By MARTY LEVINE
There have already been years of advances in understanding how electrodes can stimulate the human brain to produce sensations of movement in people’s damaged limbs (or functioning in their prostheses), aimed at allowing renewed control by the brain.
Now a team of six Pitt scientists — who recently won a Pitt Momentum Fund Scaling Award, which helps selected projects do work that may earn further and larger outside funding — will be looking to explore the issue in humans, non-human primates and rodents simultaneously.
Intracortical microstimulation (ICMS) is used widely for both clinical applications and experimentation. The goal of the team’s new project is to show that findings in mice and primates can be used to better understand ICMS in humans — and vice versa. But thus far it is still difficult to determine precisely how the stimulations, in their location and degree, can be duplicated in another species.
The two main questions the group will be asking now, according to their winning proposal: “How does ICMS activate cells and circuits in the cortex?” and “How does activation of these cells and circuits drive behavior and perception?”
While humans can tell scientists what each electrode stimulation produces — a buzzing or tingling feeling in the right hand, for instance — neither mice nor primates, of course, can do so. To get past this barrier, the group will be using transgenic mice, for one, with genetic material that has been altered to include other species’ genes that, for instance, glow when stimulated, allowing the exact stimulated cells to be pinpointed.
One member of the team, Robert Gaunt (faculty member in the Department of Physical Medicine and Rehabilitation at the School of Medicine and a leading expert on ICMS in humans), notes that, during the past decade of ICMS work, even when humans report their precise experiences with each electrode stimulation, it is very difficult to understand the “why” of the resulting sensations — why that feeling, and why there? “I have very limited tools to judge why these stimulations are different,” he says. The work of this team, Gaunt adds, will “probe the ‘why.’”
It will take the work of all team members to examine this question most fully, including designing new stimulus “trains” — sequences of stimulations using less-than-millisecond pulses — to produce different results.
Takashi Kozai (bioengineering faculty member in the Swanson School of Engineering), expert in neural devices and how stimulation neurotechnologies interact with tissue, will be examining the stimulations caused by these different trains. Alberto L. Vazquez (faculty member in Medicine’s radiology department and in Engineering’s bioengineering department), working with mice, will look at mechanisms for neuronal “recruitment” during electrical stimulation — how many cells are stimulated by an electrical pulse.
Omar Gharbawie (neurobiology faculty member in Medicine) will work with non-human primates as an important bridge between the human and the mouse work, while Bryan M. Hooks (neurobiology faculty member) will work with transgenic mice to identify which cell types in which brain regions are stimulated. Chengcheng Huang (faculty member in neuroscience), who was out of the country when the others spoke to the University Times, will develop computational models to relate the results across experiments and across species.
Determining how fast stimulation should be done and how different types of cells respond will be important, says Gaunt: “We think this may drive the peripheral and conscious experiences people have.”
The team plans to gather equivalent ICMS datasets from all three species and analyze them in the same way to compare results across the three groups, closing what they describe as “fundamental knowledge gaps about how ICMS activates cells and circuits across species.”
It is hoped that the work in primates and mice, using computer models, can help better understand the sensations that humans report during ICMS and also the reverse — that new discoveries in primates and mice can help scientists to design new ways to stimulate human brains in helpful manners for regaining limb function.
One of the challenges, Kozai says, is that the electrode-induced sensations in the brain eventually fade, and the team wants to figure out how to prolong that, “so that pressure is always pressure or temperature is always temperature.”
The impulse to extend this work from just motor control to sensations, Vazquez says, is ultimately to improve limb functioning overall.
“If they can’t feel what they are doing they can’t ever get good control,” Gaunt says of people who will ultimately benefit from this work. “How do we improve their state of life? The only way to improve progress is to bring animal and human research together.”
In the past, the National Institutes of Health — a key potential source of future funding — has been impressed by the idea of joining mice, non-human primate and human research but also was skeptical about its practicality, Gaunt says. This project aims to demonstrate that practicality.
“We want to establish Pitt as a hub for doing this kind of research,” Gharbawie says, and the Momentum Award will allow that.
“We are exceptional in terms of science, in terms of engineering, in terms of pioneering some of the patient work,” Kozai adds, “and we haven’t done a good job of communicating that and connecting with the rest of the world. How do we show our big findings that will help the rest of the world?”
Marty Levine is a staff writer for the University Times. Reach him at martyl@pitt.edu or 412-758-4859.
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