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 Publicationhttps://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.