex electrophysiological information,” said James Ross, the company’s chief technical officer. “Researchers using Axion’s technology capture biological models of human heartbeats and brain waves in a dish, which opens the door to a wide range of drug development and safety tests.”

In addition to Ross and company CEO Tom O’Brien, Axion BioSystems was founded by School of Electrical and Computer Engineering professor Mark Allen, Department of Biomedical Engineering professor Stephen DeWeerth, research engineer Edgar Brown and Swami Rajaraman, a recent Ph.D. graduate.

Axion has raised more than $9 million from private investors, grants from the National Institutes of Health’s Small Business Innovation Research (SBIR) program and early-stage funding from the Georgia Research Alliance (GRA). The company resides in laboratory and office space at the Advanced Technology Development Center (ATDC) biosciences incubator on Georgia Tech’s campus.

The company is currently working to increase the sales and adoption of its products by pharmaceutical companies, contract research organizations and academic institutions. Since it was founded in 2007, the company has grown from two to 20 employees and launched two commercial products – the Muse and the Maestro.

“The technology we licensed from the Georgia Tech Research Corporation allows us to provide two MEA systems that reduce the cost and complexity of conducting neuroscience research,” explained Ross. “Both systems consist of low-cost, disposable multielectrode arrays, and integrated circuits that eliminate stimulation artifacts and enable simultaneous stimulation and recording.”

The Muse is a bench-top system containing 64 channels for stimulating and recording electroactive tissue. The high-throughput Maestro contains 768 stimulating and recording channels, accommodates multiwell plates of up to 96 wells and is suited for large-scale cellular analysis in commercial drug screening applications.

While the company’s current efforts are focused on pharmaceutical drug screening, ongoing development is expected to result in products in the medical diagnostic and medical device arenas, Ross said.

Devices for Probing Neurons in Living Animals -- When high-fidelity recording of individual neurons in live animals is required, whole-cell patch clamp electrophysiology of neurons in vivo is the gold-standard, but it requires great skill to perform. The technique utilizes a glass micropipette to establish electrical and molecular connections to the insides of neurons embedded in intact tissue to record synaptic and ion-channel-mediated events.

Researchers at Georgia Tech and the Massachusetts Institute of Technology (MIT) have developed a simple robot that automatically performs whole-cell patch clamping in vivo. Using the robot, the researchers have demonstrated high throughput and recording quality in the cortex and hippocampus of small animals.

“With the robot, neuroscientists can achieve high-quality recordings with yields that exceed those of skilled humans at speeds sufficient to enable an unskilled human operator to clamp dozens of cells or more per day and collect data about each one’s gene expression, shape and electrical behavior,” said Craig Forest, an assistant professor in the George W. Woodruff School of Mechanical Engineering.

Applications for the autopatching robot include studying the effects of drugs on neuron electrophysiology; examining neuron behavior in disease states, such as epilepsy and narcolepsy; and classifying neuron cell types on a high-throughput scale.

The robot was designed by Forest; Georgia Tech graduate student Suhasa Kodandaramaiah; Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences at the MIT Media Lab and MIT McGovern Institute; MIT graduate student Giovanni Franzesi; and MIT postdoctoral researcher Brian Chow.

The researchers recently created a startup company, Neuromatic Devices, to commercialize the device. Development of the new technology was funded primarily by the National Institutes of Health, the National Science Foundation and the MIT Media Lab.

Maysam Ghovanloo, an associate professor in Georgia Tech’s School of Electrical and Computer Engineering, has developed a wireless system that collects neural signals from awake, freely moving animals during behavioral neuroscience research experiments. The Wireless Implantable Neural Recording (WINeR) system can simultaneously record from 32 channels for an unlimited period of time using a wireless inductive power transmission system.

“The WINeR system removes the need to tether a small animal via cable to a neural recording device during behavioral neuroscience research experiments and relieves the animal from carrying bulky batteries, thus eliminating two major sources of motion artifacts and bias,” said Ghovanloo.

WINeR is powered by the EnerCage system, which consists of an array of overlapping spiral planar coils that cover the bottom of the experimental area and enable inductive power transmission. A mobile unit attaches to the animal to regulate and deliver a constant amount of inductive power to the WINeR device and any other electrophysiology sensors used to collect data during an experiment, despite animal movements. The mobile unit also contains a small magnet that allows the animal’s location to be tracked in real time.

The researchers plan to add the functionality of wirelessly stimulating neurons to the WINeR device and increase the number of channels it provides.

Ghovanloo is collaborating with Joseph Manns, an assistant professor in the Emory University Department of Psychology, and Karim Oweiss, an associate professor in the Michigan State University Department of Electrical and Computer Engineering and the Neuroscience Program, to test the WINeR and EnerCage systems. This work is supported by the National Science Foundation and the National Institutes of Health.

To alleviate the need for electrodes implanted in the brain, researchers in the Georgia Tech Research Institute (GTRI) are collaborating with Neural Signals Inc. to explore the potential use of near-infrared fluorescent probes to wirelessly transmit neural signals from inside the brain to an external recording device.

A team led by GTRI principal research scientist Brent Wagner is investigating the possibility of connecting neurons to a wireless neural interface system that could respond to low-voltage, low-frequency electrical signals in the brain. The system would consist of a grid of gold nanoparticles, each linked via flexible strand of DNA to a semiconductor quantum dot.

With this system, when a neural cell is at rest, the quantum dot and gold nanoparticle are in close proximity, so no light is emitted from the quantum dot. When a neural cell fires, the voltage change on the neuron’s surface pushes the quantum dot away from the gold nanoparticle, allowing the quantum dot to emit light. The precise location of the quantum dot’s near-infrared luminescence can be detected using an infrared camera.

“The sensing mechanism for the system is based on energy transfer between the quantum dot and the gold nanoparticle,” said Wagner. “We think one of the major advantages of this type of system is its potential to transmit a high throughput of neural signals from multiple recording sites at the same time without the use of bulky cables or implanted electrodes.”

This project is supported by the GTRI Independent Research and Development (IRAD) program.

Researchers in the Georgia Tech School of Chemical and Biomolecular Engineering are building devices to help neuroscientists better understand how neurons in the brain contribute to an organism’s behavior.

Using inexpensive components from ordinary LCD projectors, associate professor Hang Lu can control the brain and muscles of freely moving tiny organisms, including the Caenorhabditis elegans worm that is commonly used for biological studies. Red, green and blue lights from the projector activate light-sensitive microbial proteins that are genetically engineered into the worms, allowing the researchers to switch neurons on and off like light bulbs and turn muscles on and off like engines.

The inexpensive illumination technology allows researchers to stimulate and silence specific neurons and muscles of the worms, while precisely controlling the location, duration, frequency and intensity of the light.

Use of the LCD technology to control small animals advances the field of optogenetics – a mix of optical and genetic techniques that has given researchers unparalleled control over brain circuits in laboratory animals. Until now, the technique could be used only with larger animals by placement of an optical fiber into an animal’s brain, or by illumination of an animal’s entire body.

For another project, Lu developed a microfluidic device that enables genetic studies on small organisms to be performed more quickly. An addition to the system since its original development is a laser beam that can destroy individual neurons. By monitoring the animal’s behavior after the laser ablation, the researchers can infer the function of each neuron. The process takes only 20 to 30 seconds, much less than the half hour it can take to ablate neurons using other techniques.

Lu and collaborators at the Queensland Brain Institute and the University of Queensland in Brisbane, Australia, have also adapted the original design of the microfluidic device to a curved geometry that enables positioning C. elegans bodies into lateral orientations. This alignment makes it easier to analyze neuronal developmental and disease processes that travel from the worm’s head to end or laterally across the worm’s body. Results of this research were published in April 2012 in the journal PLoS ONE.

“These systems have many applications in developmental and behavioral neuroscience of model organisms,” said Lu. “Our challenge is to make them as easy to use as possible so that the technology can make an impact in biological and medical research.”

Lu’s research is supported by the National Science Foundation, the National Institutes of Health and the Alfred P. Sloan Foundation.

Models of How the Brain Processes Information -- Christopher Rozell, an assistant professor in the Georgia Tech School of Electrical and Computer Engineering, uses mathematical models and signal processing technologies to understand how the brain organizes and processes images and sounds.

“Machine systems and the human brain perform similar tasks, such as speech recognition and computer vision, but the machines still fall far short of the human brain in these tasks, especially in the areas of power consumption and efficiency,” said Rozell.

In the brain, information about a stimulus in the outside world is communicated to higher centers in the brain by a collection of electrochemical signals present in groups of neurons. Recent evidence indicates that these groups of neurons may represent information by activating only a few of these units – known as a sparse code – and never centralizing the information in a single decision-making unit.

While sparse coding in neural systems is not well understood, Rozell and School of Electrical and Computer Engineering professor Jennifer Hasler and associate professor Justin Romberg are developing neurally plausible analog circuits to quickly find sparse codes. This approach could potentially solve problems relevant for many engineering applications much faster, while using less power than a traditional digital system.

“We don’t have the time or capability to record the characteristics and properties of each of the billions of neurons in the brain to validate our models, but we know our models of neural coding for sensory information are biophysically realistic because we verify them against published results of electrophysiology experiments,” said Rozell.

Researchers in Rozell’s laboratory are also examining what advantages a sparse code might have for the brain, which is making perceptual judgments based on visual data. By investigating how the brain transforms the outside world into meaningful representations it can work with, Rozell hopes better brain-machine interfaces can be designed, more efficient signal processing systems can be developed, and vision and hearing deficits can be corrected. This research is supported by the National Science Foundation and the National Institutes of Health.

Monitoring Activity in the Brain During Cognitive Tasks

Picking Out the Right Tool -- Choosing how to use tools to accomplish a task is a natural and seemingly trivial aspect of our lives, yet it can be very difficult for persons with certain brain injuries.

“In my laboratory, I study cognitive motor control,” said Georgia Tech School of Applied Physiology assistant professor Lewis Wheaton. “I want to understand the neural system that allows us to select the best tool to accomplish a task, pick that tool up and use it correctly to complete the task without overloading our brains with information.”

In a recent study, Wheaton identified neural activation patterns in the brain associated with watching tools used in correct and incorrect contexts. He used the functional MRI (fMRI) scanner at the Georgia State/Georgia Tech Center for Advanced Brain Imaging, along with electroencephalography (EEG), to record neural activations in the brain as healthy individuals identified whether tools shown in photographs were being used in correct or incorrect contexts. For example, a participant might be shown a hammer and nail, which is a correct tool use, or a hammer and coffee mug – an incorrect tool use.

The fMRI results revealed that when participants identified correct tool use, different parts of the brain became active compared to when they identified incorrect tool use. The EEG recordings provided additional information about the evolution of these activations over time. Activation occurred between 300 and 400 milliseconds after a correct tool use image was shown, but more quickly following onset of an incorrect tool use image. These findings were published in the journals Brain Research and Frontiers in Human Neuroscience.

Wheaton is now using the information he learned about the neural mechanisms of tool use in healthy brains to better understand tool learning and why some individuals experience impaired tool-related behavior following a stroke – a deficit called apraxia.

“In conceptual apraxia, we think the network that codes for incorrect tool use may be selectively damaged and incorrect contextual information is being passed to the areas of the brain activated by correct tool use. Because no error signal arises, contextually inappropriate use becomes possible,” said Wheaton.

Predicting an Individual’s Attentiveness -- Shella Keilholz’s long-term research goal is to build a model of spontaneous activity in the brain. As an engineer, she views the brain as a collection of hierarchical networks, with local networks of cells that work together and larger networks where information is transferred between different areas in the brain.

Keilholz is part of a team that is using the fMRI scanner at the Georgia State/Georgia Tech Center for Advanced Brain Imaging to probe the functional connectivity of the brain while an individual is performing a cognitive task requiring vigilance. The researchers are investigating whether the complex neural interactions between spatially distinct brain regions can be used to predict how well an individual will perform on cognitive tasks.

Funding for this work is provided in part by the U.S. Air Force through the Bio-nano-enabled Inorganic/Organic Nanostructures and Improved Cognition (BIONIC) Air Force Center of Excellence at Georgia Tech.

The team’s goal is to find a stable marker in the fMRI signal that is associated with cognitive processing and alertness. Initial results of their experiments show that the level of brain activity preceding the presentation of a visual stimulus can predict how fast an individual will respond to the stimulus during a vigilance task.

“U.S. Air Force analysts must remain attentive to computers and controls for hours at a time, so we are trying to develop a noninvasive way to measure the current state of an individual’s brain and determine if that person is getting off task,” said Keilholz, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “With that information, one might be able to develop a way to refocus that person and get him or her back on task, which would optimize work effectiveness and possibly save lives.”

Also contributing to this project are School of Psychology associate professor Eric Schumacher, and Air Force Research Laboratory biomedical engineer Andrew McKinley and integration manager Lloyd Tripp.

Recalling Memories -- Audrey Duarte, an assistant professor in Georgia Tech’s School of Psychology, is a cognitive neuroscientist – someone who looks at the neuroscience that supports human behavior. Duarte’s research is focused on episodic memory, which is the memory of specific events, situations and experiences. Your first day of school, attending a friend’s birthday party and what you ate for dinner last night are examples of episodic memories.

Episodic memory can be affected by a number of disorders – including stroke, dementia and Alzheimer’s disease – and even healthy aging. Through her research, Duarte is trying to understand what happens as the brain ages to cause decline in memory abilities over time.

“We want to determine if there are specific areas in the brain or specific brain networks that are disproportionately affected in a negative way by aging, causing lapses in episodic memory,” she said.

Using the fMRI scanner at the Georgia State/Georgia Tech Center for Advanced Brain Imaging, Duarte measures activity from thousands of neurons in the brain at the same time and assesses the patterns of activity while young and older adults examine and subsequently retrieve pictures of common objects from memory. Using this data, Duarte is developing strategies to help older adults better encode and retrieve episodic memories.

“By finding out where an individual’s attention is drawn when looking at a picture, we can better understand the relationship between attention and memory and look for ways to remediate impairments in episodic memory,” said Duarte.

This research is supported by the National Science Foundation, the National Institutes of Health and the American Federation for Aging Research.

Accomplishing Fine Motor Tasks -- In another project, Georgia Tech researchers are studying the effects of aging on the neural connectivity between the motor cortex and muscles during tasks that require fine motor skills.

“We know that aging and dual-task paradigms often degrade fine motor performance, so we wanted to compare the performance of young and older adults during the execution of a fine motor task alone and concurrent tasks that required substantial divided attention,” said Minoru Shinohara, an associate professor in the Georgia Tech School of Applied Physiology.

For the study, two groups of healthy adults, one group between the ages of 18 and 38 and the other between 61 and 75, performed tasks involving one-finger motor, two-finger motor, cognitive and concurrent motor-cognitive skills.

As the participants completed the tasks, Shinohara and School of Electrical and Computer Engineering graduate student Ashley Johnson examined the synchrony between two signals – an electroencephalogram (EEG) acquired from the primary motor cortex in the brain and an electromyogram (EMG) acquired from a muscle in the hands. The synchronous measurement is called corticomuscular coherence.

In the study, the older adults demonstrated higher corticomuscular coherence than the young adults during performance of both unilateral and dual tasks. Corticomuscular coherence was highest in the older adults, especially during the dual motor-cognitive task and increased with an additional task for both groups of subjects. But during the motor-cognitive task, corticomuscular coherence was negatively correlated with motor output error across young, but not older, adults. The results of the study were published online in January 2012 in the Journal of Applied Physiology.

“The findings demonstrate that older and younger adults don’t need to use the same neural strategy to accomplish the same motor performance,” said Shinohara. “We are seeing changes in neural strategies for accomplishing fine motor skills with aging.”

In addition to aging, these types of changes in neural strategies could be valuable for rehabilitation applications. Individuals with neurological deficits might benefit from using a different strategy to perform motor tasks, rather than using the same strategy they used before the deficit occurred.

Georgia Tech’s extensive involvement in neuroscience research – from basic to clinical science – reflects the interests of researchers from multiple academic departments and the Georgia Tech Research Institute (GTRI). The researchers are working to better understand how the brain works and apply this knowledge to improving brain function, which has applications for those who have sustained losses due to injuries or disease.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NS054809, NS079268, NS043486, NS48285, NS062031 and NS058465), the National Institute of Biomedical Imaging and Bioengineering (EB009437 and EB012803), the National Institute on Aging (AG035317 and AG016201), the National Institute of General Medical Sciences (GM088333), the National Eye Institute (EY019965), the National Science Foundation (ECCS-0824199, CBET-0954578, DBI-0649833, CCF-0905346 and BCS-1125683), and the U.S. Air Force (FA9550-09-1-0162). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NIH, NSF or U.S. Air Force.

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Two researchers from Georgia Tech were invited by the White House to hear the announcement live. Robert E. Guldberg, executive director for the Parker H. Petit Institute for Bioengineering and Bioscience and mechanical engineering professor along with Craig Forest, an assistant professor in mechanical engineering, were present to hear President Obama’s pledge.

“To hear the President’s announcement was exciting," Guldberg said. “Neuroengineering is a major strength at Georgia Tech and along with our state-wide partners, we are well poised to make significant contributions to this new initiative."

The project is modeled after previous scientific grant challenges, such as the Human Genome Project which mapped the human genome. Francis Collins, director, National Institute of Health, called the potential advancements from this research the next “greatest scientific frontier.”

Unlocking the human brain has the potential to impact dozens of diseases including, Parkinson’s disease, eye diseases, mental health, traumatic brain injury, to name just a few. The NIH committed $40 million from its budget for the project and other government agencies, including the National Science Foundation as well as Defense Advanced Research Projects Agency also made commitments. Additional funds will come from foundations and other non-profits.

“BRAIN represents a massive challenge across an interdisciplinary spectrum, for example, neuroengineering tool development, neuroscientific interpretation of the deluge of data to arise, and computing challenges in storage and processing,” said Forest who is currently conducting research in this area. “The magnitude of the undertaking by mankind is analogous to the Apollo Space Program or Manhattan Project in its breadth, depth, technical complexity and the need for large teams focused on ‘big science.’”

Forest recently collaborated with MIT to develop a way to automate the process of finding and recording information from individual neurons in the living brain. He was featured on CNN earlier this week for this work.

But that could soon change: Researchers at MIT and the Georgia Institute of Technology have developed a way to automate the process of finding and recording information from neurons in the living brain. The researchers have shown that a robotic arm guided by a cell-detecting computer algorithm can identify and record from neurons in the living mouse brain with better accuracy and speed than a human experimenter.

The new automated process eliminates the need for months of training and provides long-sought information about living cells’ activities. Using this technique, scientists could classify the thousands of different types of cells in the brain, map how they connect to each other, and figure out how diseased cells differ from normal cells.

The project is a collaboration between the labs of Ed Boyden, associate professor of biological engineering and brain and cognitive sciences at MIT, and Craig Forest, an assistant professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech.

“Our team has been interdisciplinary from the beginning, and this has enabled us to bring the principles of precision machine design to bear upon the study of the living brain,” Forest says. His graduate student, Suhasa Kodandaramaiah, spent the past two years as a visiting student at MIT, and is the lead author of the study, which appears in the May 6 issue of Nature Methods.

The method could be particularly useful in studying brain disorders such as schizophrenia, Parkinson’s disease, autism and epilepsy, Boyden says. “In all these cases, a molecular description of a cell that is integrated with [its] electrical and circuit properties … has remained elusive,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research. “If we could really describe how diseases change molecules in specific cells within the living brain, it might enable better drug targets to be found.”

Automation

Kodandaramaiah, Boyden and Forest set out to automate a 30-year-old technique known as whole-cell patch clamping, which involves bringing a tiny hollow glass pipette in contact with the cell membrane of a neuron, then opening up a small pore in the membrane to record the electrical activity within the cell. This skill usually takes a graduate student or postdoc several months to learn.

Kodandaramaiah spent about four months learning the manual patch-clamp technique, giving him an appreciation for its difficulty. “When I got reasonably good at it, I could sense that even though it is an art form, it can be reduced to a set of stereotyped tasks and decisions that could be executed by a robot,” he says.

To that end, Kodandaramaiah and his colleagues built a robotic arm that lowers a glass pipette into the brain of an anesthetized mouse with micrometer accuracy. As it moves, the pipette monitors a property called electrical impedance — a measure of how difficult it is for electricity to flow out of the pipette. If there are no cells around, electricity flows and impedance is low. When the tip hits a cell, electricity can’t flow as well and impedance goes up.

The pipette takes two-micrometer steps, measuring impedance 10 times per second. Once it detects a cell, it can stop instantly, preventing it from poking through the membrane. “This is something a robot can do that a human can’t,” Boyden says.

Once the pipette finds a cell, it applies suction to form a seal with the cell’s membrane. Then, the electrode can break through the membrane to record the cell’s internal electrical activity. The robotic system can detect cells with 90 percent accuracy, and establish a connection with the detected cells about 40 percent of the time.

The researchers also showed that their method can be used to determine the shape of the cell by injecting a dye; they are now working on extracting a cell’s contents to read its genetic profile.

Development of the new technology was funded primarily by the National Institutes of Health, the National Science Foundation and the MIT Media Lab.

New era for robotics

The researchers recently created a startup company, Neuromatic Devices, to commercialize the device.

The researchers are now working on scaling up the number of electrodes so they can record from multiple neurons at a time, potentially allowing them to determine how different parts of the brain are connected.

They are also working with collaborators to start classifying the thousands of types of neurons found in the brain. This “parts list” for the brain would identify neurons not only by their shape — which is the most common means of classification — but also by their electrical activity and genetic profile.

“If you really want to know what a neuron is, you can look at the shape, and you can look at how it fires. Then, if you pull out the genetic information, you can really know what’s going on,” Forest says. “Now you know everything. That’s the whole picture.”

Boyden says he believes this is just the beginning of using robotics in neuroscience to study living animals. A robot like this could potentially be used to infuse drugs at targeted points in the brain, or to deliver gene therapy vectors. He hopes it will also inspire neuroscientists to pursue other kinds of robotic automation — such as in optogenetics, the use of light to perturb targeted neural circuits and determine the causal role that neurons play in brain functions.

Neuroscience is one of the few areas of biology in which robots have yet to make a big impact, Boyden says. “The genome project was done by humans and a giant set of robots that would do all the genome sequencing. In directed evolution or in synthetic biology, robots do a lot of the molecular biology,” he says. “In other parts of biology, robots are essential.”

Other co-authors include MIT grad student Giovanni Talei Franzesi and MIT postdoc Brian Y. Chow. 

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