Researcher explores mysteries of neuronal communication

Prakash Kara, Ph.D.and colleagues at the Medical University of South Carolina have published an article in the journal "Nature" describing the results of a study that focused on finding out what drives the signals recorded during hemodynamic imaging, including fMRI, or functional magnetic resonance imaging. They discovered that blood flow may not be as tightly tied to increases in neuronal activity as previously thought. Kara, who runs the Kara lab at MUSC, explains what led to the research, what it could mean for patients and what's next.

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Q: What drew you into the field of brain research?

My overall interests in neuroscience, and this particular project being published in "Nature" on how neurons communicate with blood vessels, were accidents of sorts. I went to college with the intent of studying exercise science and sports medicine. In physiology courses, I began hearing about the various circuits in the brain that control our repertoire of behaviors. However, these were still relatively “black box” overviews, rather than microscopic-scale wiring diagrams of brain function.

I wanted to know how each neural circuit operated on the scale of individual neurons and synapses. So I thought I'd explore for a year in an honors program and then go back to my original life plans. However, by the end of that year of exploration I was hooked on neuroscience. So I embarked on a career in research and teaching.

Over the next two decades, I examined neural microcircuits responsible for seeing. It was fascinating to directly observe the patterns of electrical activity in the living brain - the controlled electrical storms - and how much it could explain how the brain works.

However, for these 20 years, I ignored studying the control of blood flow in small vessels within the brain. I had no formal training in vascular biology, which involves looking at the structure and function of microvessels.

My team and I could see blood vessels as shadows in our high-resolution imaging of neural circuits, but we viewed them as a nuisance, for the most part. We had to navigate around them for our electrode placements and we avoided them for getting the best images of neurons.

Then three things happened. First, we saw some cases in the literature on the interpretation of signals from neurons that we felt were contaminants from changes that were occurring in blood vessels. Then we discovered a dye that selectively labeled an important class of blood vessels in the brain. Finally, we realized we had a unique set of tools to advance the field of neurovascular coupling - in particular, the forms of neural activity that signal blood vessels to bring more blood, carrying oxygen and nutrients, to the most active neurons.

Q: How important is this work in terms of how it will eventually help patients?

It is difficult for scientists to rank their own research. Practically, I think our work represents a different way of thinking about how to approach solving the puzzles of how neurons communicate with blood vessels. It is not about saving lives on the seconds-to-minutes scale like a novel drug that rescues function after stroke. We are playing the long game on several fronts that are all grounded in basic science. How do brain circuits work, not just neurons but the other signaling elements also?

With more grant funding, we hope we can eventually have general and specific disease-curing benefits for humans and animals. I think our work is a stepping stone toward providing realistic expectations on what can be learned about neural circuits from data derived from brain-imaging techniques that rely on changes in the flow and oxygenation of blood—including functional magnetic resonance imaging (fMRI)—where it is often assumed that vascular changes reflect a proportional change in local neural activity.

There may be profound consequences for brain health when neurovascular signaling does not work the way we describe. This is speculation, but it is possible that one of the principles we talk about, surplus blood flow after neural activity, if absent, could degrade neural function gradually, over the span of months, years and decades.

Q: It’s an accomplishment to have articles published in journals such as "Nature," "Nature Methods"and "Science." What compels you to continue to find out more and more and make sure others know about what’s being discovered?

First, I've been lucky to have some very talented post-doctoral fellows join my laboratory over the years. They have done much of the actual work. The current publication in "Nature" has been co-authored by the following postdocs: Philip O’Herron, Pratik Chhatbar, Manuel Levy, Zhiming Shen, Adrien Schramm and Zhongyang Lu.

Second, there are mixed feelings in science about where to publish and how much to publish. I've tried to stay focused on tackling problems in neuroscience in a way nobody else has thought of and using methods or models that were originally considered to be technically difficult. This means we make slower progress. But sometimes we get lucky and show we learned something very surprising. It is comforting to see the results in a journal that gets read by scientists from many scientific disciplines.

Q: You compared our knowledge of what’s happening in brain tissue as covering only the tip of the iceberg. What may lie beneath the surface?

The brain is the most complex organ in the body. It has more than 100 trillion connections, or synapses, which is more than the number of stars in the Milky Way galaxy. “Iceberg” can apply to some very specific aspects of the way a neuron transmits electrical impulses but also more generally on the complexity of the brain.

What lies underneath? There might be a common circuit across many different regions of the brain. So if we discover this modular circuit for neural computation and neurovascular coupling, the puzzles of brain function will be greatly simplified.