Sarah Heilbronner, Ph.D.

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Associate Professor of Neurosurgery

Appointed McNair Scholar March 2023

In biology, structure and function are inextricably linked. Much of neuronal function is determined by anatomical connections - the brain’s "wiring diagram." Moreover, most brain disorders are understood to be problems not confined to the cells of a particular region, but distributed through the communication among multiple brain regions. Thus, they are essentially connectionist disorders. My laboratory’s ultimate goal is to build the wiring diagram of the human brain.

My training prepared me well for these tasks. I was a graduate student at Duke University in Dr. Michael Platt’s lab, where I recorded from single neurons as nonhuman primates carried out learning and decision-making tasks. I then moved on to my postdoctoral training with Dr. Suzanne Haber at the University of Rochester. There, I learned traditional and cutting-edge neuroanatomy. I used anatomical connectivity to establish principles of white matter organization and to determine rodent-primate homologies in frontal cortical areas. This work had substantial translational impact.

As faculty, I have established an active research laboratory spanning methodologies. One of these is anatomical tract-tracing, which is the gold standard for determining neuronal anatomical connectivity. Unfortunately, tract-tracing cannot be performed in humans. Can advanced imaging technologies solve this problem? Diffusion magnetic resonance imaging (dMRI) takes advantage of the differential diffusion of water molecules along axons to estimate connectivity between populations of neurons. Unfortunately, dMRI does not accurately match anatomical connections. Overcoming this hurdle depends on matching the tracts generated by dMRI with underlying white matter anatomy. In collaboration with Dr. Jan Zimmermann and other members of the University of Minnesota’s Center for Magnetic Resonance Research, I have developed a pipeline to combine non-invasive, dMRI-derived measures of brain connectivity with anatomical tract-tracing. I perform both anatomical tract-tracing and dMRI in nonhuman primates, and then I apply the lessons learned about dMRI’s failures to human data. Furthermore, in collaboration with Dr. Taner Akkin, I am combining tract-tracing and polarization-sensitive optical coherence tomography. At the conclusion of these studies, we hope to build toward an accurate wiring diagram of nonhuman primate and human brains.

With these maps in hand, we expect to link structure (in the form of anatomical connectivity) with function (from electrophysiology and neuroimaging). We have already published one study demonstrating the value of this approach. In collaboration with Dr. Ben Hayden, I examined functional properties of neurons in orbitofrontal and posterior cingulate cortices that were structurally distinguished on the basis of anatomical connectivity.

Another way of approaching brain connectivity is via functional connectivity, which measures how correlated neural signals are across regions over time. Functional connectivity is a useful and popular tool in human MRI; however, its biological basis is poorly understood. My goal is to improve the interpretability of functional connectivity by chemogenetically manipulating circuits and measuring the effects on functional connectivity. I characterized the anatomical distribution of viral expression in the nonhuman primate brain to guide our usage of chemogenetic tools. I also helped to develop a robust pipeline for measuring functional connectivity in nonhuman primates at 10.5T. I expect these experiments will significantly contribute to our understanding of functional connectivity MRI work in human populations.

Rodents are essential nonhuman animal models in the field of neuroscience. Unfortunately, rodent brains are certainly not human brains. I use connectivity as a defining metric of brain regional similarity across species. In my laboratory’s first published work on this subject, we analyzed anatomical connectivity between the rat posteromedial cortex and various prefrontal cortical and striatal regions. The coming years will require comparing these connectivity maps to those from nonhuman primates and humans, as well as expanding them to other regions, to establish translational value.

Finally, neuromodulation tools like deep brain stimulation and transcranial magnetic stimulation offer the tantalizing possibility of manipulating brain connections in order to treat psychiatric and neurological disorders. With my recent move to Baylor College of Medicine, I plan to use the accurate wiring diagrams we are generating to inform targeting for neuromodulation solutions for human brain disorders.