USC to Lead Largest fMRI Study of Eight Psychiatric Disorders

The Keck School of Medicine of USC will lead a five-year effort to reanalyze more than 94,000 functional brain scans from 257 research sites in 27 countries using a single shared processing method — an attempt to answer a question psychiatry has struggled to test at scale, whether different diagnoses share the same underlying brain behavior.

The National Institutes of Health is funding the work with a $3.2 million grant. The project, called the Global Initiative for Harmonized Functional MRI in Psychiatry, will draw on scans from participants aged 4 to 95. Investigators describe it as the largest functional MRI study ever conducted, measured both by the number of people scanned and by the number of laboratories taking part.

The bottleneck was never the scanners

Functional MRI records brain activity indirectly, by tracking shifts in blood oxygen while a person lies still in a scanner. When two regions rise and fall together over time, researchers treat them as functionally connected, and the pattern of those connections is what the project will compare across disorders.

The problem is that comparing results across labs has been close to impossible. Sites use different scanners, different preprocessing steps and different analysis choices, so a finding in one disorder is rarely measured the same way as a finding in another. A single study also rarely enrolls enough people to detect small effects.

This project attacks that directly. Eight separate international research groups, each already focused on one condition, have agreed to run their scans through the same standardized processing pipeline — the same sequence of software steps for cleaning a scan and measuring connectivity. According to the investigators, it is the first global effort to standardize how functional brain scans are analyzed in psychiatry.

"Until now, a finding in autism and a finding in schizophrenia could come from very different analysis choices, so we couldn't line them up fairly," said Clara Moreau, an assistant professor of psychiatry at the Université de Montréal and co-chair of the ENIGMA functional MRI working group. "Agreeing on a targeted multiverse approach, which is used across the world and across disorders, lets us identify distinctive features of these conditions for the first time."

Eight conditions, one dataset

The project covers schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder and anorexia nervosa.

That list is itself a statement about how the field is organized. The conditions span psychotic illness, mood disorders, trauma-related illness, developmental conditions and an eating disorder — categories that historically have been studied by separate research communities with separate funding streams and separate journals.

"There is broad agreement that many of the conditions we study in psychiatry share common roots in the brain, yet research on each condition still happens largely in isolation, partly because comparing many diagnoses at once on a large scale is so difficult," said Frank Hillary, a professor of psychology and neurology at Pennsylvania State University. "One critical goal of this project is to develop shared methods for studying how brain networks function, so that different areas of psychiatry can be examined side by side to better understand their similarities and differences."

The effort expands the ENIGMA Consortium, a network of more than 2,500 scientists in 47 countries that has spent years assembling the largest brain imaging studies of neurological and psychiatric disease.

Testing whether the diagnostic families are real

Earlier genetic work has suggested that these conditions cluster into three loose families: mood and psychotic disorders, developmental disorders, and compulsive disorders. One question the project is designed to answer is whether brain function organizes the same way — which would be evidence that the groupings reflect shared biology rather than shared symptom descriptions.

Paul Thompson, associate director of USC's Stevens Neuroimaging and Informatics Institute, director of ENIGMA and the project's principal investigator, framed the payoff in terms of treatment rather than taxonomy. "When every lab processes its scans the same way, we can finally discover which brain abnormalities are shared across disorders and which are specific," he said. The goal, he added, is to find "brain signatures that are the most sensitive to each illness, to help us target treatments and predict treatment response."

The combined dataset is also large enough for machine learning methods, which need volume to find reliable patterns. The team plans to use those tools to search for markers too subtle for smaller studies to detect.

What the grant does not buy

This is a data project, not a clinical trial. No new treatment is being tested, and the release describes analysis of scans that have already been collected rather than a new round of imaging. The money covers five years of coordination and analysis, so no finding is imminent.

That distinction matters for anyone reading the announcement as a step toward a diagnostic test. A brain signature that distinguishes schizophrenia from bipolar disorder, or that predicts who will respond to a particular therapy, is the ambition. Whether resting-state connectivity can actually carry that signal at the individual level is the open question, and it is the reason the field has produced many small, unreplicated findings rather than a usable biomarker.

The inclusion of anorexia nervosa is the least familiar piece for readers who follow addiction and mental health, and one of the more interesting. A Danish cohort published this week found that off-schedule puberty raised anorexia odds in girls — a result that locates part of the risk in developmental timing rather than in a single disrupted circuit, which is the kind of question harmonized imaging data is meant to be able to test across disorders.

For the broader mental health field, the practical value of harmonized methods may arrive before any biological finding does: a shared pipeline is what allows eight research communities to check each other's work, and that is a precondition for anything larger being believed.