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Published Online: 16 December 2019

Individual Patterns of Abnormality in Resting-State Functional Connectivity Reveal Two Data-Driven PTSD Subgroups

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Adi Maron-Katz, Ph.D., Yu Zhang, Ph.D., Manjari Narayan, Ph.D., Wei Wu, Ph.D., Russell T. Toll, Ph.D., Sharon Naparstek, Ph.D., Carlo De Los Angeles, M.S., Parker Longwell, B.A., Emmanuel Shpigel, B.A., Jennifer Newman, Ph.D., Duna Abu-Amara, M.P.H., Charles Marmar, M.D., and Amit Etkin, M.D., Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 177, Number 3
https://doi.org/10.1176/appi.ajp.2019.19010060
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Abstract

Objective:

A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD.

Methods:

Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone–exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the “normative population.” Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles.

Results:

The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data.

Conclusions:

The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.

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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 177 • Number 3 • March 01, 2020
Pages: 244 - 253
PubMed: 31838870

History

Received: 21 January 2019
Revision received: 30 July 2019
Accepted: 19 September 2019
Published online: 16 December 2019
Published in print: March 01, 2020

Keywords

  1. Posttraumatic Stress Disorder
  2. Models/Theories Of Psychiatry

Authors

Affiliations

Adi Maron-Katz, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Yu Zhang, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Manjari Narayan, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Wei Wu, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Russell T. Toll, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Sharon Naparstek, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Carlo De Los Angeles, M.S.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Parker Longwell, B.A.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Emmanuel Shpigel, B.A.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Jennifer Newman, Ph.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Duna Abu-Amara, M.P.H.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Charles Marmar, M.D.
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Amit Etkin, M.D., Ph.D. [email protected]
Department of Bioengineering (Toll) and Department of Psychiatry and Behavioral Sciences and Wu Tsai Neurosciences Institute (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin), Stanford University, Stanford, Calif.; VA Palo Alto Health Care System and Sierra Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif. (Maron-Katz, Zhang, Narayan, Wu, Toll, Naparstek, De Los Angeles, Longwell, Shpigel, Etkin); School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China (Wu); Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury and Department of Psychiatry (Newman, Abu-Amara, Marmar), New York University Langone School of Medicine, New York.
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Notes

Send correspondence to Dr. Etkin ([email protected]).
Presented at the 2018 annual meeting of the Society of Biological Psychiatry, New York, May 10–12, 2018.

Competing Interests

Dr. Naparstek receives research support from the Israel Science Foundation (grant 98/17). Dr. Marmar receives research support from the Brockman Foundation, the City of New York, Cohen Veterans Bioscience, Cohen Veterans Network, the Department of Defense, the Home Depot Foundation, the National Institute on Alcohol Abuse and Alcoholism, the McCormick Foundation, the Robin Hood Foundation, the Steven and Alexandra Cohen Foundation, and the U.S. Army; he holds equity options in and has served as an adviser to Receptor Life Sciences; and he has served as a consultant to the George W. Bush Institute. Dr. Etkin holds equity in Akili Interactive, Mindstrong Health, and Sizung, and he has received salary and equity from Alto Neuroscience. The other authors report no financial relationships with commercial interests.

Funding Information

Cohen Veterans Bioscience
National Institute of Health (NIH): DP1 MH116506
Sierra-Pacific Mental Illness Research, Education and Clinical Center (MIRECC) at the Palo Alto VA
The Steven A. and Alexandra M. Cohen Foundation
Supported by grants from the Steven and Alexandra Cohen Foundation and from Cohen Veterans Bioscience to Drs. Etkin and Marmar.

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