Corpus callosum in maltreated children with posttraumatic stress disorder: A diffusion tensor imaging study

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Abstract

Contrary to expectations derived from preclinical studies of the effects of stress, and imaging studies of adults with posttraumatic stress disorder (PTSD), there is no evidence of hippocampus atrophy in children with PTSD. Multiple pediatric studies have reported reductions in the corpus callosum — the primary white matter tract in the brain. Consequently, in the present study, diffusion tensor imaging was used to assess white matter integrity in the corpus callosum in 17 maltreated children with PTSD and 15 demographically matched normal controls. Children with PTSD had reduced fractional anisotropy in the medial and posterior corpus, a region which contains interhemispheric projections from brain structures involved in circuits that mediate the processing of emotional stimuli and various memory functions — core disturbances associated with a history of trauma. Further exploration of the effects of stress on the corpus callosum and white matter development appears a promising strategy to better understand the pathophysiology of PTSD in children.

Introduction

Child abuse is frequently associated with long-term significant psychiatric sequelae, and currently little is known about the mechanisms that initiate and maintain the various forms of psychopathology associated with early trauma. While not all abused children develop difficulties, many experience a chronic course of psychopathology, with posttraumatic stress disorder (PTSD) one of the most common psychiatric sequelae of child maltreatment (Molnar et al., 2001).

Preclinical studies suggest that stress early in life can promote long-term changes in stress reactivity and brain development (Kaufman et al., 2000). These studies provide a valuable heuristic in understanding the pathophysiology of PTSD in adults, with many of the biological alterations associated with early stress in preclinical studies reported in adults with PTSD and other stress-related disorders. The application of research findings from these preclinical studies in understanding the neurobiology of PTSD in children, however, is somewhat limited.

One of the best replicated findings in adults with PTSD is reduction in hippocampal volume (Bremner, 2006). Pediatric studies have failed to detect a reduction (Carrion et al., 2001, De Bellis et al., 1999, De Bellis et al., 2002, Tupler and De Bellis, 2006). Instead, children with PTSD have been found in two independent samples to have reduction in the medial and posterior region of the corpus callosum (CC) (De Bellis et al., 1999, 2002). Reduction in CC area has likewise been reported in psychiatric inpatients with a history of maltreatment compared with psychiatric and healthy controls without a history of early childhood trauma, with half the children in the maltreatment group meeting criteria for PTSD at discharge (Teicher et al., 2004). It has also recently been documented in adults with PTSD as well (Villarreal et al., 2004).

To the best of our knowledge, there is only one published structural MRI study in prepubescent non-human primates subjected to early stress (Sanchez et al., 1998). Consistent with the child investigations described above, this study also failed to find evidence of hippocampal atrophy, and instead reported reductions in the medial and posterior CC.

Given prior results suggesting children, adolescents, and adults with PTSD show atrophy of the medial and posterior CC – the primary white matter tract in the brain – we used diffusion tensor imaging (DTI) in the current investigation to assess possible changes in myelination or white matter coherence in these regions. DTI is a relatively new technique that provides data on white matter microstructure based on properties of diffusion. Fractional anisotropy (FA), a scale- and orientation-independent measure of diffusion derived with DTI (Pierpaoli and Basser, 1996), is the primary outcome measure examined in the current report. FA is not a direct measure of myelination, but a measure of anisotropy in water diffusion, which increases with myelination (McGraw et al., 2002; Snook et al., 2005). To the best of our knowledge, this is the first investigation to utilize DTI in maltreated children. Given that exposure to excessive levels of stress hormones has been found to suppress glial cell division critical for myelination (Lauder, 1983), it was hypothesized that maltreated children with PTSD, compared with normal controls, would have reduced FA in the medial and posterior regions of the CC.

Section snippets

Subjects

The sample included 32 children: 17 maltreated children (7 males and 10 females) who met criteria for PTSD secondary to intrafamilial abuse; and 15 demographically matched normal controls with no current or lifetime history of psychiatric illness (7 males and 8 females). All the children within the PTSD group had a history of protective services intervention for indicated allegations of child maltreatment, and the absence of maltreatment in the controls was verified by parent and child reports,

Group differences on DTI measures

Table 1 presents group means, effect sizes (Cohen's d) and univariate comparisons for corpus DTI data. Compared with controls, maltreated children with PTSD had significantly reduced FA in two of the four predicted corpus regions (anterior and posterior midbody), and a trend toward significantly reduced FA in a third region (splenium) (Fig. 1).

Correlation between DTI measures and clinical ratings

FA measures in regions 2 (Rho =  0.40, P < 0.02), 4 (Rho =  0.43, P < 0.02), and 7 (Rho =  0.38, P < 0.03) of the corpus callosum correlated significantly with total

Discussion

As predicted, the maltreated children had reduced FA in the medial and posterior regions of the CC. The FA changes in the CC observed in this study may be due to reduced myelination or other subtle alterations in axonal structure (e.g., neurofilaments, microtubules). CC myelination occurs in a rostral–caudal sequence and continues throughout childhood into early adulthood (Giedd et al., 1996). Consequently, it has been suggested that different regions of the CC might have different windows of

Acknowledgments

The authors thank the children and families, the staff at the State Department of Children and Families, and the clinicians at Clifford Beers Clinic that facilitated the completion of this work. The authors also acknowledge Deborah Lipschitz, M.D., and Damion Grasso, M.A., for their help in the collection of the clinical data and derivation of best estimate psychiatric diagnoses. This research was funded by grants from the NIH: 1R01MH65519-01 (JK), P50 AA-12870-04 (JHK, JK); support from the

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