NIH-Funded Project Will Use Micro and Macro to Understand Our Dynamic Brains

Crossing space and time (left to right): Shella Keilholz, Garrett Stanley, Chethan Pandarinath
Crossing space and time (left to right): Shella Keilholz, Garrett Stanley, Chethan Pandarinath

Shella Keilholz and Garrett Stanley both study the brain, but sometimes it’s like they’re looking at two completely different organs. Keilholz works at the systems level, the whole organ. Stanley gets down to the individual neuron.

With the support of the National Institutes of Health (NIH), they’re going to work to marry the two approaches and unlock new understanding of how our brains function — macro and micro.

“The goal is to develop an entirely new theoretical and computational framework for connecting different scales of complex brain activity through cutting-edge approaches in brain imaging and electrophysiology, data sciences, and machine learning,” said Stanley, Carol Ann and David D. Flanagan Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “We have assembled a team of investigators who will span experimental and computational areas.”

The team will be led by Keilholz, principal investigator for the project titled “Crossing Space and Time: Uncovering the Nonlinear Dynamics of Multimodal and Multiscale Brain Activity,” which has been awarded $1.1 million over three years through the NIH’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Assistant Professor Chethan Pandarinath also is part of the research team.

The team intends to avoid the limitations of previous brain studies, which have focused on individual cells or circuits, instead approaching the brain, “as a complex, dynamic system with activity occurring at many different space and time scales, from single synapses at a millisecond to whole brain modulation at minutes, days, even years,” said Keilholz, herself on a second BRAIN Initiative project. “To tie these things together, you need different imaging modalities, because you can’t measure the same sort of activity across scales with the same approach.”

It’s a collaboration that Keilholz and Stanley have been contemplating for about 10 years, since they first taught a class together.

“Garrett works more at the cellular level, and I work more at the systems level, and we want to try to meet in the middle,” Keilholz said.

Stanley added: “Shella is coming from the human-imaging side of things, and I’m coming from the single-cell side. She was coming from one angle and I was coming from another, and over time, we started to speak each other’s language.”

Stanley’s lab at Georgia Tech listens to the brain’s conversations at the cellular level, focusing on the pathways and circuits underlying sensory activity, using multisite, multielectrode recording, optical imaging, behavior, and patterned stimulation with the long-term goal of providing some surrogate control for circuits involved in sensory signaling, for normal function and for pathways injured through trauma or disease.

The Keilholz Mind Lab, which is located at Emory, uses noninvasive functional magnetic resonance imaging (fMRI) “to cover the whole brain, but you’re not looking at neural activity directly, you’re looking at things related to the hemodynamic response instead. With this BRAIN Initiative proposal, the idea is to nudge up to what Garrett’s doing.”

The idea, essentially, is to merge Keilholz’s systems-wide imaging with Stanley’s more invasive localized probing at the neuron level, “something we can bridge over into a noninvasive technique that can ultimately be applied in humans,” she said.

Pandarinath’s Systems Neural Engineering Lab, with its deep expertise in machine learning, “is expected to develop the tools we need to go from one scale to another and from invasive to noninvasive,” Keilholz said.

It’s the latest effort in trying to eavesdrop, look at, and understand the human brain, with its complex galaxy of 100 billion chattering neurons holding cellular conversations through more than 100 trillion synaptic connections — a dense and noisy communication network wrapped within a three-pound mass of tissue packed snugly inside our skulls.

Keilholz, Stanley, and Pandarinath are hoping to make more sense of the whole package, therefore developing a better understanding of the problems underlying disorders like Alzheimer’s disease, Parkinson’s disease, autism, depression, traumatic brain injury, and a rogues’ gallery of other of other maladies that continue to take a devastating toll on people and society.

“Ultimately, we are focused on human health and neurological diseases and disorders, which currently do not have adequate treatments, because these things occur in such complex ways, affecting entire circuits and networks,” Stanley said.

Keilholz said she thinks in terms of what she called “brain weather, using these things to know it’s likely to be a sunny day or a stormy day, to look for long-term changes in climate that might be mental health problems or other problems.

What we all really want to do is be able to look at a person’s brain and say, ‘This is why you are depressed,’ or ‘This is why this is happening, so let’s drive that back to normal,’” she said. “That’s what we’re ultimately going for.”