Leila Nabulsi, PhD, a postdoctoral researcher in computational neuroscience at the Keck School of Medicine of USC’s Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI) has received funding to expand research on the neurocircuitry that underlies bipolar disorder. Nabulsi was awarded the prestigious 2025 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, a highly competitive grant that provides early-career researchers with crucial pilot funding to pursue new avenues in mental health research.
Bipolar disorder is characterized by alternating episodes of unusually high and low mood. Neuroimaging research to date has traced its origins to the limbic system (a group of structures in the deep brain linked to a range of emotions, cognitions and behaviors) and its connections with other centers in the brain.
“Those centers are very important for emotion regulation and reward-related behavior, which are closely linked to the range of symptoms we see in individuals with bipolar disorder,” Nabulsi said. “But the majority of studies conducted so far have been small—with about 100 individuals per study—making it unclear if findings generalize.”
With the new grant, which provides $70,000 of support in 2025, Nabulsi will expand her research program, which has already begun to pinpoint where and how bipolar disorder disrupts brain function. The project will leverage advanced analytical techniques, as well as the power of the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium, which unites researchers and imaging and clinical data around the world to provide large, powerful and diverse samples for scientific discovery.
“We’re working to build a database of bipolar disorder-specific brain changes, which may ultimately improve both diagnosis and treatment of the condition,” Nabulsi said.
Disentangling medication effects
Most neuroimaging studies of bipolar disorder have looked at small, primarily Caucasian samples, which makes it hard to generalize results to the broader population. Another major limitation of the existing research: Much of it is confounded by medication effects.
“Individuals with bipolar disorder are typically prescribed a range of medications over their lifetime, including at the time of brain scan collection, so it’s challenging to determine which brain changes are due to the medications and which are due to the disorder itself,” Nabulsi said.
Fortunately, the ENIGMA bipolar disorder dataset, which includes brain MRI scans collected by more than 200 research groups around the world, is large, diverse and detailed enough to begin parsing out medication effects and the disorder itself. Nabulsi and her colleagues are now analyzing data on medication type, dosage and duration from more than 3,700 participants.
“With the ENIGMA bipolar disorder sample, we can start to disentangle the effects of the medication from the underlying brain changes associated with the disorder itself,” she said.
Pinpointing changes in the brain
The new funding will allow Nabulsi to more closely investigate changes in white matter (the tracts that connect one part of the brain to another) by comparing individuals with and without bipolar disorder. Already, she has begun mapping these pathways on a very fine scale, finding microstructural changes in the white matter that links the limbic system and the basal ganglia. That has helped confirm that the structural changes in bipolar disorder are anatomically tied to the very brain regions that regulate mood, motivation and emotional processing.
A cutting-edge technique called bundle analytics, or BUAN, is now affording researchers a closer look at white matter than ever before. BUAN allows Nabulsi to analyze brain scans and virtually “travel” along pathways in the brain, comparing pooled data on people with bipolar disorder to those without. This approach helps pinpoint the exact locations along these pathways where disruptions in connectivity appear.
“We can map, along the tract, exactly where connectivity changes occur in bipolar disorder. That’s a very advanced way of looking at microstructural alterations in the brain,” Nabulsi said.
Advanced statistical methods are also supporting the new research project, including the application of graph theory, a mathematical approach that models the organization of the brain’s white matter networks. Using graph theory, Nabulsi is analyzing how the organization of brain networks differs between those with and without bipolar disorder, as well as how effectively neural information travels across these networks.
Using these methods and the ENIGMA bipolar disorder dataset, Nabulsi is studying how measures of symptoms severity in bipolar disorder (the number of manic or depressive episodes a person has had, for example) relate to changes in the brain. She is also investigating how medication—such as type, dosage, and duration—are linked to white matter changes.
Ultimately, compiling such details about brain changes in bipolar disorder could deepen our understanding of the brain's circuitry, symptom progression and treatment in bipolar disorder. It can also help researchers find new biomarkers, potentially paving the way for more targeted interventions and personalized treatment strategies.
“Right now, diagnosis and treatment of bipolar disorder is pretty much dependent on psychiatric evaluation and trial-and-error to see what medications work,” Nabulsi said. “We hope this work could one day help to identify biologically-grounded approaches to treatment.”
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