Research seeks noninvasive study of brain chemicals

Currently, there are only invasive methods to monitor neurochemicals in the brain. Researchers in the Department of Chemistry are developing methods to change that.

“We’re trying to develop a noninvasive spinal tap,” providing information on neurochemicals without having to use needles, explained Associate Professor Bhavya Sharma. 

The project in the Sharma Raman Lab is in its third year of support from Wellcome Leap, a global network aiming to foster breakthroughs in human health in less than a decade. 

Sharma’s research is one of a dozen projects funded under a $50 million Multi-Channel Psych (MCPsych) program, which aims for faster, more effective treatment of anhedonic depression, a severe type of depression characterized by an inability to experience joy or pleasure. Wellcome Leap notes that depression is the third leading cause of disability—affecting 264 million people a year—and while a third respond well to an initial treatment, nearly as many require two to four treatment trials.

Currently determining the cause and effective treatment of depression can be based on trial and error, based on symptoms and subjective observation. Identifying neurochemical abnormalities could lead to more effective treatment faster. Being able to detect and quantify dopamine and other neurochemicals with a noninvasive technique could ultimately allow for targeted treatment.

Advancing Spectroscopy

Sharma came to the University of Tennessee, Knoxville, in 2015, and established an interdisciplinary group researching areas of analytical and physical chemistry, biology, and materials science. Her work in developing novel Raman spectroscopic methods for neurochemical sensing earned her the 2021 Emerging Leader in Molecular Spectroscopy Award.

To detect neurochemicals in the brain, she has been using two techniques: surface-enhanced Raman spectroscopy (SERS) and surface-enhanced spatially offset Raman spectroscopy (SESORS). 

“Raman spectroscopy is a light scattering technique that gives you very specific information about molecules, because it’s based on how a molecule vibrates,” explained Sharma. In SERS, a laser is shined on the surface of metal nanoparticles that are mixed with the molecules of interest. The unique information about the molecule is gathered from the light that scatters back. She’s combining Raman spectroscopy with multivariate analysis to identify chemicals and determine their concentrations.

“A lot of neurochemicals have very similar chemical compositions, and we can identify them specifically because of the sensitivity of our technique,” Sharma said.

SESORS combines SERS with spatially offset Raman spectroscopy (SORS), a method that allows for collecting information from sub-surface layers in multilayered samples. While SORS and SESORS have been applied for identifying chemicals in bottles and diagnosing bone disease through the skin, Sharma originally hypothesized that SESORS could be applied to examining the neurochemicals in the brain, with the skull as the top layer and the brain the sub-surface layer, and that is part of what she has been researching at UT. 

The researchers first demonstrated the technique using agarose gel to mimic brain tissue and measuring the signal of neurochemicals through bone. “We were actually able to demonstrate we could do this at physiologically relevant concentrations,” Sharma said. 

One challenge for using the technique to analyze neurochemicals in vivo is the thickness of the human skull. Through the Wellcome Leap MCPsych program, Sharma is investigating the possibilities of applying SESORS to measure neurochemicals in the cerebrospinal fluid, much like a spinal tap without needles, although instead of at the lower back, measurements are being made at the neck. 

This work, which is in the process of being patented, is in collaboration with Brian Whitlock, the Charles and Julie Wharton Professor of Food Animal Field Services at the UT’s College of Veterinary Medicine, and her co-principal investigator on the project. “This would not be possible without him,” Sharma said, noting Whitlock’s expertise in neuroendocrinology and neurochemistry.