Abnormalities of white matter integrity in the corpus callosum of adolescents with PTSD after childhood sexual abuse: a DTI study

Childhood psychotrauma is a prevalent and important predictor of both child and adult psychopathology as well as a number of somatic disorders [1, 26, 31, 45]. Preclinical research in rodents and non-human primates has shown that structure and functioning of the developing brain are highly vulnerable to the effects of adversity, especially in certain critical time windows. In animal studies, childhood adversity was found to be associated with changes in brain circuitry involved in stress and emotion regulation, such as the hippocampus and certain prefrontal regions, possibly underlying vulnerability to the impact of stressors later in life [12, 25, 32, 41]. In adult humans, a history of chronic traumatization during childhood and adolescence was found to be associated with structural and functional damage in key elements of emotion and stress regulating brain circuitry, for example in the hippocampus in adults reporting childhood abuse or in the medial prefrontal cortex in adults reporting childhood emotional maltreatment [5, 56]. Bearing in mind the neuroplasticity of the maturing human brain [8], a thorough understanding of the human neurobiology underlying the psychological sequelae of childhood and youth psychotrauma may hold promise for developing appropriate interventions to alter adverse neurodevelopmental trajectories [22]. Some recent reviews and meta-analyses have addressed structural brain alterations following childhood trauma in both adolescents and (young) adults with and without psychopathology [11, 40, 60]. The studies included in these reviews and meta-analyses often used different approaches and varied in sample size. Nevertheless, next to findings in the cerebellum and sensory cortex, most of the results from reviews and meta-analyses point toward involvement of the corpus callosum (CC) and corticolimbic circuits in the pathophysiological sequelae of psychotrauma in children and young adults.

Diminished white matter (WM) integrity can constitute one element of abnormalities in corticolimbic and related circuitry. Diminished structural integrity may impede adaptive emotional and cognitive functioning, thereby rendering an individual vulnerable to childhood and adult psychopathology.

A promising tool for examining the structural integrity of WM in children and youth who experienced psychotrauma is diffusion tensor imaging (DTI). Fractional anisotropy (FA) is the most commonly used DTI parameter and reflects the degree of diffusion directionality of water, which in white matter can be influenced by structural properties such as axonal density, organization and myelinization. Smaller FA values are associated with decreased white matter integrity. To further interpret differences in FA, additional parameters such as the mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) can be assessed as well.

So far, four studies in children and youth have employed DTI to examine the effects of psychotrauma on white matter integrity in the developing brain and several reported abnormalities in the CC, but also in other areas. The first small study, in children who had been subjected to early socioemotional deprivation (N = 7), found decreased FA in the left UF [14]. The second study, in a group of children (N = 17) with post-traumatic stress disorder (PTSD) following varying forms of maltreatment, found reduced FA in the medial and posterior subregions of the CC [24]. The third study looked at the influence of Early Life Stress (ELS) on FA of the genu of the CC across the life span in healthy individuals. The results showed a lower FA in the youngest (8–12 years) and oldest (51–72 years) ELS age groups compared to non-exposed controls, suggesting that the effect is independent from the presence of psychopathology [44]. This was corroborated in the fourth study by Huang and Rao, in adolescents exposed to childhood maltreatment but without a history of psychiatric illness, who showed decreased FA values compared to controls in the left and right superior longitudinal fasciculi, right cingulum bundle, left inferior fronto-occipital fasciculus and splenium of the CC [21]. None of these studies investigated additional DTI parameters and only a region-of-interest (ROI) approach was used, which may have led important alterations in WM microstructure outside the ROI to go unobserved. Furthermore, study populations were heterogeneous for type of child adversity, which might have resulted in heterogeneous neuroimaging findings and differences in psychopathological sequelae.

The aim of our study was to investigate white matter integrity in a group of adolescents with psychopathology related to childhood sexual abuse (CSA) and matched healthy controls. We chose CSA as this is a prevalent form of child psychotrauma and a frequent cause of PTSD [15, 27]. This study is the first to focus on integrity of white matter tracts in a group of adolescents who had all experienced CSA. Based on previous neuroanatomical studies in children and youth as well as in adults, we hypothesized a reduced FA in the CC, the UF and the cingulum, although findings have not been unequivocal. We also aimed to investigate the possible relationship between FA and clinical symptoms in the patient group. Next, we also planned an exploratory whole brain analysis to detect aberrant FA values in areas outside our a priori defined ROIs.

From the original total of 22 PTSD and 30 control adolescents, three controls were excluded because of image artifacts in T1-weighted anatomical scans. Further, two adolescents with PTSD were excluded because of image artifacts in the DTI dataset, resulting in a final sample of 20 adolescents with PTSD. From the remaining 27 controls, 20 subjects were group-wise matched on age and gender with the PTSD adolescents. Eventually, 40 participants (20 PTSD and 20 controls) were included. Of the 20 PTSD participants, 19 fulfilled all PTSD criteria on the ADIS, while one had sufficient PTSD symptoms, but with limited interference. Since earlier research showed that persons with subthreshold PTSD in many aspects resemble PTSD patients, we decided to include this patient [10].

The majority of participants was female (88 %, see Table 1). Of the participants with PTSD, 15 had comorbid anxiety disorders, most often more than one. Eight had a comorbid depressive disorder and one an oppositional defiant disorder (ODD). All controls and 16 adolescents with PTSD were drug and treatment naïve. Two adolescents with PTSD were on stable SSRI treatment and two used amphetamines (not on the day of scanning).

The PTSD group had a significantly lower FIQ than controls [F(1, 38) = 8,14, p < 0.01] and more subjects in the post-pubertal phase (50 versus 25 %). As expected, there was a significant main effect of group on the TSCC scale scores [with and without controlling for age and FIQ; F(7,28) = 6,48, p < 0.01]. The PTSD group had significantly higher scores on all TSCC scales (all with p < 0.01).

We examined white matter integrity in a sample of adolescents with CSA-related PTSD, using an ROI and an additional exploratory whole brain approach. We hypothesized reduced FA in a number of relevant white matter tracts: the CC, UF and cingulum. Compared to the control group, our adolescent PTSD group only showed decreased FA in areas of the CC, with additional DTI parameters suggesting demyelinization and dysmyelinization in these areas. We also found a significant correlation (uncorrected) between FA in the CC and Anger scores on the TSCC in the adolescents with CSA-related PTSD.

This study is the first to report on white matter integrity in a group of adolescents with CSA-related PTSD. The results of our study are in line with the findings of the recent DTI study by Jackowski and colleagues, who examined the CC in a group of children with PTSD following various forms of intrafamilial maltreatment, and also found reduced FA in several subregions of the CC [24]. Our findings are in line with recent reviews indicating that the most consisting finding in youth with psychotrauma is structural abnormalities of the CC, in contrast to the reduction of hippocampal volume typically reported in adults with PTSD [5, 40].

The CC is known to change throughout life, but most dramatically during childhood and adolescence [2, 30]. These developmental changes in the CC are the consequence of varying degrees of axonal myelinization, redirection, and pruning, reflecting a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas. The general trend during adolescence is toward increasing FA and decreasing MD [43]. This CC maturation parallels puberty development suggesting gonadal hormonal influences [2]. For this reason, we included PDS scores as regressor. However, we must acknowledge that a simple linear regression of pubertal stage and total brain volume may still not sufficiently account for the results as they are known not to be linear across adolescence.

Early traumatization is likely to have a major influence on the integrity of the CC, as the processes of myelinization and selective pruning are typically influenced by stress hormones [52, 54]. Of importance, the smaller FA values we found in the CC of the PTSD group were due to increases in RD and MD, known to reflect demyelinization (less development of the myelin sheet) and dysmyelinization (aberrant development of the myelin sheet), linking the abnormalities of the CC integrity to the possible influence of stress hormones. Supporting this possible association, a recent study found that in rhesus monkeys exposed to early maternal abuse, cortisol levels at the time of abuse correlated with abnormalities in white matter connectivity in the CC, brain stem and other brain areas in adolescence [20]. Our results are in line with the study of Teicher et al. who, comparing abuse and neglect, found that sexual abuse was the strongest factor influencing CC size in girls [53].

Recent topographic research on the CC is beginning to map the different regions of the CC and their connections. Apart from frontal connections, the body of the CC also has connections with subcortical nuclei [21]. Changes in the midbody of the CC in children and adolescents who experienced psychological trauma could be related to disturbances in connectivity with limbic subcortical nuclei, resulting from or underlying the disturbances in emotion regulation.

We found a negative association in the adolescent PTSD group between FA in the CC and the TSCC Anger subscale. This in contrast to the result of the small DTI study in socioemotional deprived children with PTSD [14] in which correlations of FA measures in the CC were found with total anxiety scores, panic scores and separation anxiety scores. This may be due to methodological differences as well as the populations studied. A preclinical study in male non-human primates examined the effects of early life stress on hippocampal volume and CC development and found a significant inverse relationship between CC mid-sagittal area in adult monkeys and the response toward an intruder which typically consists of a mixture of aggressive and anxious behavior [23]. In a recent DTI study in male adolescents with conduct disorder, Zhang et al. report increased structural connectivity in the genu and body of the CC [61]. Impulsivity correlated positive with WM integrity, which is the opposite pattern of what we found in our study. This suggests that different pathophysiological mechanisms are involved, which is in accordance with the putative mechanisms described in the literature. For instance, Raine et al. hypothesize that structural abnormalities in the CC are a consequence of an early arrest of the normal neurodevelopmental process of axonal pruning, while the abnormalities in myelinization following CSA may be more linked to detrimental stress hormone influences [39].

We believe the relatively homogeneous sample and the state-of-the-art DTI approaches are strengths of our study, although several potential limitations should be taken into account. While we know that gender influences brain development and the reaction to psychological trauma, we included gender as a regressor, but could not further explore this issue because our participants are mainly girls. Full scale IQ measures differed significantly between the PTSD group and controls. Several studies report a negative effect of ELS on cognitive function [13, 37]. In this respect intellectual ability in the PTSD group and the control group might originally have been more equal. The New Zealand longitudinal birth cohort study [28] instead points to IQ as a risk factor for the development of PTSD. In the discussion about lower IQ being a consequence or a predictor of PTSD, it is suggested that trauma severity overrules IQ as a predictor [33] which could be the case in our study where all included adolescents fulfilled symptom criteria for PTSD diagnosis although this was not an inclusion criterion, but here too results are inconclusive [6]. Navas-Sanchez et al. [35] found a positive correlation between IQ and FA in the CC in math gifted adolescents compared to controls matched for age and academic level. Other studies report about correlations, mostly positive, of cognitive function with FA in several WM tracts [17, 42]. To decrease the potential influence of IQ on the white matter integrity differences we included IQ as a covariate in our analyses, but clearly further research is needed to unravel the exact relationship between childhood adversity, IQ and WM integrity in adolescence.

The normal increase of FA in the CC during adolescence is related to pubertal development. Therefore, the PDS score is chosen as nuisance regressor instead of age. The PTSD group was older and more advanced in pubertal stage. Because of the expected increase, the decrease in FA found in the PTSD group cannot be a consequence of normal (pubertal) development.

Two adolescents with PTSD were on stable SSRI treatment. Omitting these two participants from our analyses did not have any effect on the results. To our knowledge no influence of SSRIs on the CC is reported [9].

Patients were selected based on the presence of CSA and all except one, who fulfilled PTSD criteria except interference, showed CSA-related PTSD. Hence, we cannot differentiate whether the neuroimaging results were a consequence of exposure to trauma or the (development of) PTSD pathology or reflect an underlying vulnerability. Previous research in twins discordant for combat exposure suggests that anatomical abnormalities may indeed represent pre-existing vulnerability factors [16]. The ideal cross-sectional design to disentangle the effects of exposure, psychopathology and resilience would have incorporated a CSA group with psychopathology, a CSA group without psychopathology and a non-exposed, healthy control group [55]. Furthermore, we could not assess the influence of timing and duration of the CSA in our study, which is thought to be highly relevant in children and youth.

About one-third of the subjects also reported physical abuse, but as we did not assess experiences of other forms of psychotrauma we could have missed other prevalent traumatic experiences, like emotional maltreatment, which might be associated with the presence of DTI abnormalities in our sample.

In conclusion, our DTI findings in this sample of adolescents with CSA-related PTSD point at the involvement of the CC in brain alterations associated with juvenile sexual psychotrauma, and together with recent animal data can be taken to point at the influence of stress hormone levels on CC integrity. Clearly, longitudinal studies till mid-adulthood are needed to further elucidate the role of altered CC white matter integrity in the biopsychological consequences of early traumatization and to examine its malleability.