The brain, a dynamic organ fueled by electricity and chemicals, communicates through signals across its various regions. Researchers employ diverse technologies to decipher these signals and delve into brain function. Functional MRI (fMRI), for instance, tracks brain activity by monitoring changes in blood flow.

Yen-Yu Ian Shih, PhD, a neurology professor at the University of North Carolina (UNC) and associate director of its Biomedical Research Imaging Center, and his team have long explored how neurochemicals in the brain influence neural activity and blood flow, impacting fMRI measurements. Their recent study validates their concerns about the complexity of interpreting fMRI data.

“Neurochemical signaling to blood vessels is less frequently considered when interpreting fMRI data,” says Shih, who also leads the Center for Animal MRI. “In our study on rodent models, we showed that neurochemicals, aside from their well-known signaling actions to typical brain cells, also signal to blood vessels, and this could have significant contributions to fMRI measurements.”

Their findings, published in Nature Communications, stem from a $3.8-million grant from the National Institutes of Health and UNC’s investments in supporting the installation and upgrade of two 9.4-Tesla animal MRI systems and a 7-Tesla human MRI system at the Biomedical Research Imaging Center.

When activity in neurons increases in a specific brain region, blood flow and oxygen levels increase in the area, usually proportionate to the strength of neural activity. Researchers decided to use this phenomenon to their advantage and eventually developed fMRI techniques to detect these changes in the brain.

For years, this method has helped researchers better understand brain function and influenced their knowledge about human cognition and behavior. The new study from Shih’s lab, however, demonstrates that this well-established neurovascular relationship does not apply across the entire brain because cell types and neurochemicals vary across brain areas.

Shih’s team focused on the striatum, a region deep in the brain involved in cognition, motivation, reward, and sensorimotor function, to identify the ways in which certain neurochemicals and cell types in the brain region may be influencing fMRI signals.

For their study, Shih’s lab controlled neural activity in rodent brains using a light-based technique, while measuring electrical, optical, chemical, and vascular signals to help interpret fMRI data. The researchers then manipulated the brain’s chemical signaling by injecting different drugs into the brain and evaluated how the drugs influenced the fMRI responses.

They found that in some cases, neural activity in the striatum went up, but the blood vessels constricted, causing negative fMRI signals. This is related to internal opioid signaling in the striatum. Conversely, when another neurochemical, dopamine, predominated signaling in striatum, the fMRI signals were positive.

“We identified several instances where fMRI signals in the striatum can look quite different from expected,” says Shih. “It’s important to be mindful of underlying neurochemical signaling that can influence blood vessels or perivascular cells in parallel, potentially overshadowing the fMRI signal changes triggered by neural activity.”

Members of Shih’s lab traveled to the U.K.-based University of Sussex, where they were able to perform experiments and further demonstrate the opioid’s vascular effects. They collected human fMRI data at UNC’s 7-Tesla MRI system and collaborated with Stanford University researchers to investigate findings using transcranial magnetic stimulation, a procedure stimulating the human brain with magnetic fields.

This deeper understanding of fMRI signaling will enable basic science researchers and physician scientists to offer more precise insights into neural activity changes in healthy brains and neurological or neuropsychiatric disorders.