Neuroimaging Studies in Children with PTSD

One of the best replicated findings in adults with PTSD is reduction in hippocampal volume (Bernstein et al 1997; Bremner et al 1995; Bremner et al 1997; Driessen et al 2000; Gurvits et al 1996; Villarreal et al 2002; Vythilingam et al 2002). Preclinical studies of the effects of stress suggest a minimum of three mechanisms by which hippocampal atrophy may result in individuals with PTSD: neuronal atrophy, neurotoxicity, and disruption of neurogenesis. In animals, three weeks of exposure to stress and/or stress levels of glucocorticoids can cause neuronal atrophy in the CA3 region of the hippocampus (Watanabe et al 1992; Woolley et al 1990). At this level, glucocorticoids produce a reversible decrease in number of apical dendritic branch points and length of apical dendrites of sufficient magnitude to impair hippocampal dependent cognitive processes (Watanabe et al 1992). More sustained stress and/or glucocorticoid exposure can lead to neurotoxicity -- actual permanent loss of hippocampal neurons through binding of glutamate to N-methyl-D-aspartate (NMDA) receptors. Rats exposed to high concentrations of glucocorticoids for approximately 12 hours per day for three months experience a 20% loss of neurons specific to the CA3 region of the hippocampus (Sapolsky et al 1985). Evidence of stress induced neurotoxicity of cells in this region has been reported in non-human primates as well (Sapolsky 1996; Uno et al 1994). Reductions in hippocampal volume may also be affected by decreases in neurogenesis which results from decreased expression of Brain Derived Neurotrophic Factor (BDNF) caused by elevated glucocorticoids (Cameron and Gould 1996). The granule cells in the dentate gyrus of the hippocampus continue to proliferate into adulthood, and neurogenesis in this region is markedly reduced by stress.

Multiple pediatric studies, however, failed to detect hippocampal atrophy in children with PTSD (Kaufman et al 2004). De Bellis and colleagues published the first structural MRI study in children and adolescents with PTSD. The study included 44 maltreated children and adolescents with PTSD and 61 matched controls (De Bellis et al 1999). Contrary to expectations derived from preclinical studies of the effects of early stress on hippocampus structure (Sapolsky 2000), and imaging studies of adults with PTSD (Bremner 1999), there was no evidence of hippocampal atrophy in the children and adolescents with PTSD. The failure to show hippocampal atrophy in children with PTSD was replicated in a small sub-sample of DeBellis’ original cohort that underwent longitudinal neuroimaging assessments two years after the initial assessments (De Bellis et al 2001), and two additional independent samples (Carrion et al 2001; De Bellis et al 2002).

Instead of hippocampal atrophy, children and adolescents with PTSD had reduced medial and posterior corpus callosum area (De Bellis et al 1999). This is a finding that has likewise been replicated in an independent sample of children with PTSD (De Bellis et al 2002), and also reported in psychiatric inpatients with a history of maltreatment when compared to psychiatric and healthy controls without a history of early childhood trauma (Teicher et al 2004).

To the best of our knowledge, there is only one published structural MRI study in pre-pubescent non-human primates subjected to early stress (Sanchez et al 1998). Most preclinical studies of the effects of early stress have examined the impact of early stress on the neurobiology of adult animals, with emerging findings suggesting important developmental differences in the neurobiological correlates of stress across the lifecycle. Consistent with the work of DeBellis and others, the study that examined the effects of early stress on prepubescent primates failed to find evidence of hippocampal atrophy, and instead reported reductions in the medial and posterior portions of the corpus callosum.

Given prior results suggesting that children and adolescents with PTSD show atrophy of the medial and posterior regions of the corpus callosum – the primary white matter tract in the brain -- our group utilized Diffusion Tensor Imaging (DTI), together with standard structural MRI, to assess brain changes associated with PTSD in maltreated children (Jackowski et al submitted for publication). DTI is a relatively new application of MRI technology that measures the extent and direction of diffusion of water in the brain, and can be used to assess the integrity of white matter tracts (Duncan et al 2004; Jackowski et al 2005). One of the main measures derived from DTI are fractional anisotropy (FA). FA assesses the directionality of diffusion, is greatest in axons, and increases with myelination and age in normal child development (Mukherjee and McKinstry 2006). Seventeen maltreated and 16 demographically-matched normal controls participated in the investigation. Maltreated children with PTSD had reduced fractional anisotropy in the medial and posterior region of the corpus callosum. Reduction in corpus callosum area was also detected in the splenium, and maltreated children with PTSD had decreased total cortical white matter volume.

As stated previously, results from this and other studies suggest that the neurobiological effects of stress vary at different developmental periods. Further exploration of the effects of stress on the development of the corpus callosum and other white matter tracts, together with the incorporation of functional MRI methodologies to examine regional connectivity, appear promising strategies to better understanding the etiology and pathophysiology of PTSD in children.