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Research Paper
Open Access

Moral wounds run deep: exaggerated midbrain functional network connectivity across the default mode network in posttraumatic stress disorder

Braeden A. Terpou, Chantelle S. Lloyd, Maria Densmore, Margaret C. McKinnon, Jean Théberge, Richard W. J. Neufeld, Rakesh Jetly and Ruth A. Lanius
J Psychiatry Neurosci February 17, 2022 47 (1) E56-E66; DOI: https://doi.org/10.1503/jpn.210117
Braeden A. Terpou
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Chantelle S. Lloyd
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Maria Densmore
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Margaret C. McKinnon
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Jean Théberge
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Richard W. J. Neufeld
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Rakesh Jetly
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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Ruth A. Lanius
From the Department of Neuroscience (Terpou, Neufeld), the Department of Psychiatry (Lloyd, Densmore, Théberge, Neufeld, Lanius), the Department of Medical Biophysics (Théberge), the Department of Psychology (Neufeld), Western University, London, Ont.; the Imaging Division, Lawson Health Research Institute (Densmore, Lanius), the Department of Psychology, Neuroscience, and Behaviour (Lloyd), the Department of Psychiatry and Behavioural Neurosciences (McKinnon), McMaster University, Hamilton, Ont.; Mood Disorders Program, St. Joseph’s Healthcare (McKinnon), Hamilton, Ont.; Homewood Research Institute (McKinnon, Lanius), Guelph, Ont.; Canadian Forces, Health Services (Jetly), Ottawa, Ont.
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    Figure 1

    In GIFT, independent component 3 (shown above) was correlated very strongly with the DMN mask. Independent component 3 included key DMN-related hubs, such as the mPFC, the PCC and the precuneus. It also included supplementary DMN-related areas, such as the middle cingulate cortex and the bilateral temporal lobes, but these areas revealed less functional network connectivity than the hubs. We also observed clusters in the insula, midbrain and cerebellum, which are not generally thought to be involved in the DMN (indicated by an asterisk). DMN = default mode network; fMRI = functional MRI; GIFT = Group ICA of fMRI Toolbox; ICA = independent component analysis; mPFC = medial prefrontal cortex; PAG = periaqueductal grey; PCC = posterior cingulate cortex.

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    Figure 2

    (A) Top: the whole-brain image shows a thresholded independent component 3 (k > 35 cut-off) and the DMN-related spatial correlation value. Bottom: midbrain PAG functional network connectivity clusters that were more strongly involved in the DMN in participants with civilian-related PTSD versus healthy controls exposed to moral injury have been superimposed onto the cropped brainstem and cerebellum mask from the SUIT toolbox. (B) This summary image interprets the functional connectivity revealed in the present study and the study by Terpou and colleagues.43 In PTSD, we suspect that the DMN-related hubs — namely the mPFC, PCC and precuneus — reveal strong functional connectivity during DMN-mediated processing, similar to healthy controls. However, Terpou and colleagues43 found stronger PAG-directed functional connectivity to DMN-related hubs in PTSD, a finding that converges with the stronger PAG functional network connectivity we found in the present study. Taking these findings together, we suggest that the PAG may be driving the DMN in people with PTSD, primarily in a bottom–up manner; functional connectivity is mediated by the insula and directed toward the DMN. DMN = default mode network; FWE = family-wise error; mPFC = medial prefrontal cortex; PAG = periaqueductal grey; PCC = posterior cingulate cortex; PCUN = precuneus; PTSD = posttraumatic stress disorder; ROI = region of interest; SUIT = Spatially Unbiased Infratentorial Template.

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    Table 1

    Participant clinical and demographic characteristics

    Characteristic*Military- and law-enforcement-related PTSDCivilian-related PTSDHealthy controls exposed to a moral injury event
    Participants, n282818
    M/F, n25/39/197/11
    Age, yr49 ± 849 ± 833 ± 11
    Clinician-Administered PTSD Scale, total score40.9 ± 7.9†41.7 ± 6.6†0 ± 0
    Clinician-Administered PTSD Scale, criterion D15.4 ± 3.5†15.4 ± 3.2†0 ± 0
    Childhood Trauma Questionnaire, total score52.8 ± 24.2†65.7 ± 23.4†30.3 ± 8.4
    Multiscale Dissociation Inventory, total score60.3 ± 16.3†68.0 ± 17.8†35.6 ± 5.2
    Moral Injury Events Scale, total score39.9 ± 6.9†39.3 ± 7.7†25.9 ± 9.6
    World Health Organization Disability Assessment Schedule 2.0, total score30.3 ± 9.3†31.6 ± 8.7†12.9 ± 1.7
    Major depressive disorder, recurrent, nCurrent: 9
    Past: 0
    Current: 21
    Past: 0
    Current: 0
    Past: 0
    Major depressive disorder, single episode, nCurrent: 4
    Past: 1
    Current: 0
    Past: 0
    Current: 0
    Past: 0
    Prescribed psychotropic medication, n‡23100
    • F = female; M = male; PTSD = posttraumatic stress disorder.

    • ↵* Values are mean ± standard deviation, unless otherwise indicated.

    • ↵† Significantly higher clinical symptom values relative to healthy controls, based on 1-way analysis of variance and follow-up t tests (p < 0.05).

    • ↵‡ See Appendix 1 for a full breakdown of the psychotropic medications prescribed, the class they belonged to, and how many past and present prescriptions were recorded in each group.

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    Table 2

    Group differences: functional network connectivity*

    Independent componentContrastBrain regionCluster, kMNI coordinates, x, y, zt statisticZ scorepFDR (peak)
    Independent component 3: DMN (whole brain)Civilian-related PTSD > military- and law-enforcement-related PTSDPrecuneus4314, −46, 545.675.380.009
    Independent component 3: DMN (region of interest)Civilian-related PTSD > healthy controlsPeriaqueductal grey390, −32, −84.954.750.028
    Cerebellar lobule VII4910, −66, −404.444.290.046
    Military- and law-enforcement-related PTSD > healthy controlsPeriaqueductal grey604, −30, −24.224.090.076†
    • DMN = default mode network; FDR = false discovery rate; MNI = Montreal Neurological Institute; PTSD = posttraumatic stress disorder.

    • ↵* Group-level functional network connectivity across the independent component correlated to the DMN is displayed for whole-brain and region-of-interest analyses; t contrasts were evaluated at a significance threshold of pFDR < 0.05, k > 10 (peak-corrected).

    • ↵† Denotes a group difference approaching significance.

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    Table 3

    Clinical correlations: functional network connectivity

    Independent componentGroupClinical score (direction)Brain regionCluster, kMNI coordinates, x, y, zt statisticZ scorepFDR (peak)
    Independent component 3: DMN (whole brain)Military- and law-enforcement-related PTSDState: shame (−)Precentral gyrus24−36, −28, 408.295.180.049
    Independent component 3: DMN (region of interest)Military- and law-enforcement-related PTSDState: shame (+)Cerebellar lobule IX242, −56, −248.105.120.006
    PTSDClinician-Administered
    PTSD Scale, total score (+)
    Cerebellar lobule VII2842, −60, −345.104.580.041
    Clinician-Administered
    PTSD Scale, total score (−)
    Brainstem1914, −16, −184.964.480.049
    • DMN = default mode network; FDR = false discovery rate; MNI = Montreal Neurological Institute; PTSD = posttraumatic stress disorder.

    • Clinical correlations across group-level functional network connectivity are displayed; t contrasts were evaluated at a significance threshold of pFDR < 0.05, k > 10 (peak-corrected).

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Journal of Psychiatry and Neuroscience: 47 (1)
J Psychiatry Neurosci
Vol. 47, Issue 1
23 Feb 2022
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Moral wounds run deep: exaggerated midbrain functional network connectivity across the default mode network in posttraumatic stress disorder
Braeden A. Terpou, Chantelle S. Lloyd, Maria Densmore, Margaret C. McKinnon, Jean Théberge, Richard W. J. Neufeld, Rakesh Jetly, Ruth A. Lanius
J Psychiatry Neurosci Feb 2022, 47 (1) E56-E66; DOI: 10.1503/jpn.210117

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Moral wounds run deep: exaggerated midbrain functional network connectivity across the default mode network in posttraumatic stress disorder
Braeden A. Terpou, Chantelle S. Lloyd, Maria Densmore, Margaret C. McKinnon, Jean Théberge, Richard W. J. Neufeld, Rakesh Jetly, Ruth A. Lanius
J Psychiatry Neurosci Feb 2022, 47 (1) E56-E66; DOI: 10.1503/jpn.210117
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