Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME_INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME_INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (X²(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (X²(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (X²(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001 ), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001 ), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001 ), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001 ), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001 ). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p_-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

The hypothalamus is critical for regulation of the hypothalamic-pituitary-adrenal (HPA) axis and response to stress. Adverse childhood experience (ACE) can affect brain structure, which may contribute to development of posttraumatic stress disorder (PTSD) after subsequent adult trauma. It is unclear, however, if ACE history is particularly associated with aspects of hypothalamic structure which contribute to development of PTSD. To address this issue, the present study longitudinally assessed hypothalamic volumes and their associations with ACE and early post-trauma stress symptoms in subjects who did or did not develop PTSD during 12 months after adult trauma. 109 subjects (18–60 years, F/M = 75/34) completed the PTSD Checklist (PCL) questionnaire for post-trauma stress symptoms, the Childhood Trauma Questionnaire (CTQ) for ACE assessment, and an initial MRI brain scan for hypothalamic volume measurement, within 2 weeks after adult trauma. At post-trauma 12 months, subjects underwent a subsequent PTSD diagnosis interview using the Clinician-Administered PTSD Scale (CAPS), and a follow-up MRI scan. Left and right hypothalamus volumes at 2 weeks after adult trauma negatively correlated with CTQ scores. Right hypothalamus volume at this early time mediated an association between ACE and PTSD symptoms 12 months later. Right hypothalamus volumes also remained persistently smaller from 2 weeks to 12 months after trauma in survivors who developed PTSD. These results suggest that smaller right hypothalamus volume may be related to ACE history in ways that contribute to PTSD development after trauma in adulthood.

Background: Adverse childhood experiences (ACEs) have been linked to brain development and mental disorders, however, the impact of the age of occurrence of ACEs on thalamic volume and post-traumatic stress disorder (PTSD) after adult trauma remains unclear. This study assessed associations between ACEs at different ages to thalamic volumes and PTSD development following acute adult trauma.Methods: Seventy-nine adult trauma survivors were recruited immediately after trauma. Within 2 weeks of the traumatic event, participants completed the PTSD Checklist (PCL) to assess PTSD symptoms, the Childhood Trauma Questionnaire (CTQ) and Childhood Age Range Stress Scale (CARSS) to evaluate ACEs and perceived stress level at preschool (<6 years old) and school (6–13 years old) ages, and structural magnetic resonance imaging (sMRI) to measure thalamic volumes. Participants were divided into three groups: those who experienced no childhood trauma or stress (non-ACEs), those who experienced childhood trauma and stress onset at preschool ages (Presch-ACEs), and those who experienced childhood trauma and stress onset at school ages (Sch-ACEs). At 3 months, participants underwent PTSD symptom evaluation using the Clinician Administered PTSD Scale (CAPS).Results: Adult trauma survivors in the Presch-ACEs group had higher CTQ and CAPS scores. In addition, survivors in the Presch-ACEs group had smaller thalamic volume compared to survivors in the non-ACEs and Sch-ACEs groups. Furthermore, smaller thalamic volume moderated a positive association between post-trauma 2-week PCL and subsequent 3-month CAPS scores.Discussion: Earlier occurrence of ACEs was associated with smaller thalamic volume, which appears to moderate a positive association between early posttraumatic stress symptom severity and PTSD development after adult trauma. This raises the possibility that early occurrence of ACEs may impact thalamic structure, specifically a reduction in thalamic volume, and that smaller thalamic volume may contribute to susceptibility to PTSD development after adult trauma.