A new global study aims to map the brain signatures of bipolar disorder to transform understanding of the disease

A new study, led by USC Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI), will explore structural alterations in the brains of people with bipolar disorder (BD), a chronic mental illness with one of the highest rates of attempted suicide — and for which no biological tools currently exist to guide diagnosis or treatment. The goal is to transform researchers’ understanding of the disease in the hopes of developing more effective treatments.

Christopher R.K. Ching, PhD, assistant professor of research neurology at the Stevens INI, part of the Keck School of Medicine of USC, will lead a global network of psychiatric researchers in collaboration with Matthew Kempton, PhD, of King’s College London. The NIH-funded project supports efforts by the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium’s Bipolar Disorder Working Group (ENIGMA-BD), which Ching chairs. ENIGMA-BD has fostered successful global collaborations among more than 230 researchers since 2012, resulting in the most extensive studies of BD and the brain ever conducted. 

“By combining existing brain imaging and clinical data samples from leading research groups around the world, we are hoping to break new ground in mapping the brain signatures of BD as well as how they compare to other conditions like major depressive disorder (MDD), which share similar risk factors, symptoms, and treatments,” says Ching.

The team will use a large-scale analysis approach called voxel-based morphometry (VBM), which allows scientists to map subtle structural alterations across the entire brain. Unlike other neuroimaging methods that tend to average features across larger predefined brain regions, this technique enables precise, fine-resolution mapping of the emotion and reward processing centers affected in BD and other regions like the cerebellum often overlooked in prior studies. For years, the cerebellum was primarily regarded as a region responsible for motor control; however, emerging research increasingly suggests that it also plays a crucial role in cognitive processes and may function abnormally in individuals with mental illness.

Kempton and his team have recently applied the same methodology in the most extensive imaging study of early-onset psychosis. “We found widespread reductions in gray but not white matter volume in those with early onset psychosis using the ENIGMA VBM tool, and we are excited to be collaborating with Dr. Ching and ENIGMA-BD to map brain abnormalities in bipolar disorder. Using this methodology will allow us to map the changes in brain structure in remarkable detail in such a large sample, “ notes Kempton.

A key feature of the project is the unprecedented sample sizes pooled through ENIGMA-BD, including over 3,500 individuals with BD and nearly 9,000 healthy controls from 45 international study samples. Most traditional studies involve fewer than 100 participants. By integrating existing datasets and increasing sample sizes, the team enhances the statistical power to identify subtle brain alterations and improve the generalizability of the findings, as they are drawn from diverse populations worldwide.

“This marks an exciting new phase for the ENIGMA Consortium,” says Paul M. Thompson, PhD, ENIGMA Consortium director and Stevens INI associate director. “By analyzing the largest-ever worldwide data collection, Dr. Ching is discovering the brain circuitry involved in bipolar disorder and how commonly prescribed medications influence the brain. Neuroimaging data has not been studied at this scale, and Dr. Ching’s global team is creating new leads to optimize treatment.”

The project’s primary goals include:

• Mapping brain differences in BD: Analyzing brain scans from 3,500 individuals with BD and 8,500 healthy controls from 45 research centers to identify detailed patterns associated with BD clinical subtypes, illness severity, treatment effects, co-occurring conditions, and sociodemographic factors.
• Comparing BD and major depression: Exploring similarities and differences between BD and major depression using data from 22,500 participants across 133 cohorts, the largest-ever sample for such comparisons. Because the conditions share key symptoms, risk factors, and treatments, this transdiagnostic analysis aims to map the shared and unique brain signatures, which are needed to improve biologically driven diagnoses and predict individualized treatments best suited for each patient.

“The USC INI stands at the forefront of brain mapping, and our commitment to global collaboration and expertise in data sharing makes us a leader in ambitious projects such as these,” says Stevens INI Director Arthur W. Toga, PhD. “This new project embodies our dedication to coordinating and applying our expertise to large-scale studies that can directly impact public health. The findings mark an essential step to revolutionize how we diagnose and treat mood disorders, offering hope to millions of individuals and families affected worldwide.”

---

---