Analyzing brain data that is usually discarded by investigators, researchers at Yale have discovered important details about how variability of brain signals and brain-wide neural disruptions may contribute to symptoms of schizophrenia. The results, which could lead to biological markers for this complex and potentially disabling neuropsychiatric disease, are reported online ahead of print in the Proceedings of the National Academy of Sciences.
Previous studies on this topic have typically discarded global brain signals due to methodological reasons, treating it as a clinically meaningless variable. However, the Yale team suggests that the global signal, averaged across the brain, is profoundly altered in schizophrenia. "To our knowledge these results provide the first evidence that global whole-brain signals are altered in schizophrenia, calling into question the standard removal of this signal in clinical neuroimaging studies," said Alan Anticevic, assistant professor in psychiatry at the Yale School of Medicine and senior author of the study.
These novel results have vital and broad implications in the search for new biomarkers of neuropsychiatric illnesses, a search that is a prominent goal of the National Institute of Mental Health. Identifying new ways of classifying mental disorders based on observable behavior and neurobiological measures could lead to earlier interventions and improved patient outcomes.
Additionally, the team used mathematical models, built from the level of neurons, to simulate brain-wide activity and inform neurobiological mechanisms behind reported findings. Perturbing the strength of overall connectivity inside the mathematical model closely matched schizophrenia results. The team's state-of-the-art mathematical models were developed by John Murray, a post-doctoral associate at New York University, and Xiao-Jing Wang, professor of neural science at New York University and provost of NYU Shanghai. Murray and Wang are co-authors of the study.
"Our findings provide strong evidence that schizophrenia is associated with increased widespread neural variability, a diagnostically-specific effect that was also related to patients’ symptoms." said Genevieve Yang, an MD/PhD candidate at Yale School of Medicine and first author of the study.
Other Yale-affiliated authors on the study are Christopher Pittenger, Aleksandar Savic, John H. Krystal, Godfrey D. Pearlson, and David C. Glahn.
Anticevic is affiliated with the National Institute of Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center and the Yale Department of Psychology and the Interdepartmental Neuroscience Program.
Financial support for this research was provided by the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, the Fulbright Foundation, the Brain and Behavior Research Foundation and the Yale Center for Clinical Investigation.
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- John Krystal, MDRobert L. McNeil, Jr. Professor of Translational Research and Professor of Psychiatry, of Neuroscience, and of Psychology; Co-Director, Yale Center for Clinical Investigation; Chair, Psychiatry; Chief of Psychiatry, Yale-New Haven Hospital; Director: NIAAA Center for the Translational Neuroscience of Alcoholism; Director, Clinical Neuroscience Division, VA National Center for PTSD
- Christopher Pittenger, MD, PhDElizabeth Mears and House Jameson Professor of Psychiatry; Deputy Chair for Translational Research, Psychiatry; Director, Clinical Neuroscience Research Unit, Psychiatry; Director, Yale Program for Psychedelic Science, Psychiatry; Director, Yale Center for Brain and Mind Health, Yale School of Medicine; Director, Yale OCD Research Clinic, Psychiatry; Director, Neuroscience Research Training Program, Yale Department of Psychiatry