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Empowering Neural Engineering

Some of the earliest neural engineering work in the field was – pun unintended – conducted at U-M, including the invention of the first silicon neural electrode by Kensall Wise, professor emeritus of BME and Electrical Engineering and Computer Science.

Today a cluster of innovative, accomplished faculty is driving the field forward, working side-by-side with clinicians in the U-M Medical School to focus on translational applications to improve the lives of patients.

Brain-machine interfaces and prosthetic hand control

Cynthia Chestek | Assistant Professor | Director, Cortical Neural Prosthetics Laboratory

Chestek’s lab works to restore natural movement to individuals who have lost the use of their hands, whether due to amputation, spinal cord injury or other cause of paralysis. Her work includes improving neural signal control of prosthetics and natural limbs through novel and improved brain-machine interfaces, functional electrical stimulation and assistive exoskeletons.

Cynthia Chestek, BME Professor, and Zachary Irwin, BME PhD Student. Photo: Joseph Xu

Toward that goal, Chestek and collaborators are developing new electrodes. She and Professor Euisik Yoon recently demonstrated an eight-micrometer carbon-fiber probe. Research to date has shown that the probes cause significantly less scarring and immune response than conventional larger electrodes.

In a collaborative project with Parag Patil, MD, to develop a system for brain controlled functional electrical stimulation, Chestek and her students apply machine learning algorithms to neural signals recorded by 100-channel implanted arrays. Using Kalman filters and regression techniques, the objective is to understand the relationships between hand movements and their respective neuron firing rates.

In collaboration with Paul Cederna, MD, professor of surgery and chief of plastic surgery, Chestek’s lab has been conducting pre-clinical work on hand control using neural signals. One of the barriers to nerve-controlled prosthetic limbs has been the small signal. The team’s work found muscle grafted to the ends of split nerves – a procedure Dr. Cederna performs on patients suffering from painful nerve growths following amputation – can amplify neural signals to the point they can control a prosthetic hand.

Chestek joined the BME faculty in 2012 and jokes that she will be here forever. “At U-M, we have a Top 10 engineering school and a Top 10 medical school — I came here for the very strong collaborations and, because of the doctors, I’ll never leave. I collaborate with a surgeon on every project. There’s a fertile group of clinicians here who are deeply invested in this technology and to bringing it to clinical practice.”

Neurostimulation for chronic pain

Scott Lempka | Assistant Professor |Neuromodulation Laboratory

For the 25 million Americans and countless others around the globe who suffer from chronic pain, Lempka’s work holds great promise. Research in his lab focuses on neuromodulation for managing chronic pain and, although such techniques have been used for years, only about 50 percent of patients get relief. In those who do, however, it’s often not enough to make a real impact on their quality of life.

The Neuromodulation Lab develops computer
models of the electric fields generated by the
stimulation and the direct neural response.

To identify and better understand the specific mechanisms by which neurostimulation works, and why it works for some patients and not others, Lempka’s group takes an engineering approach to develop patient-specific computer models. The models are generated from quantitative and qualitative clinical data, obtained from CT, MRI and functional MRI imaging, and how patients respond to different stimulation parameters.

In recently published work, Lempka and colleagues describe a first-in-man clinical trial of deep brain stimulation for post-stroke pain that targets alternate pathways, specifically those related to emotions and behavior, rather than sensation. The areas targeted, the ventral striatum/anterior limb of the internal capsule, have been widely studied and safely used in treatment of obsessive compulsive disorder and refractory depression. Although pain intensity wasn’t significantly reduced in the study, participants’ reports of anxiety and depression related to the pain were.

“This tells us we should consider changing what we consider a success with these neurostimulation therapies. Rather than fixating on pain intensity, we should shift our focus to reducing pain-related suffering or disability,” says Lempka, who joined the BME faculty in January 2017 and is excited about further research. “Working with U-M’s clinical pain research groups and pain management specialists will help us not only better understand how neurostimulation works on pain but also to develop innovative and more effective patient-specific therapies.”

Lempka, S. et al. Randomized clinical trial of deep brain stimulation for poststroke pain. Annals of Neurology, 2017; 81 (5): 653; DOI: 10.1002/ana.24927.

Improving quality of life for the visually impaired

James Weiland | Professor | BioElectronic Vision Lab

Weiland is co-developer of a bioelectronic retinal prosthesis, or so-called bionic eye, which electrically stimulates the retina and can partially restore vision to individuals who have lost their sight due to inherited retinal disease. The Argus II was approved by the U.S. Food and Drug Administration in 2013 and has since been implanted in over 200 people worldwide, including 10 at the Kellogg Eye Center at U-M.

Weiland’s BioElectronic Vision Lab investigates the fundamental mechanisms underlying the ways in which implantable and wearable electronic systems interact with the natural visual system and other senses. He has demonstrated the feasibility of using MRI and fMRI in patients with the retinal prosthesis to better understand how the visual pathways in the brain respond to sight recovery and also how these pathways adapt to process other sensory input, including tactile input, in a phenomenon known as cross-modal activation.

In addition, Weiland and researchers in his lab are studying how these prosthetic systems affect the anatomy and functioning of the visual system over time in order to optimize existing and future devices. His lab is also developing a wearable, smart camera system that can work with the Argus or as a standalone assistive technology for the visually impaired.

Findings from these studies will lead to further refinements to the Argus II to enhance vision restoration. Involving Argus patients in evaluating design changes is a key aspect to his research program.

Weiland earned his MS and PhD degrees in BME and returned to campus to join the BME faculty in January 2017, after holding faculty appointments at Johns Hopkins University and University of Southern California.

“Ann Arbor has always been a second home for me,” Weiland says. “When an opportunity became available to join the BME department, it was difficult to not explore the possibility. The more I visited and talked with faculty and students in BME and Ophthalmology, the more the move made sense. The excellence of the engineering and medical schools was a strong attraction.

Root causes: Bioelectronics to restore organ function

by Kim Roth

The work of Assistant Professor Tim Bruns has been recognized with a highly competitive National Science Foundation Faculty Early Career Development (CAREER) Award. The five-year award will fund Bruns’ winning proposal, “Modeling dorsal root ganglia: Electrophysiology of microelectrode recording and stimulation.”

Bruns directs the U-M Peripheral Neural Engineering and Urodynamics (pNEURO) Lab, which develops bioelectronic interfaces with the peripheral nervous system to understand systems-level neurophysiology as well as to restore autonomic organ function. Dorsal root ganglia (DRG), which lie near the spinal cord and contain the cells of multiple, converging peripheral sensory nerves, have been an important focus of his research.

“Many peripheral nerves are small and hard to access, so when we’re trying to learn about these sensory systems, recording and decoding signals from the DRG can simplify the process while still giving us important clues about what’s happening,” Bruns says.

But electrodes used to record signals from or stimulate DRG have shortcomings that lessen the efficacy of current and potential therapies and slow research efforts. With the CAREER Award, Bruns will study and model the anatomy and behavior of neurons in the DRG to better understand how they interact with electrodes and, ultimately, improve upon existing technology.

Mapping DRG

While many researchers have examined individual nerve cells in the DRG, Bruns is one of the first to study their arrangement, electrical behavior, and interactions at a systems level within the DRG.

In work recently published in Journal of Neuroscience Methods, Bruns and lab members found concentrations of nerve cells in different areas of the DRG and demonstrated a novel way to quantify their patterns and distribution.

Through collaborations with U-M Electrical Engineering and Computer Science faculty, his team is using the findings to develop improved microelectrodes, including a new, flexible, non-penetrating thin-film array that better matches the shape of the DRG and may reach more neurons with better long-term viability than current devices.

Student Zachariah Sperry demonstrates a novel thin-film electrode array that is being developed in collaboration with Electrical Engineering researchers. Bruns’ lab members have worked with slugs to validate use of the electrode, and examine slug neural activity, prior to focused testing in our large-animal bladder focused experiments. Photo by Marcin Szczepanski/Multimedia Director and Senior Producer, University of Michigan, College of Engineering

Toward restored bladder function

In the case of bladder dysfunction, sensory neuron signals recorded from particular DRG can help researchers and clinicians learn more about the bladder’s state. The DRG also can serve as a target for nerve stimulation therapies, including closed-loop systems that provide electrostimulation when bladder pressure approaches a critical threshold.

Bruns’ team is studying the effectiveness of new algorithms to estimate bladder pressure from DRG signals and also has demonstrated the use of microelectrodes to monitor and modulate lower urinary tract behavior from DRG signals and DRG stimulation, both in animal models. These are the first long-term, behavioral experiments examining bladder function at DRG, providing a clearer path towards clinical relevance.

Tim Bruns, Assistant Professor of Biomedical Engineering at Michigan Engineering and his students observe the buccal mass of an aplysia Californica (sea slug) moving. From left are Ahmed Jiman, Aileen Ouyang, Tim Bruns and Zachariah Sperry. Photo by Marcin Szczepanski/Multimedia Director and Senior Producer, University of Michigan, College of Engineering

Improving sexual dysfunction

Some patients using existing bladder pacemakers to improve bladder function have reported improvements in sexual function, too. Bruns and colleagues in the U-M Medical School believe neurostimulation may hold promise as a potential treatment for female sexual dysfunction (FSD). In pre-clinical research, his lab has found that peripheral nerve stimulation can increase vaginal blood flow, a proxy for assessing sexual arousal.

“In terms of importance, these are quality of life issues and incredibly important to patients, yet few researchers are working in these areas,” says Bruns. In collaboration with a urogynecologist in the U-M Medical School, Bruns recently conducted a patient survey to assess interest in neuromodulation for FSD. Over 700 respondents in Michigan completed the survey.

“…These are quality of life issues and incredibly important to patients, yet few researchers are working in these areas”Tim Bruns

The team now is leading an active clinical study that runs through early 2018. All three women who have completed the study so far had significant improvement in the Female Sexual Function Index, an assessment tool to gauge key aspects of sexual function in women.

Controlling blood glucose

In a small, exploratory study of kidney neuromodulation to control blood glucose, researchers in Bruns’ lab have found that stimulation in particular ranges can prevent the organs from reabsorbing sugar and boost glucose excretion from the body. The early findings are laying a foundation for further work to develop potential non-pharmacologic approaches to treating diabetes.

“FSD may affect up to 40 percent of adult women; millions of men and women suffer from bladder control issues; and diabetes affects nearly 10 percent of the U.S. population,” Bruns notes. “As we better understand how nerves control the ways in which our organs function and as we develop new interfaces for interacting with neurons, we’re finding more and more opportunities to improve quality of life for these, and other, patient populations – there’s so much we can do, especially when we work closely with clinicians.

“As we better understand how nerves control the ways in which our organs function and as we develop new interfaces for interacting with neurons, we’re finding more and more opportunities to improve quality of life for these, and other, patient populations”Tim Bruns

Bruns’ DRG work is funded by National Science Foundation CAREER Award 1653080, National Institutes of Health NIBIB SPARC grant U18EB021760, and Craig H. Neilsen Foundation grant 314980.

For more information on the FSD clinical trial, visit https://clinicaltrials.gov/ct2/show/NCT02692417 or contact Bruns at bruns@umich.edu

$7.75M for mapping circuits in the brain A new NSF Tech Hub will put tools to rapidly advance our understanding of the brain into the hands of neuroscientists.

The technology exists to stimulate and map circuits in the brain, but neuroscientists have yet to tap this potential.

Now, developers of these technologies are coming together to demonstrate and share them to drive a rapid advance in our understanding of the brain, funded by $7.75 million from the National Science Foundation.

“We want to put our technology into the hands of people who can really use it,” said Euisik Yoon, leader of the project and professor of electrical engineering and computer science at the University of Michigan.

By observing how mice and rats behave when certain neural circuits are stimulated, neuroscientists can better understand the function of those circuits in the brain. Then, after the rodents are euthanized, they can observe the neurons that had been activated and how they are connected. This connects the behavior that they had observed while the rodent was performing a controlled experiment with a detailed map of the relevant brain structure.

We can achieve structural and functional mapping at an unprecedented scale. Euisik Yoon, BME and EECS professor

It could lead to better understanding of disease in the brain as well as more effective treatments. In the nearer term, the details of neural circuitry could also help advance computing technologies that try to mimic the efficiency of the brain.

Over the last decade or so, three tools have emerged that, together, can enable the mapping of circuits within the brain. The most recent, from U-M, is an implant that uses light to stimulate specific neurons in genetically modified mice or rats and then records the response from other neurons with electrodes.

Probes like this one, which stimulate neurons with light and then record activity with electrodes, are just one facet of the technology suite that can help neuroscientists map circuits in the brain. Photo: Fan Wu, Yoon Lab, University of Michigan

Unlike earlier methods to stimulate the brain with light, with relatively large light-emitters that activated many nearby neurons, the new probes can target fewer neurons using microscopic LEDs that are about the same size as the brain cells themselves. This control makes the individual circuits easier to pick out.

The “pyramidal” neurons that cause action—rather than inhibit it—will be genetically modified so that they respond to the light.

“They are just one of the neuron types we are seeking to map,” said John Seymour, one of the co-investigators and U-M assistant research scientist in electrical engineering and computer science. “If you can record from motor cortex pyramidal neurons, you can predict arm movement, for example.”

To visualize the structure of pyramidal cells and other kinds of neurons, researchers need a way to see each tree in the brain’s forest. For this, co-investigator Dawen Cai, U-M assistant professor of cell and developmental biology, has been advancing a promising approach known as Brainbow. Genetically modified brain cells produce fluorescent tags, revealing each cell as a random color.

When it is time to examine the brain, a technique to make the brain transparent will remove all the fatty molecules from a brain and replace them with a clear gel, making it possible to see individual neurons. It was pioneered by another co-investigator, Viviana Gradinaru, who is a professor of biology and biological engineering at the California Institute of Technology.

“Not only may we understand how the signal is processed inside the brain, we can also find out how each neuron is connected together so that we achieve structural and functional mapping at an unprecedented scale,” Yoon said.

While these are the central tools, others at Michigan are working on methods to make the electrodes that record neuron activity even smaller and therefore more precise. In addition, a carbon wire electrode design could even pick up the chemical activity nearby, adding measurements of neurotransmitters as a new dimension of information.

To share these new tools, the team will bring in neuroscientists for annual workshops and then provide them with the hardware and software they need to run experiments in their own labs. For the tools that prove to be most useful, they will seek commercialization opportunities so that they remain available after the project ends.

The project is called Multimodal Integrated Neural Technologies (MINT) and has been awarded as a 5-year National Science Foundation NeuroNex Technology Hub.

Other co-investigators include Cynthia Chestek, U-M assistant professor of biomedical engineering; James Weiland, U-M professor of biomedical engineering; Ken Wise, the William Gould Dow Distinguished University Professor Emeritus of Electrical Engineering and Computer Science at U-M; and György Buzsáki, professor of neuroscience at New York University. Seymour and Yoon are also affiliated with biomedical engineering at U-M. Cai is affiliated with Michigan Medicine.

The neural probes with micro LEDs are made in the Lurie Nanofabrication Facility at U-M.

Original Publication: https://news.engin.umich.edu/2017/08/7-75m-for-mapping-circuits-in-the-brain/

Written By: Kate McAlpine, Senior Writer & Assistant News Editor, Michigan Engineering Communications and Marketing

Cover Caption: To follow the long, winding connections among neurons, a technique called “Brainbow” labels each neuron a random color. Credit: Dawen Cai, Cai Lab, University of Michigan

Video Caption: John Seymour explains how the new grant will help neurotechnologists further research to enable a better understanding of the pathways in the brain.

Tim Bruns wins NSF CAREER Award

U-M BME assistant professor Tim Bruns has received a prestigious National Science Foundation Faculty Early Career Development (CAREER) Award. Bruns leads the Peripheral Neural Engineering and Urodynamics Lab (pNEURO Lab) in Biomedical Engineering. The group is interested in developing interfaces with the peripheral nervous system to restore function and to examine systems-level neurophysiology, primarily focusing on organ function. Bruns will use his award to study and model the behavior of neurons within dorsal root ganglia (DRG), unique structures next to the spinal cord that contain converging sensory nerves. This work will inform research and development of novel microelectrodes designed to record and stimulate DRG. Research in this area could lead to the restoration of nerve function for a wide range of disorders.

2016 NSF Fellowships

Three BME students won prestigious National Science Foundation (NSF) Graduate Research Fellowships in 2016. They include PhD students Chrono Nu from Cindy Chestek’s Cortical Neural Prosthetics Lab and Peter Washabaugh from Chandramouli Krishnan’s Neuromuscular and Rehabilitation Robotics Laboratory, as well as master’s student Makeda Stephenson from Scott Hollister’s Scaffold Tissue Engineering Group.

Nu, who has also been awarded a Department of Defense (DoD) National Defense Science and Engineering Graduate (NDSEG) Fellowship, is using data from cortical recording systems to conduct computational analyses of brain activity in primates, such as decoding motor-related neurological signals. Washabaugh is working to design robotic devices for use in physical therapy and to explore the neuromuscular changes associated with these therapies. Stephenson is developing functional architectures for tissue engineering scaffolds.

A ‘Communication Breakdown’ During General Anesthesia

From: http://labblog.uofmhealth.org/

By: Haley Otman

May 09, 2016 2:39 PM

When ketamine is used for general anesthesia, two connected parts of the cortex turn to “isolated cognitive islands.”

It’s a topic that has long captivated doctors, scientists and the public — what exactly happens in your brain when you’re oblivious on the operating table?

Some anesthesia drugs work in a straightforward manner by dampening down neurons in the brain. The mechanism of one anesthetic, however, has proved elusive: ketamine.

Certain doses of ketamine induce general anesthesia, though brain activity can still be robust, says Cynthia Chestek, Ph.D., co-senior author of a new study in NeuroImage.

Ketamine is used often in patient care and in laboratory settings. The new paper examines the neurological mechanisms at work during ketamine anesthesia.

Co-senior authors Chestek and anesthesiologist George Mashour, M.D., Ph.D., led the research team, which took precise measurements down to the level of neurons in animal models.

“We found that general anesthesia reflects a communication breakdown in the cortex, even though sensory information is getting processed,” Mashour says. “But the processing appears to occur in isolated cognitive islands.”

Turns out, two adjacent parts of the brain that work together in the waking state simply stop talking to each other under general anesthesia. When awake, communication between the primary somatosensory cortex and the primary motor cortex is critical to normal function.

“This supports the idea that what anesthesia does to cause unconsciousness is interrupt communication between brain areas, stopping the processing of higher-level information,” says first author Karen Schroeder, a doctoral candidate in the U-M Department of Biomedical Engineering. “This was the first time anyone directly observed the interruption between the two areas using individual neurons.”

Different fields collaborating

Chestek’s biomedical engineering lab focuses on brain machine interfaces, recording activity of neurons and reading motor commands and sensory information in real time.

“This turned out to be really useful for the researchers in anesthesiology,” Chestek says. So her team got on board to measure both areas of the brain, which kept firing during anesthesia.

“As soon as we injected ketamine, the sensory information disappeared from the motor cortex. Normally these areas are tightly connected.”

The group plans to continue this work, turning next to investigate the level of anesthesia at which these changes in communication start to occur. They’re also looking into what the groups of neurons are doing under anesthesia when they are still active but no longer communicating with each other.

“These insights could potentially improve our ability to monitor patients’ level of consciousness,” Schroeder says.

Funding for the work came from the National Institutes of Health.