Introduction

Early life trauma (ELT) experienced during childhood and adolescence plays a critical role in the physical and mental development of an individual. Intensive exposure to stress during this critical developmental period can lead to chronic mental health conditions later in life [1]. Previous research has shown that exposure to traumatic stressors in early life has neurobiological implications (for a recent review see 2). The brain regions affected due to these adversities are the same found to be implicated in several psychiatric illnesses including depression and anxiety disorders [3]. These regions mainly include the emotional brain circuitry comprising of the anterior cingulate cortex [4] and the hippocampus-amygdala limbic regions [5,6]. An early impairment in these brain structures during brain development may affect the functioning of the hypothalamic-pituitary-adrenal axis later in life, altering cortical feedback-regulation and thus leading to increased vulnerability for stress-related psychiatric disorders [2]. Further, exposure to early life adversities moderate genetic risk for developing depression and anxiety [7,8]. There is also evidence that exposure to early life stressors may affect different brain regions at different phases during neuro-development. For example: childhood stress has been associated with reduced hippocampal volume in adults [9,10] but not in children [11]; whereas volume and white matter microstructure in the corpus callosum is found affected in both children [12] and older adults [12,13]. This may reflect age-specific interactions between early trauma exposure and brain structure.

Despite increasing knowledge about the gross morphometric and volumetric changes of these different brain regions following ELT exposure, little is known about the effect of ELT on cortical thickness. Grey matter measurements of volume are confounded by sulcal folding –cortical volume is a combination of thickness and surface area. Hence cortical thickness may be a more sensitive marker of grey matter alteration than is volume [14]. Recent work has also shown that both these neuroimaging measures maybe genetically independent [15]. Recent advances in automated methods for accurately measuring cortical thickness provide a powerful tool for studying this measure in large cohorts of subjects, increasing statistical power.

The current study is the first to determine whether exposure to ELT is associated with alterations in cortical thickness using these methods. Our focus on the cingulate and limbic emotion brain circuitry is based on evidence that this particular network is sensitive to stress exposure and is affected in numerous stress-related neuropsychiatric disorders [4-6]. We have previously demonstrated considerable heterogeneity in both cortical thickness-volume and white matter maturation in the limbic lobes [16], accordingly, in the current study we evaluate the individual sub regions of this brain system. We specifically hypothesize the anterior cingulate and the amygdala-hippocampus limbic regions to be altered with ELT exposure.

The second focus of this study was to use Diffusion Tensor Imaging (DTI) to determine whether any alterations in the macrostructural integrity of the emotion brain system were also evident at the microscopic level in the corresponding white matter. DTI is a non-invasive MRI technique that measures the integrity of white matter tracts in vivo by calculating the diffusion of water within specific regions of the brain. The metric commonly used is fractional anisotropy (FA), with lower FA values reflecting reduced white matter integrity. The decision to include DTI data is based on evidence that changes in cortical grey matter may be associated with changes taking place in the underlying white matter [16] and that white matter disruptions have been implicated in affective disorders [17]. There is also recent evidence that healthy participants with a greater familial risk for depression and exposure to more early life adversities have altered white matter integrity than those who had experienced low early life trauma exposure [18].

To test the impact of early trauma on neurobiological development, neuroimaging data from 352 participants across the entire lifespan, as part of the Brain Resource International Database (BRID) [19,20], was analyzed. We compared participants with high vs. low exposure to ELT. Additionally, this study extended previous research by investigating whether the effect of early trauma exposure on brain structure is reflected during a particular phase of the lifespan. We subdivided our sample into four age groups on the basis of major milestones in psychological adjustment (children, adolescents, young-middle adults or older adults). We hypothesized that individuals with High-Trauma exposure would exhibit reduced (a) cortical thickness, (b) volume in the anterior cingulate and amygdala-hippocampal limbic regions, and (c) microstructural integrity of the corresponding white matter pathways compared with those with Low-Trauma.

Materials and Methods

Cortical thickness & volumetric analysis

Cortical surface reconstruction and volumetric segmentation was performed in an automated manner on the 3D T1 weighted structural images using the Freesurfer image analysis suite (v4.3) (http://surfer.nmr.mgh.harvard.edu/). The technical details of these procedures are described elsewhere [16]. Briefly, for each subject, the boundary between the grey and white matter and the outer pial surface of the cortex were segmented. Cortical thickness measurements at each point across the cortical mantle were calculated as the closest distance from the gray/white boundary to the gray/CSF boundary [23]. The cortical surface and subcortical regions were automatically labeled [24]. For this study, the rostral and caudal anterior cingulate cortex (ACC) and amygdala and hippocampus limbic regions were analyzed. The individual cortical regions were also grouped into frontal, occipital, parietal and temporal lobes for lobe-wise analyses. Figure 1 shows the different brain lobes and the cingulate sub-regions parcelled using freesurfer for a representative dataset.

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Figure 1. Grey matter and white matter regions of interest used in the study.

(top row) Different brain lobes (A) and the rostral and caudal anterior cingulate sub-regions (B) parcelled using freesurfer for a representative dataset (bottom row (C)). Fractional anisotropy skeleton (in green) representing the major white matter tracts for all subjects is overlaid on the MNI standard brain. Sections of the tract sekeleton representing the cingulate and limbic white matter tracts are shown: cingulum cingulate bundle (orange); cingulum hippocampus bundle (pink); fornix (yellow); stria (blue) and uncinate fasciculus (red).

Abbreviations: ACC, anterior cingulate cortex.

https://doi.org/10.1371/journal.pone.0075524.g001

Results

Discussion

The present study utilized multiple structural MR imaging methods to examine the impact early life trauma has upon brain circuits associated with depression and anxiety. The main findings were concentrated during adolescence: cortical thickness of the rostral ACC and and the volume of the amygdala was reduced in the 13-18year high ELT exposure group only.

Neuroimaging techniques have allowed studying in-vivo brain changes with age. These are mainly developmental maturation changes until young adolescence, followed by an age-related slow decline in cortical volume and thickness during young-middle adulthood and an accelerated decline thereafter [28]. Particularly during childhood to young adulthood an early heterochronicity in grey matter maturation trajectories between individual sub-regions has been observed, with the timing and sequence of development shown to follow that of cognitive function [28]. At a cellular level, this variation in cortical maturation is likely to be due to a combination of myelination and synaptic pruning [29]. This period of neurodevelopment where the human brain is changing dynamically is also the key risk period for onset of mental disorders - half of all lifetime cases starting at the age of 14 years and almost three-fourths of those by 24 years [30]. Specifically, anxiety disorders have a median age-onset as early as 11years while depressive disorders at 30years. Using data from across the entire lifespan, we found that brain alterations due to exposure to ELT are apparent during this same neurodevelopmental phase. These findings are observed in an otherwise healthy sample, suggesting they may be trait-like markers for how trauma impacts the brain to confer susceptibility to depression and anxiety. However this warrants longitudinal follow-up and cannot be ascertained using cross-sectional data in this study.

While previous MRI studies on ELT exposure and brain structure have focused on volumetric measurements of specific brain regions, the current study is the first to evaluate alterations in cortical thickness. Cortical thickness is a measure of separation of the grey and white matter surfaces at every point of the cortex and more directly reflects change in grey matter in comparison to volume. Recent work has shown that both these measures are driven by distinct genetic factors [15,31], which emphasizes a complementary evaluation of both measures to identify suitable imaging phenotypes. This is particularly relevant for ELT, as exposure to trauma in early life has been shown to be a moderator of genetic risk in development of clinical depression [7]. Identifying imaging endophenotypes will help better understand how genetic risk and exposure to ELT translates to clinical symptomology.

Impacts on grey matter volume due to ELT were evident for the amygdala. This finding is noteworthy in the context of the known increased risk for depression and anxiety with ELT exposure. Previous research has demonstrated volume reductions in the hippocampus and the amygdala associated with ELT [11]. Our data showed robust evidence of decreased volume in amygdala but not in the hippocampus. Hippocampal findings in depression have shown to be highly variable across studies and mainly related to length and number of depressive episodes [32]. Negative life stressors have also shown to predict longitudinal hippocampal volume change [33]. Further, previous work using functional MRI have also shown that resting state connectivity of the posterior cingulate with the amygdala is altered in patients with PTSD related to ELT [34]. Amygdala dysfunction in adults with childhood maltreatment has also been previously reported [10]. Additionally there is clear evidence that negative life stressors have an immediate neurobiological impact on both these regions. A study on earthquake survivors observed both amygdala-hippocampal resting state functional connectivity and hippocampal volume to be reduced within 25 days post trauma in survivors [35,36].

Reductions in cortical thickness due to ELT exposure were in the rostral portion of the ACC. Our current findings extend on those reported in previous studies, which showed a volume reduction in the ACC among adults who had experienced childhood trauma [10,13]. For our analysis cohort, the volume of the ACC was not significant during adolescence (p=0.083) or for the adult cohort (p>0.05). We feel our current analysis represents a refinement on this previous observation, with the differences between these observations likely due to the different methodological approaches (volume analysis in VBM versus precise surface-based anatomical measurements in freesurfer). The ACC is a key structure, which regulates emotion reactivity via its direct connections to the amygdala, hence reductions in both these regions imply a significant structural alteration in the emotional reactivity circuitry that has these two regions as its core. Dysregulation of this same cingulate-limbic circuitry has often been observed in both depression and PTSD [37].

It is interesting to note, however, that significant differences in cortical thickness and volume were mainly found in the adolescent participants – reflecting vulnerability of these brain regions during this neurodevelopmental phase. Several other explanations are possible to explain these heterogeneous findings across age. Firstly, although these are cross-sectional data, it is possible that there is functional recovery of both these brain regions, after relief from early stressors, and the normalized volumes are a reflection of effective coping strategy in these participants to avoid clinical levels of depression and/or anxiety. It is also possible that our retrospective self-report measure underestimated ELT in the older adult cohort, who may have recall difficulties for more distal than current traumatic events. Thirdly, our cohort are free of a clinical history or diagnosis of depression or anxiety at time of participation, hence there may be a selection bias against structural damage due to ELT particularly in the older subjects – since subjects with neuropsychiatric disease presenting in later life which may be partly attributable to ELT would be excluded from the study. This latter point implies that the adolescents showing significant structural change in our study may represent a different population from the older subjects. However, only longitudinal data could further evaluate this interesting proposition. Despite these potential confounders, our data represent a fascinating “snapshot” of structural change due to exposed early trauma. The mostly adolescent loss in grey matter in these regions may represent a transient vulnerability to disorders associated with emotional dysregulation. Investigations of the interaction of genetic risk factors and ELT for neuropsychiatric outcomes observe a similar attenuation of these interactive effects in older adults [38].

The lack of significant findings with regard to the limbic and cingulate white matter fiber tracts is suggestive that the volume and cortical thickness loss may reflect a form of limited structural change due to ELT, where change was restricted to the cortex in healthy participants. Previous imaging studies in PTSD, major depression disorder patients, and healthy controls with greater familial risk for depression have reported altered FA values in the limbic white matter [17,18,39]. In our healthy cohort, the absence of clinically detectable symptoms may reflect the relative normality of the underlying white matter – even in the presence of detectable grey matter changes. Therefore, it’s possible that white matter connectivity effects may be detected in ELT cohorts with either a clinical diagnosis or with abnormal but non-clinically diagnostic scores.

The current study is limited by the fact that it does not take into account the different types of traumatic exposures or the timing of these exposures relative to neurodevelopment. There is some evidence supporting the concept that different brain regions may have their own developmental time windows when they are maximally vulnerable to the effects of ELT [40]. In addition to timing, it seems likely that certain types of traumatic events may have a greater impact on brain structure then others, although this can be challenging to evaluate given the frequency of multiple types of trauma exposure for individuals with any history of ELT. The absence of white matter alterations with ELT should be interpreted with caution especially in consideration of the DTI MRI sequence used in the study. Although this sequence was optimized for the available scanners at time of acquisition, the DTI spatial and directional resolution is limited in comparison to those available on newer scanners. This dataset however has been shown to be sensitive in mapping developmental changes across the entire lifespan [16]. The study is also limited by the small available sample size in the high ELT group for both adolescent and children. Closer look at the data verifies that outliers did not influence the main results seen for the adolescent group. However for the children group, the sample size is too low to draw any reliable interpretations.

In summary, the current analysis is the first to evaluate effects of early trauma on cortical thickness, volume and white matter associated with the emotional brain circuitry in the same cohort. Our findings show that exposure to early life trauma is associated with alterations in brain regions previously implicated in adult psychopathology, despite the absence of clinically significant psychiatric symptoms. These effects were most prominent during adolescence – a neurodevelopment period that is peak for risk and onset of depressive disorders. These structural markers will serve as useful endophenotypes in understanding how genetic, biological and environmental risk factors may have control in moderating effects of early life adversities in the development of depression and anxiety.

Supporting Information

Acknowledgments

We acknowledge the data and support provided by BRAINnet; www.BRAINnet.net, under the governance of the BRAINnet Foundation. BRAINnet is the scientific network that coordinates access to the Brain Resource International Database for independent scientific purposes.