Research ArticlePsychiatry

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaal3236
DOI: 10.1126/scitranslmed.aal3236
  • Fig. 1 Impaired verbal memory delayed recall is associated with poor within-VAN resting-state fMRI connectivity in patients with PTSD (study 1).

    (A) Three-dimensional renderings of fMRI images for a previously identified set of seven canonical cortical connectivity networks. SMN, somatomotor network; DAN, dorsal attention network; FPCN, frontoparietal control network; DMN, default mode network; VAN, ventral attention network. (B) Comparison of memory task performance between healthy individuals and PTSD patient groups. Only blunted verbal learning delayed recall in patients with PTSD survived FDR correction across the neurocognitive tests examined (group difference generalized linear mode, Wald χ2 = 6.0, P = 0.014, PFDR = 0.0431; # represents FDR P < 0.05). (C) Group differences in fMRI connectivity within and between the labeled fMRI networks. Healthy individuals, PTSD patients with impaired memory, and PTSD patients with intact memory were compared using a generalized linear model. The plot shows −log10(P value) of the effect of the three-level group comparison. Only within-VAN connectivity survived FDR correction (Wald χ2 = 14.8, P = 0.0006, PFDR = 0.015; white asterisk). (D) Bar graph showing the group effect on within-VAN connectivity, demonstrating impaired connectivity only in the PTSD patients with impaired memory, relative to both the healthy group and the group of PTSD patients with intact memory. *P < 0.05, ***P < 0.001. Bar graphs present means and SEM for normally distributed variables; box and whisker plots show medians, interquartile ranges, minima, and maxima for variables with skewed distributions.

  • Fig. 2 Impaired verbal memory delayed recall is associated with poor within-VAN resting-state fMRI connectivity in patients with PTSD (study 2).

    (A) Group differences in within-VAN fMRI connectivity comparing healthy individuals, PTSD patients with impaired memory, and PTSD patients with intact memory in a generalized linear model. Study 2 used the same cutoffs and analytical approaches as study 1. As with study 1, there was a reduction in fMRI connectivity in the VAN only in the PTSD patients with impaired memory relative to both the healthy group and the PTSD patient group with intact memory (Wald χ2 = 11.4, P = 0.003). (B) The memory-related impairment in within-VAN fMRI connectivity also survived FDR correction across all network pairs (PFDR = 0.009). The plot shows −log10(P value) of the effect of the three-level group comparison. *P < 0.05, **P < 0.01. Shown are means and SEM.

  • Fig. 3 Poor treatment outcome for patients with both impaired memory and within-VAN connectivity (study 1).

    Patients with PTSD in study 1 took part in a clinical trial in which they were randomized to an evidence-based psychotherapy treatment (prolonged exposure psychotherapy) or were wait-listed for this treatment (comparison arm). (A) Generalized linear mixed model in an intent-to-treat analysis revealed a moderation of treatment outcome by brain and behavioral metrics (i.e., a treatment group by memory by connectivity by time interaction). A median split on the fMRI connectivity variable is shown and illustrates the mixed model result (i.e., low/high fMRI connectivity in the VAN). (B) Within-VAN fMRI connectivity likewise survived FDR correction across all network pairs in the moderation of treatment outcome (PFDR = 10−7; white asterisk) based on the treatment group by memory by connectivity by time interactions term. The plot shows −log10(P value) of the moderation term (i.e., treatment group by memory by connectivity by time interaction) for each network pair.

  • Fig. 4 Within-VAN fMRI connectivity and memory recall in PTSD patients before and after psychotherapy treatment.

    Within-VAN connectivity (A) and delayed recall of verbal memory (B) were assessed in study 1 patients with PTSD both before and after either prolonged exposure psychotherapy or being wait-listed for this treatment. No significant differences were observed in either measure as a function of treatment (prolonged exposure psychotherapy versus wait-list: group × time linear mixed models). Bar graphs show means and SEM for normally distributed variables; box and whisker plots show medians, interquartile ranges, minima, and maxima for variables with skewed distributions.

  • Fig. 5 Within-VAN resting-state fMRI connectivity and EEG responses after single TMS pulses.

    Individual differences in fMRI connectivity were correlated with the neural responses to noninvasive transcranial magnetic brain stimulation of different brain regions in healthy individuals and patients with PTSD. (A) A TMS pulse was delivered to one of the brain stimulation sites. These sites were identified on the basis of independent component analyses of resting-state fMRI data from a separate group of participants (shown in yellow). The TMS targets (white spheres) were either in the anterior middle frontal gyrus (aMFG, part of the VAN) or posterior middle frontal gyrus (pMFG, part of the FPCN). (B) Quantification of EEG signals in response to spTMS covering both TER and ERSP. Dashed line indicates the timing of the TMS pulse. (C) A significance plot of the generalized linear models relating individual differences in within-VAN fMRI connectivity across all participants (healthy individuals and patients with PTSD) to differences in each EEG measure. This is shown for each of the stimulation sites (i.e., left and right aMFG/VAN and left and right pMFG/FPCN). To derive each EEG measure, an average was taken of that measure for each of the source-localized vertices comprising the VAN. Thus, each participant’s single within-VAN fMRI connectivity measure was correlated with single measures of each participant’s EEG responses after TMS stimulation within the VAN (evoked at each stimulation site). Only ERSP measures for right aMFG/VAN stimulation survived FDR correction (denoted by asterisks). The plot shows −log10(P) for the correlation of within-VAN fMRI connectivity with spTMS/EEG measures. (D) Scatter plot of one of the FDR-significant relationships, demonstrating that individuals with lower within-VAN fMRI connectivity had greater alpha-range desynchronization 400 to 600 ms after the TMS pulse (i.e., below-baseline alpha power). (E) ERSP plots showing the correlation in (D). ERSP values were averaged for participants in the top and bottom third of the within-VAN fMRI connectivity distribution to visualize the correlation findings across the whole time-frequency range. The data show prolonged alpha-range desynchronization from ~400 to ~800 ms after the TMS pulse delivered to the right aMFG/VAN in those individuals with reduced within-VAN fMRI connectivity.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/11/486/eaal3236/DC1

    Materials and Methods

    Fig. S1. Overview of the experimental design.

    Fig. S2. Neurocognitive task performance in patients with PTSD.

    Fig. S3. No relationship between the memory/connectivity-related phenotype and symptoms in patients with PTSD (studies 1 and 2).

    Fig. S4. CONSORT diagram for the study 1 treatment component.

    Fig. S5. Individual data points for verbal memory delayed recall, within-VAN fMRI connectivity, and percent change in CAPS total scores with treatment in study 1 participants completing the prolonged exposure psychotherapy arm.

    Table S1. Demographic and clinical characteristics of participants in studies 1 and 2.

    Table S2. Details of traumas for study 1 and 2 participants.

    Table S3. Demographic and clinical characteristics of participants according to memory-based groupings.

    Table S4. Demographic and clinical characteristics of participants for the intent-to-treat analysis of treatment outcome and its moderation by verbal memory impairment and within-VAN fMRI connectivity.

    Table S5. Demographic and clinical characteristics of participants in study 2 who underwent spTMS/EEG.

    References (7695)

  • This PDF file includes:

    • Materials and Methods
    • Fig. S1. Overview of the experimental design.
    • Fig. S2. Neurocognitive task performance in patients with PTSD.
    • Fig. S3. No relationship between the memory/connectivity-related phenotype and symptoms in patients with PTSD (studies 1 and 2).
    • Fig. S4. CONSORT diagram for the study 1 treatment component.
    • Fig. S5. Individual data points for verbal memory delayed recall, within-VAN fMRI connectivity, and percent change in CAPS total scores with treatment in study 1 participants completing the prolonged exposure psychotherapy arm.
    • Table S1. Demographic and clinical characteristics of participants in studies 1 and 2.
    • Table S2. Details of traumas for study 1 and 2 participants.
    • Table S3. Demographic and clinical characteristics of participants according to memory-based groupings.
    • Table S4. Demographic and clinical characteristics of participants for the intent-to-treat analysis of treatment outcome and its moderation by verbal memory impairment and within-VAN fMRI connectivity.
    • Table S5. Demographic and clinical characteristics of participants in study 2 who underwent spTMS/EEG.
    • References (7695)

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