Creating Precision Brain Charts to Understand Psychosis Spectrum Symptoms

By Barbara Drosey

Researchers are creating an open resource that will help to assess the complex neurodevelopmental features of psychosis spectrum (PS) symptoms, including schizophrenia. Their goal is to create brain profiles that show how PS symptoms evolve during brain maturation, paying close attention to the developmental epochs where risk for PS is hypothesized to emerge.

Schizophrenia, for example, is typically diagnosed in late adolescence to early adulthood following the onset of symptomatic behavior. Using novel genomics and brain imaging methods, the investigators aim to ascertain where the disruption occurs along the neurodevelopmental growth trajectory that leads to mental illness and add a complementary method to their diagnostic toolbox.

The collaborative study team is assembling expertise in psychiatric and developmental brain imaging, imaging-genetics, and neuroinformatics to capitalize on their work with the Lifespan Brain Chart Consortium dataset. The dataset represents more than 100,000 individuals with preliminary data covering the entire lifespan from more than 130,000 MRI scans from more than 300 MRI scanners.

Aaron Alexander-Bloch, MD, PhD, director of the Brain-Gene-Development Lab in the Department of Child and Adolescent Psychiatry and Behavioral Sciences at Children’s Hospital of Philadelphia, received a National Institutes of Health grant to delve into these precision brain charts and develop a standardized frame of reference for brain anatomy and psychiatric neuroimaging to enhance risk assessment of neurodevelopmental conditions.

“The resulting multiscale brain charts will further progress in a particularly challenging area of this field — identifying imaging-genomics markers indicative of risk of psychosis spectrum disorders, including schizophrenia,” said Dr. Alexandar-Bloch, who is also assistant professor of Psychiatry at the University of Pennsylvania.

Previous work led by researchers from the Brain-Gene-Development Lab and the University of Cambridge created BrainChart, a robust tool that enables researchers to analyze brain development in children against standardized reference charts. Their BrainChart work provides a springboard for researchers to develop a similar but more detailed tool for a wider range of imaging phenotypes derived from quantitative measurements from brain MRI scans, such as regional brain volume, cortical thickness, cortical surface area, and folding of the cerebral cortex.

The study team will use advanced, reproducible methods for quality control, image processing, and harmonization to create and maintain an open resource researchers can use to identify heritable brain profiles. Multiscale brain charts will demonstrate normative trends that coincide with a normal growth trajectory, providing transformative potential for studies of brain development associated with the evolution of psychosis spectrum symptoms.

“Brain scans may never prove a definitive diagnostic tool but are one critical piece of evidence that plays into the diagnostic journey,” Dr. Alexander-Bloch said.

Dr. Alexander-Bloch and his team recently received another NIH grant to investigate a methodological breakthrough in functional magnetic resonance imaging (fMRI) that enables researchers to identify genetic contributions to the central executive network of the human brain, which regulates executive function, goal-oriented task completion, problem solving, and leveraging working memory in decision making.

Compared to standard fMRI approaches, which are not able to delineate a person’s unique network topography, personalized functional networks (PFNs) capture individualized aspects of brain function that have unique associations with clinical and developmental outcomes.

Identifying genetic loci that influence the development of PFNs and contribute to psychiatric risk will lead to novel mechanistic insights into central executive network dysfunction in individuals with mental illness. This work will contribute to a better understanding of PS disorders through more precise imaging phenotypes and improve classification of at-risk patients. Ultimately, the researchers aim to develop a useful tool for targeted neuromodulation guided by individualized neurogenetics.

The researchers will investigate PFNs in genetically informative open fMRI datasets including the Adolescent Brain and Cognitive Development Study, a large imaging dataset curated by the National Institute for Health that includes longitudinal data as well as a large twin sample, the UK Biobank, and locally acquired fMRI data on 22q11.2 deletion syndrome. These datasets will enable researchers to connect the dots between inherited polygenic effects and rare copy number variants, which are hypothesized to influence individualized functional network topography, and represent a component of risk for psychiatric illness.

“For example, there are hundreds of genetic loci that influence risk for schizophrenia, but with very few exceptions, we do not know why or how they manifest that risk,” Dr. Alexander-Bloch said. “Brain imaging is a means to understand the neurobiological mechanisms that could help explain how genetic risks can manifest with clinical risk.”

Among the collaborators in psychiatric and developmental brain imaging, imaging-genetics, and neuroinformatics who contribute to Dr. Alexander-Bloch’s work are Jakob Seidlitz, PhD, postdoctoral research scientist in the Brain-Gene-Development Lab; Raquel Gur, MD, PhD, director of the Lifespan Brain Institute; Theodore Satterthwaite, MD, director of the Penn Lifespan Informatics & Neuroimaging Center; and Joseph Glessner, PhD, technical director in the Center for Applied Genomics.