Introduction

Early life interpersonal trauma (ELT) exposure is associated with increased risk of developing mental health disorders and functional impairments, including posttraumatic stress disorder (PTSD). Substantial scientific efforts have identified potential neurobiological correlates of ELT and PTSD, resulting in a wide knowledge base which suggests that both are characterized by extensive structural deficits, including reduced gray matter volume (GMV) of brain regions within emotion processing and cognitive control circuits [1,2,3,4]. Despite the depth of research into GMV correlates as they relate to ELT and PTSD, fewer investigations have examined the impact of ELT and PTSD on cortical thickness (CT). Whereas GMV estimations contain information about surface area and CT, examination of CT separate from GMV provides an anatomically distinct structural measure that can confer regionally specific information about the cortical surface in health and disease states [5]. Therefore, CT can reveal a precise picture of disease-related structural alterations in the cortex that may be obscured by composite measures, such as GMV.

It is well established that CT follows a normative developmental trajectory, with cortical thinning throughout childhood and adolescence associated with increased cognitive performance through facilitating more efficient communication throughout the cortex [6, 7]; however, normative cortical thinning can become disrupted. One hypothesis for this disruption is through excitotoxic glutamate transmission during chronic stress, such as trauma exposure, contributing to reduced structural integrity and disordered cortical thinning [8, 9]. Alterations in normative cortical thinning may be ameliorated for trauma-exposed adolescents in supportive social contexts [10] or could persist into adulthood, where childhood trauma would be reflected in greater thickness of cortical areas that typically thin during the course of development. Alternatively, the acute impact of ELT on cortical integrity could be reflected differently in adolescents vs. adults, as compensatory adaptations may lead to distinctive signatures of ELT in the adult cortex. One of the aims of the following analysis is to address this gap in knowledge by determining whether CT correlates of ELT differ between adolescents and adults.

Literature regarding whole-brain CT alterations in trauma-exposed patients suggests that trauma exposure is related to reduced CT throughout the brain in both children and adults [11,12,13,14,15], with some evidence suggesting increased CT in the rostral middle frontal gyrus [12] and paracentral gyrus and posterior cingulate cortex [13] in individuals with ELT. Notably, much of this work has been conducted in adult male combat veterans [13, 15, 16], thereby limiting the inferences that can be made regarding structural alterations in females with interpersonal violence (IPV) exposure. Though evidence suggests that IPV exposure is a substantial risk factor for developing PTSD relative to other types of traumatic experiences (e.g., motor vehicle accidents, natural disasters, etc.) [17,18,19] and females are at a higher risk compared to males of developing PTSD following trauma exposure [20, 21], females with IPV exposure are underrepresented in studies of structural neural alterations in PTSD.

While trauma exposure is inherent to a PTSD diagnosis, it is important to understand how neural correlates of early trauma exposure may differ from those of PTSD, as this information could be clinically relevant. For example, if CT alterations are unique to ELT vs. PTSD and these alterations affect different psychological processes, it may be important to target, rehabilitate, or compensate for those specific processes. Existing whole-brain studies suggest that CT is reduced in several cortical regions in children and adolescents with ELT [11, 22], as well as in adults with PTSD [16, 23]. However, few studies have investigated the unique cortical signatures of ELT separate from PTSD in adults, and no studies to our knowledge have investigated this question in an adolescent sample. Results from adult studies are mixed, suggesting potential differential effects of ELT and a PTSD diagnosis on CT in cross-sectional studies with combat veterans [13, 15]. As such, it is unclear how the CT correlates observed in adolescents with ELT translate to differences in CT observed in combat-exposed adults with ELT and whether trauma exposure at an early age has lasting effects on CT into adulthood. Finally, because CT estimates result from a developmental process that could be interrupted in adolescent PTSD but is less likely to be interrupted in adult PTSD, a specific investigation into the differences in CT between adolescents and adults with PTSD is needed to better understand the trajectory of cortical development following the onset of psychological symptoms.

The following study aims to address substantial gaps in the literature regarding the associations among ELT, PTSD, developmental stage, and CT using a large sample (n = 253) of adolescent and adult females with and without IPV exposure before age 18 years. Through a whole-brain, vertex-wise approach, we investigate the distinct effects of ELT and PTSD diagnosis on CT and whether differences in these structural correlates are dependent upon participant age group.

Methods

Participant recruitment

Adolescent females aged 11–18 years and adult females aged 20–50 years were recruited through 7 studies at 2 sites: the University of Arkansas for Medical Sciences (UAMS; Little Rock, AR; n = 161; 96 adolescents) and the University of Wisconsin, Madison (UW; Madison, WI; n = 92; 35 adolescents). All studies were approved by the respective Institutional Review Boards, and details from some of these studies are reported elsewhere [24,25,26,27]. The present analyses do not repeat prior published reports from these studies, and though some individuals participated in multiple studies, participant data were not repeated in these analyses.

Two adolescent studies recruited both non-trauma-exposed healthy adolescents (n = 59) and adolescents with IPV exposure (n = 41). Inclusion criteria for healthy comparisons included female sex, absence of trauma exposure, absence of current psychiatric disorders, and absence of psychiatric medication use. Inclusion criterion for the trauma-exposed participants was a positive history of IPV exposure and was not dependent on the type or severity of psychiatric symptoms. A third adolescent study recruited specifically for IPV-exposed, treatment-seeking adolescents with a current diagnosis of PTSD (n = 31). For one of the three adult studies, women with a primary diagnosis of PTSD and IPV exposure were specifically recruited (n = 85), while the remaining two adult studies recruited both women with PTSD and healthy controls. Inclusion criteria for the PTSD group in all studies were a primary diagnosis of PTSD, IPV exposure, and female sex. Inclusion criteria for the control groups were the same for adults as for adolescents. Exclusion criteria for all participants included internal metal or other magnetic resonance imaging (MRI) contraindications, major medical disorders, and endorsement of psychotic symptoms. All adult participants and adult caregivers of adolescent participants provided informed consent before completing study procedures. All minors provided informed assent.

Assessments

For all subjects, trauma histories were assessed with the National Women’s Survey and National Survey of Adolescents [18, 28] trauma section, which is a structured interview with behaviorally specific questions to assess physical abuse by a caregiver, physical assault, sexual assault, witnessed violence, and other stressful life events. Trauma exposure load is measured by the sum of different endorsed traumatic event categories. ELT exposure was identified as occurring before age 18 years. Presence of mental health disorders were assessed with the Mini-International Neuropsychiatric Interview for Children and Adolescents (n = 88) [29] and Kiddie Schedule for Affective Disorders and Schizophrenia (n = 43) [30]; and all adults were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV) [31]. All interview-based assessments were conducted by trained clinical interviewers. PTSD symptoms were assessed with the UCLA-PTSD Reaction Index (UCLA-RI) in the adolescent sample [32] and the PTSD Checklist for DSM-5 (PCL-5) [33] for two adult studies (n = 96) and the PTSD Checklist-Civilian Version for DSM-IV (PCL-C) [34] for one study (n = 26). In order to compare across versions of the PCL, PCL-C scores were converted to PCL-5 scores using an established and validated crosswalk procedure using equipercentile equating [35].

Additional assessments to characterize the sample included self-report measures of childhood maltreatment on the Childhood Trauma Questionnaire (CTQ) [36], depression symptoms from the Short Mood and Feelings Questionnaire (SMFQ) [37] in the adolescent sample and Beck Depression Inventory-II (BDI-II) [38] in the adult sample, and anxiety symptoms from the Child Behavior Checklist-Child Version (CBCL) [39] for the adolescents and the Positive and Negative Affect Schedule- Negative Scale (PANAS) [40] for the adult sample.

Data acquisition and quality control

See Supplemental Material.

Image preprocessing and analysis

See Supplemental Material.

Vertex-wise CT analysis

To conduct a vertex-wise analysis of group differences in CT across the brain, we first generated cortical surface files for each subject through FreeSurfer’s automatic reconall pipeline in version 6.0.0 (http://surfer.nmr.mgh.harvard.edu/). Subject surface files were registered to the FreeSurfer average template (fsaverage), which is constructed from scans of 40 healthy adult subjects [41] and smoothed with a 15-mm full-width half-maximum kernel in order to compare differences in CT across subjects. Next, vertex-wise linear model tests across the cortical surface were conducted using AFNI’s 3dttest++ function [42]. Predictors of CT included total number of ELT exposures and its interaction with binarized age group (adolescents or adults), as well as PTSD diagnosis and its interaction with age group. Age was binarized because continuous age was non-normally distributed (SW test p < 0.001; Table S1) and therefore did not suit the assumptions of a general linear model. All comparisons controlled for image acquisition site (UW or UAMS). To control for multiple comparisons, the AFNI slow_surf_clustsim.py function was used on the group-level fsaverage surface. The uncorrected p threshold was specified at 0.001 and 10,000 Monte Carlo simulations were run to generate the minimum surface cluster area unlikely to be detected by chance (p < 0.05).

Second-level region of interest (ROI) analysis

Finally, cortical regions that were found to be significantly different between groups (i.e., PTSD vs. controls) or to significantly correlate with ELT load above the area threshold were extracted using AFNI SurfClust and were carried forward to second-level analyses that were conducted with subsets of participants with ELT or PTSD. Linear models controlling for continuous participant age and acquisition site determined the relationships between PTSD symptom severity and CT of extracted clusters at the individual level. Because different assessments were used to evaluate PTSD symptom severity (UCLA-RI for adolescents and PCL-5 for adults), second-level analyses were conducted separately for each age group. To further evaluate whether normal developmental variation in CT confounds interpretations of the relationships of ELT and PTSD with CT, additional models within each age group assessed these relationships with and without including continuous age as a covariate. Due to the high psychological comorbidity and psychotropic medication use of the female-specific sample, supplementary analyses were conducted controlling for diagnoses of comorbid anxiety disorders (AD), major depression disorder (MDD), substance use, psychotropic medication, and contraceptive use to understand the specificity of CT relationships to ELT and PTSD. Separate models for each relevant covariate were constructed due to the high collinearity of these variables with ELT and PTSD diagnoses. Additional follow-up analyses utilized continuous measures of depression symptoms from the SMFQ [37] and BDI-II [38] and anxiety symptoms from the CBCL [39] and PANAS [40] to investigate the relationship between CT and comorbid psychological symptoms.

Results

Participant demographics

All sociodemographic information for the sample is provided in Table 1. Within the adolescent sample, the non-trauma-exposed comparison group (NTC) did not differ from the trauma-exposed control group (TEC) or the PTSD group in race, but the TEC group was slightly older on average than both the NTC (t(88) = 2.27, p = 0.026) and PTSD group (t(70) = 2.01, p = 0.045), and a higher percentage of the TEC group were taking contraceptives compared to both the NTC (χ2(1) = 12.08, p = 0.001) and PTSD groups (χ2(1) = 4.27, p = 0.039). Within the adult sample, NTC and PTSD groups did not differ in age, race, or contraceptive use.

Table 1 Clinical and demographic characteristics of the sample.
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In both age groups, trauma-exposed individuals with and without PTSD demonstrated significantly higher CTQ total scores than NTC individuals (ps < 0.001, Table 1). Additionally, CTQ total scores were higher in the adult PTSD group compared to the adolescent TEC (t(129) = 3.87, p < 0.001) and adolescent PTSD (t(139) = 3.60, p < 0.001) groups. The adult PTSD group also reported more assault exposures, including physical assault and physical abuse by a caregiver than both adolescent trauma-exposed groups (see Table 1). While the adult PTSD group endorsed more sexual assault exposures than the adolescent TEC group (t(129) = 3.25, p = 0.002), the adults with PTSD did not differ from the adolescents with PTSD in total number of sexual assault exposures (t(139) = 0.26, p = 0.792). Additionally, the adolescents with PTSD endorsed more sexual assault exposures before age 18 years than the adults with PTSD (t(139) = 2.78, p = 0.006). Importantly, however, the adult PTSD group did not differ from either the adolescent TEC (t(129) = −0.93, p = 0.356) or PTSD (t(139) = 0.49, p = 0.626) group in total number of assault exposures before age 18 years, which was the primary measure of ELT exposure in this analysis.

Effect of ELT exposure on CT

Vertex-wise linear model tests across the cortical surface revealed a significant main effect of ELT exposure, such that participants across both age groups with a higher number of ELT exposures demonstrated less thickness of the left posterior middle cingulate cortex (pMCC; area = 205.1 mm2, t(246) = −4.26, p < 0.001, corrected; Fig. 1A and Table 2). With the sample restricted to only participants with ELT, the inverse relationship between ELT exposures and pMCC CT remains for both adolescents (t(68) = −2.31, p = 0.024) and adults (t(82) = −2.09, p = 0.040; Fig. 1B and Table 3) when controlling for continuous age and acquisition site. This relationship cannot be explained by comorbid AD, MDD, substance use, psychotropic medication, or contraceptive use (Fig. S1 and Table S2). By contrast, there were no significant clusters observed for the age group × ELT interaction term at the voxel-wise level or for the continuous age × ELT interaction term at the cluster level (Table S3), thereby failing to identify CT correlates of ELT that differed between adolescents and adults.

Fig. 1: Number of early life trauma exposures is inversely related to thickness of the left posterior middle cingulate cortex.
figure 1

Vertex-wise linear model tests across the cortical surface revealed one region on the cortical surface that survived Monte-Carlo correction for multiple comparisons and were associated with early life trauma exposure: the left posterior middle cingulate cortex (A). Across both adolescent and adult participants, a higher number of trauma exposures before age 18 years was associated with reduced thickness of this region (B). pMCC posterior middle cingulate cortex.

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Table 2 Significant cortical thickness clusters from vertex-wise analysis.
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Table 3 Statistics for the relationship between thickness of significant clusters and clinical variables for posttraumatic stress disorder and early life trauma exposure.
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Effect of PTSD on CT

Vertex-wise linear model tests across the cortical surface revealed a significant main effect of PTSD such that PTSD diagnosis was related to greater thickness of the left intraparietal sulcus (IPS; area = 207.9 mm2, t(246) = 3.79, p < 0.001, corrected; Fig. 2A), left angular gyrus (AG; area = 203.5 mm2, t(246) = 3.84, p < 0.001, corrected; Fig. 2E), and right IPS (area = 211.9 mm2, t(246) = 3.84, p < 0.001, corrected; Fig. 2I and Table 2). These effects were independent of age group in all clusters (Fig. 1B, F, J and Table 2). There were no significant clusters observed for the age group × PTSD interaction term at the voxel-wise level or for the continuous age × PTSD interaction term at the cluster level (Table S3), thereby failing to identify CT correlates of PTSD that differed between adolescents and adults.

Fig. 2: PTSD diagnosis and symptom severity are associated with increased thickness of the left angular gyrus and bilateral intraparietal sulcus.
figure 2

Vertex-wise linear model tests across the cortical surface revealed three regions on the cortical surface that survived Monte-Carlo correction for multiple comparisons and were associated with PTSD diagnosis: the left angular gyrus and bilateral intraparietal sulcus (A, E, I). Across both the adult and adolescent age groups, PTSD diagnosis was associated with increased thickness of these cortical regions (B, F, J). Thickness in these regions also correlated with PTSD symptom severity in the adults but not the adolescents with PTSD, as measured by the UCLA-RI in the adolescent sample (C, G, K) and the adjusted PCL-5 in the adult sample (D, H, L). This relationship was maintained in adults when controlling for all relevant clinical variables, including major depression, anxiety disorders, substance use disorder, psychotropic medication use, and contraceptive use. IPS intraparietal sulcus, TEC trauma-exposed controls, PTSD posttraumatic stress disorder, UCLA-RI UCLA PTSD Reaction Index, PCL-5 PTSD Checklist. Error Bars—standard error of the mean. One adult subject was missing PCL-5 information and one adolescent subject was missing UCLA-RI information and therefore were left out of these analyses.

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In order to investigate whether the IPS and AG clusters that demonstrated significantly greater thickness in the PTSD group related to PTSD symptom severity, we followed up the vertex-wise analysis with linear models on each significant cluster within the subset of participants that met diagnostic threshold for PTSD in each age group. In the adolescents, regression models controlling for continuous participant age and acquisition site failed to reveal any significant relationships between thickness and PTSD symptom severity in any of the three clusters (Table 3) and CT was not related to depression or anxiety symptoms (Figs. S5–S7B, C and Table S6). Conversely, in the adults, regression models with and without controlling for participant age (Table S4) and acquisition site revealed that IPS and AG thickness were positively related to PTSD symptom severity in the subset of participants with PTSD, indicating that adult women with elevated PTSD symptoms demonstrated greater thickness of the left IPS (t(95) = 3.00, p = 0.003; Fig. 1C and Table 3), left AG (t(95) = 2.55, p = 0.012; Fig. 1H and Table 3), and right IPS (t(95) = 2.55, p = 0.012; Fig. 1L and Table 3). CT relationships with all three regions are retained when controlling for comorbid AD, substance use disorders, psychotropic medication use, and contraceptive use (Figs. S2–S4 and Table S5), and continuous depression and anxiety symptoms are unrelated to CT in these regions (Figs. S5–S7D, E and Table S6). When controlling for MDD, the relationships between PTSD symptoms and CT of the left AG and right IPS are slightly reduced (ps = 0.05, Table S5). Additional vertex-wise analyses within each age group failed to reveal evidence for an ELT × PTSD diagnosis interaction or an ELT × PTSD symptom severity interaction (Fig. S8 and Table S7).

Discussion

The present results reveal distinct CT signatures of ELT and PTSD, which are shared across adolescent and adult females with exposure to IPV. Specifically, vertex-wise linear models revealed evidence of a unique CT signature of ELT in the left pMCC, whereby thickness is inversely related to ELT exposure, such that adolescents and adults who endorse more episodes of trauma exposure before age 18 years show less CT of the left pMCC. Interestingly, we did not observe any significant age group × ELT interactions, which failed to support a hypothesis of developmentally specialized relationships between ELT and CT. Instead, the effects we observed are present across age groups in the sample, indicating that distinct neural correlates of ELT are shared across developmental timepoints. Additionally, we provide evidence for increased CT in the IPS and AG in both adolescents and adults who meet diagnostic threshold for PTSD. Thickness in the IPS and AG was positively correlated with total PTSD symptom severity in the adult PTSD group only, indicating that CT may serve as a general marker of psychopathology in adolescents that does not linearly scale with disorder severity.

Little extant research has investigated connections between trauma exposure and MCC structure and function, so the finding of an inverse relationship between CT of the pMCC and ELT exposure is a unique contribution to this literature. In fact, the significance of CT of the MCC is largely unexplored, with limited existing research suggesting that reduced CT in this region may be related to chronic pain sensation [43]. The function of the MCC is better characterized than the clinical implications of its thickness, with evidence suggesting that the MCC is an important region for integrating negative affect, cognitive control, and pain processing [44]. Though deficits in these functions are present in trauma-exposed individuals, the MCC is rarely investigated in the context of trauma exposure. One meta-analysis revealed increased activation of the MCC in IPV-exposed subjects across tasks in functional MRI (fMRI) [45], indicating that MCC activation might contribute to deficits in task performance for individuals with trauma exposure. To our knowledge, however, thickness of the MCC has yet to be investigated in specific populations with ELT. One potential reason for this lack of research is that many CT studies are conducted at the ROI level on a priori regions that literature suggests are canonically impaired in individuals with ELT, which generally include limbic and prefrontal structures involved in emotional regulation [46]. Future research should utilize a whole-brain, vertex-wise approach, similar to the method described in this study, to better characterize the relation between clinical factors and CT, absent of biases from a priori ROI approaches.

Previous evidence suggests that CT of the IPS is related to cognitive performance in children, adolescents, and adults, such that individuals with reduced thickness exhibit better visuospatial working memory, nonverbal reasoning, and visuomotor set shifting [47, 48]. Additionally, the IPS is a key component of the frontoparietal cognitive control network, the activity of which shifts from parietal to frontal regions throughout development as the cortex thins to promote specialized learning [49]. Similarly, the AG, located in the inferior parietal lobe, is implicated as a major hub for multisensory integration, attention, and information processing [50]. Importantly, the parietal cortex also modulates emotional reappraisal [51] and emotion perception across age groups [52], which can be impaired in individuals with PTSD [53, 54]. Consistent with evidence suggesting that adults with PTSD show impairments in verbal learning, sustained attention, and working memory [55], it is possible that disruptions in the specialization of frontoparietal network activity are reflected in increased CT of parietal regions and affect cognitive processing and emotional regulation in individuals with PTSD.

Thickness of the cerebral cortex is linked to developmental stage, with negative linear associations between age and CT across typically developing child and adolescent samples [6, 7]. As such, the present results demonstrating consistent regions of altered CT in both adolescents and adults with trauma exposure may be indicative of disruptions in normative cortical thinning in childhood that persist into adulthood. A longitudinal analysis is merited to provide evidence for this hypothesis. Conversely, the effect of PTSD symptoms on CT of the IPS and AG did differ between age groups such that CT in these three regions was positively associated with PTSD symptoms in adults but not in adolescents with PTSD. In adolescents, PTSD diagnosis was associated with more thickness of the IPS and AG but was unrelated to PTSD symptom severity, suggesting that CT serves as an neural identifier of psychopathology rather than an indicator of disorder severity in this age group. Research in adolescent MDD has revealed similar cortical markers where adolescents with MDD display greater CT relative to non-MDD controls [56]. One study also demonstrated a potential clinical utility for CT identifiers in predicting the onset of MDD in adolescent girls [57], suggesting that cortical indicators of psychological disorders, such as the IPS and AG markers revealed in this analysis, may be useful predictors of symptom severity in adulthood.

Our results provide evidence that distinct CT correlates related to both ELT and PTSD are shared among samples of adolescents and adults, suggesting that cortical markers of trauma exposure and clinical diagnoses are present in adolescence and adulthood. While this finding is important for deepening our understanding of the effects of trauma exposure and psychopathology on the structure of the brain, the functional relevance of CT markers is yet unclear. While some limited evidence exists linking CT to blood-oxygen-level-dependent (BOLD) activation in the frontoparietal attention network [47] and cingulate cortex [58] during cognitive testing in healthy adults, another study found no evidence for a relationship between CT and BOLD activation during a working memory task in healthy adolescents [59], suggesting that the association between structure and function in the developing brain is unclear. Importantly, no studies to our knowledge have investigated the relation between CT and brain function in fMRI tasks within subjects with trauma exposure or PTSD. More work is needed to determine the clinical significance of regionally increased or decreased CT for individuals with ELT and PTSD. Future studies should build on the groundwork established by the analyses presented in this paper to examine both structure and function of gray matter in clinical groups to identify clinical usage for structural markers.

While the large sample size of mixed developmental age groups across two different sites and vertex-wise approach are strengths of this study, limitations exist. First, the scanners differed between the data collection sites, thereby creating a source of variance. Though all structural scans were processed through the same FreeSurfer version on the same operating system and acquisition site was included as a covariate in all analyses, differences in MRI scanners may have impacted final results. However, the multi-site nature of these analyses is also a strength due to the direct replication of findings within groups from different geographic regions. Second, this sample included cross-sectional data from both adult and adolescent participants with different assessments used to collect information on PTSD and mental health symptoms. The use of different scales precludes direct comparison of mental health symptoms across age groups and the age range for the adolescents (11–18 years) was restricted compared to the adults (20–50 years), which could be limitations for the age group-specific analyses. Third, though one goal of these analyses was to characterize CT alterations in females, thereby filling a major gap in the literature, the degree to which our results generalize to males is unknown. In addition, we lacked data on hormonal status among our participants and therefore cannot evaluate the potential variance related to menstrual or pubertal status. Finally, because our analyses utilized data from multiple studies with differing inclusion criteria, protocol differences may be contributing to unexplained variance within the dataset. Similarly, lack of a trauma-exposed control group in the adult sample and an adult group that was disproportionately comprised of PTSD patients compared to controls is also a limitation. All adults with trauma exposure also met criteria for PTSD, so we were unable to directly compare the effect of trauma exposure absent of PTSD in our adult sample to the adolescent group. Future studies should include a trauma-exposed control group and balance controls and patients in the adult sample to directly compare across age groups.

Funding and disclosure

The authors have no disclosures or conflicts of interest to report. Research in this publication was supported by the National Institute of Mental Health and the National Institutes of Health under awards T32MH018931-31, F31MH122047, T32GM007507, MH119132, MH108753, MH106860, and MH097784.