Commentary on PTSD discussion

I have enjoyed reading the frank and lively discussion of controversies surrounding the interpretation of hippocampal atrophy in posttraumatic stress disorder (PTSD). Echoing Roger Pitman’s characterization of scientific as opposed to legal debates, I applaud the search for new explanations and the collection of new data to resolve the current uncertainties regarding the causes, cellular basis, and mechanism for the reported smaller hippocampal volumes in PTSD. This brief commentary upon the commentaries will summarize what I conclude are the four main areas of uncertainty in the existing data and then will summarize what the commentators think are the types of information that must be gathered. In the process I shall make some comments on possible cellular processes and mechanisms. The four uncertainties concern the underlying nature of the neuroanatomical changes that lead to a smaller hippocampus, the life history of this reduced volume in an individual, the relative importance of glucocorticoids in the processes that can lead to atrophy of the hippocampus, and the status of the hypothalamic pituitary adrenal (HPA) axis in PTSD. First, the neuroanatomical basis of the smaller hippocampus is far from clear, and this is an issue that I feel was not sufficiently emphasized in the commentaries. MRI imaging will never have sufficient resolution to reach the cellular level, and algorithms for analysis of MRI images have not yet been carried to the levels of individual hippocampal subregions, something that is feasible with existing MRI resolution. The reason why this is potentially important is that animal studies using repeated stress have revealed that there are three ways to reduce hippocampal volume by affecting neurons (McEwen, 1999): 1) reductions of dendritic length in pyramidal and granule neurons; 2) suppression of dentate gyrus neurogenesis and replacement of granule neurons; and 3) permanent loss of neurons. In addition, painstaking studies on human autopsy tissue have revealed loss of glial cells in the amygdala and prefrontal cortex, which may also apply to the hippocampus (Rajkowska et al., 1999; Sheline et al., 1998). The animal model studies indicate that dendritic remodelling after chronic stress is reversible (McEwen, 1999). The same is likely to be true of neurogenesis suppressed by stress. Since glial cells are replaced in the adult brain, the loss of glial cells may also be reversible. One question for PTSD is whether agents like phenytoin and tianeptine that prevent or reverse morphological changes in animal models (McEwen, 1999) might reverse hippocampal volume decreases. This is an indirect way of getting at the issue of reversibility vs. irreversibility. A reduction in glial or neuronal cell number or a decreased branching of dendrites might be responsible for a congenitally smaller hippocampal volume, a possibility that Dr. Pitman discusses, and this brings us to the second area of uncertainty, namely, that published studies showing hippocampal atrophy lack a longitudinal component. While the time interval between trauma and atrophy is consistent with a long-term, progressive change and permanent damage to the hippocampus, there are other possibilities. As suggested by Pitman, the hippocampus may start out smaller due to genetic factors. Alternatively, it may become smaller later as a result of early life events. Genetic and experiential factors are not mutually exclusive and may very well interact, and the potential role of childhood abuse as a factor deserves further investigation. There is evidence that individuals with a history of PTSD are more likely to have experienced physical or sexual abuse as children (Kaufman and Charney, 1999). Interestingly, one study showed that girls with a history of childhood abuse did not show selectively decreased hippocampal volume while at the same time showing a smaller overall cerebral volume, with larger ventricles and a smaller corpus callosum (DeBellis et al., 1999b). One possible interpretation of this data is that the reported selective hippocampal shrinkage in older subjects is not an immediate consequence of trauma but develops later in life as a result of ongoing neural and endocrine activity and the cumulative effects of life experiences. Longitudinal studies are required to answer this question. The third area of controversy concerns the relative importance of glucocorticoids in the mechanisms that produce atrophy. As indicated by both Drs. Bremner and Yehuda, animal models have shown that glucocorticoids work synergistically with excitatory amino acid transmitters and serotonin to produce dendritic remodelling and to regulate neurogenesis, albeit in different ways (McEwen, 1999), as follow: