Abstract
Objective: Case-control study design and disease heterogeneity may impede biomarker discovery in brain disorders, including serious mental illnesses. To identify biologically and/or behaviorally driven as opposed to diagnostically driven subgroups of individuals, the authors used hierarchical clustering to identify individuals with similar patterns of brain activity during a facial imitate/observe functional MRI task. Methods: Participants in the Social Processes Initiative in Neurobiology of the Schizophrenia(s) study (N=179; 109 with a schizophrenia spectrum disorder and 70 healthy control participants) underwent MRI scanning at three sites. Hierarchical clustering was used to identify new data-driven groups of participants; differences on social and neurocognitive tests completed outside the scanner were compared among the new groups. Results: Three clusters with distinct patterns of neural activity were found. Cluster membership was not related to diagnosis or scan site. The largest cluster consisted of “typical activators,” with activity in the canonical “simulation” circuit. The other clusters represented a “hyperactivating” group and a “deactivating” group. Between-participants Euclidean distances were smaller within clusters than within site or diagnostics groups. The deactivating group had the highest social cognitive and neurocognitive test scores. The hierarchical clustering analysis was repeated on a replication sample (N=108; 32 schizophrenia spectrum disorder, 37 euthymic bipolar disorder, and 39 healthy control participants), which exhibited the same three cluster patterns. Conclusions: The study findings demonstrate replicable differing patterns of neural activity among individuals during a socio-emotional task, independent of DSM diagnosis or scan site. The findings may provide objective neuroimaging endpoints (biomarkers) for subgroups of individuals in target engagement research aimed at enhancing cognitive performance independent of diagnostic category.
| Original language | English |
|---|---|
| Pages (from-to) | 521-530 |
| Number of pages | 10 |
| Journal | American Journal of Psychiatry |
| Volume | 176 |
| Issue number | 7 |
| DOIs | |
| State | Published - 2019 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2019 American Psychiatric Association. All rights reserved.
Funding
Supported by NIMH grants 1/3R01MH102324–01 (to Dr. Voineskos), 2/3R01MH102313–01 (to Dr. Malhotra), and 3/3R01MH102318–01 (to Dr. Buchanan). The authors thank Joanna Collaton, Jessica D’Arcey, Shelley Grady, Adriana Halaby, Jef West, Rebecca Ruiz, John Fitzgerald, Kathryn Rhindress, Kristin Minara, Tracy A. Giordonello, Lara Prizgint, Simran Kang, Taylor Marzouk, Sana Ali, Bernie Kompancaril, Christopher Morell, Danielle Beech, Darren Phane, George Nitzburg, Ivana De Lucia, and Natasha Bennett for collecting behavioral and neuroimaging data; Nancy Lobaugh for managing and maintaining the consistency of the Centre for Addiction and Mental Health MRI equipment; and Steve Hawley, Jon Pipitone, Dawn Smith, John Cholewa, and Tom Wright for data management. The authors acknowledge the contributions of the remaining members of the Social Processes Initiative in Neurobiology of the Schizophrenia(s) (SPINS) group: Will Carpenter, Jen Zaranski, Eric Arbach, Sharon August, Peter Kochunov, Peter Kingsley, Xiangzhi Zhou, Sofia Chavez, Gary Remington, Judy Kwan, Christina Plagiannakos, Mikko Mason, Marzena Boczulak, Dielle Miranda, Philipp Homan, and Michael Green. Dr. Buchanan is an advisory board member for Avanir Pharmaceuticals, Astellas Pharma, Boehringer Ingelheim-RCV, Intracellular Therapies, Lundbeck, and Roche; he serves as a consultant for Takeda and Upsher-Smith Laboratories and as a data and safety monitoring board member for Pfizer. Dr. Mulsant has received research support from Brain Canada, the Canadian Institutes of Health Research, the Centre for Addiction and Mental Health (CAMH) Foundation, the Patient-Centered Outcomes Research Institute, NIH, Eli Lilly (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design (software used in a study by CAMH Foundation), and Happyneu-ron (software used in a study by Brain Canada); he owns stock in General Electric. Dr. Gold receives royalty payments from the Brief Assessment of Cognition in Schizophrenia. Dr. Foussias has served as an investigator on research sponsored by Medicure, Neurocrine Bioscience, and Hoffmann-La Roche; he has served on advisory boards for Hoffmann-La Roche and Takeda and has received speaker’s fees from Hoffmann-La Roche, Lundbeck, and Novartis. Dr. Malhotra receives consulting fees from Genomind, Biogen, and Concert Pharmaceuticals. The other authors report no financial relationships with commercial interests.
| Funders | Funder number |
|---|---|
| NIH-funded | |
| National Institutes of Health | |
| National Institute of Mental Health | 2/3R01MH102313–01, 3/3R01MH102318–01, R01MH102324 |
| Eli Lilly and Company | |
| Patient-Centered Outcomes Research Institute | |
| Fondation Brain Canada | |
| Centre for Addiction and Mental Health | |
| Centre for Addiction and Mental Health Foundation | |
| Canadian Institutes of Health Research |
