Synopsis

Keywords: Psychiatric Disorders, Trauma, Adverse childhood experiences, PTSD, White matter integrity

Adverse childhood experiences (ACE) are well-known risk factors for the development of PTSD later in life. The overall effect of ACE on WM integrity and the moderation effect of PTSD in this relation are still being researched. Using a total of 78 participants with any form of ACE, we show that ACE was negatively correlated with WM integrity in the genu and body of the corpus callosum and the bilateral uncinated fasciculus after controlling for overall psychological burden. The overall strength of this effect changed in corpus callosum and uncinated fasciculus when PTSD was added as a moderator variable.

Background:

Adverse childhood experiences (ACE) are well-known risk factors for the development of post-traumatic stress disorder (PTSD) later in life⁽¹⁾. The underlying white matter brain changes that explain the effect of ACE and the moderating role that PTSD diagnosis plays are still being researched. Psychiatric research supports differences in ACE-affected individuals with and without PTSD⁽²⁾. This provides firm ground for examining the moderation role PTSD diagnosis may have in the relation between ACE and WM anomalies. The current study tested the overall effect of ACE on WM integrity and the moderation effect of PTSD in this relation in a well-defined ACE sample after controlling for other psychosocial comorbidities. Based on literature, we hypothesized that ACE would be negatively correlated with WM integrity in the frontal, temporal and occipital cortices which are known to regulate emotion, behavior, and cognitive functioning. We hypothesized that the group with both ACE and PTSD diagnosis would show a more pronounced negative effect in ACE-related WM integrity regions. Secondly, we focused on the effect that specific subtypes of ACE (i.e., abuse and neglect) would have on WM integrity. Again, based on literature we hypothesize abuse-specific deficits in the superior longitudinal fasciculus (SLF) and anterior corona radiata ⁽³⁾ as well as neglect-specific effects in the anterior thalamic radiata ⁽⁴⁾. Finally, from a subgroup sample of persons with severe ACE, we extracted an ACE-, sex-, and age-matched sample looking at the differences between subjects with and without PTSD. We hypothesize that the PTSD group would have lower WM integrity in inferior frontal occipital fasciculus (IFOF) and arcuate fasciculus (AF) when compared to non PTSD group.

Methods:

A total of 78 participants with any form of ACE were included in this study. 24 of the 78 participants were diagnosed with PTSD at the time of the study. Participants completed the childhood trauma questionnaire (CTQ) and a structured clinical interview for DSM-5 (SCID-II) to ascertain PTSD diagnosis. Variables of interest such as CTQ sum score (62.54±19.94), CTQ abuse score (35.91±13.17) and CTQ neglect score (26.63±8.59), age (31.64±10.79yrs) and sex (65F), were computed after. Diffusion MRI scans (82 volumes, 3 at b=0 and 79 at b=1000 s/mm²) were then acquired to assess the WM integrity. Diffusion data were then denoised and subsequent corrections for bias field, eddy currents, and motion were performed. FA, MD and L1 maps for all subjects were created with fslfit and TBSS analyses was performed. Voxel-wise statistical analysis of individual skeleton maps were performed using multiple regression models and a paired t-test model (for the PTSD subgroup sample study) and corrected for multiple correction error at p=0.05 using FSL’s randomise. Age, sex and overall psychosocial burden (measured by the Brief Symptom Inventory (BSI)) were controlled for in all analyses. Subgroup sampling was performed using cardinality from R MatchIt⁽⁵⁾ package with gurobi optimiser (Figure 1).

Results:

ACE, measured by CTQ sum score was negatively correlated with fractional anisotropy (FA) in the genu and body of the corpus callosum (CC) and the bilateral uncinated fasciculus (UF)/inferior frontal occipital fasciculus (IFOF) pathway after controlling for overall psychological burden (Figure. 2 A, red color bar). Also, persons with ACE and PTSD showed reduced FA in whole CC, left UF, compared to person with ACE and no PTSD (Figure. 2 A, blue color bar). ACE subtypes (i.e. abuse & neglect) showed no significant relationship with WM integrity. In our subgroup sample study, PTSD group had lower FA in the Left Superior Longitudinal Fasciculus (SLF), Left IFOF, and Left posterior CC compared to non PTSD group (Figure. 2 B). MD and L1 showed no significant results in all analyses.

Discussion & Conclusion:

Using a whole-brain analysis, we found significant negative correlation between ACE (measured with the CTQ sum score) and WM integrity (measured by FA) in the genu & body of CC and bilateral UF/IFOF pathway after controlling for overall psychological burden. These results are consistent with what has previously been reported in the literature ^(3,6,7). An interesting part of this study is the significant moderation effect of PTSD in persons with ACE. As a more negative effect was seen in the CC, whose function is to ensure that both sides of the brain can communicate with each other and a less negative effect was seen in the bilateral uncinate fasciculus. This could support the underling psychopathology that although persons with ACE are more prone to having PTSD and the presence of PTSD causes reduced communication between both brain hemispheres and does not impair the decision-making in the frontal lobe. Our ACE subtype analyses did not support our hypotheses of ACE abuse-specific and neglect-specific effects on WM integrity. Meaning that for this study, only a combined effect of abuse and neglect affected WM integrity. Matching the effect of ACE, sex and age in our PTSD subgroup sample we show that persons with PTSD have reduced WM integrity compared to those without PTSD in regions involved in goal-oriented behavior (i.e. IFOF) and emotional regulation (i.e. AF/SLF)⁽⁶⁾.

Acknowledgements

We thank all members of the GKR2350/A1 research team for their assistance and thank all participants for their collaboration. This study was funded by the German Research Foundation and the Central Institute of Mental Health, Mannheim, Germany.

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