Background-Previous magnetic resonance imaging studies of posttraumatic stress disorder reported hippocampal volume loss. The goals of this study were 1) to determine the relationship between hippocampal atrophy and posttraumatic stress disorder in the absence of alcohol abuse, and 2) to test if loss of N-acetylaspartate (a neuron marker) in the hippocampus of posttraumatic stress disorder occurs separate from atrophy. In addition, volume changes in the entorhinal cortex were also explored.

Studies have shown differences in neuropsychological functioning between groups with posttraumatic stress disorder (PTSD) and control participants. Because individuals with PTSD often have a history of comorbid alcohol abuse, the extent to which an alcohol confound is responsible for these differences remains a concern. The current study compares neuropsychological testing scores in 4 groups of veterans with and without PTSD (PTSD+ and PTSD-, respectively) and with and without a history of alcohol abuse (ETOH+ and ETOH-, respectively): n for PTSD+/ETOH- = 30, n for PTSD+/ETOH- = 37, n for PTSD-/ETOH+ = 30, and n for PTSD-/ETOH- = 31. Results showed that PTSD, when alcohol, educational level, vocabulary, and depression are controlled for, was associated with decreased verbal memory, attention, and processing speed performance. Alcohol abuse history was associated with decreased visual memory performance. By controlling for alcohol and depression, the authors can more conclusively demonstrate that verbal memory and attention differences are associated with PTSD.

This study compared attention and declarative memory in a sample of combat veterans with posttraumatic stress disorder (PTSD, n = 24) previously reported to have reduced concentrations of the hippocampal neuronal marker N-acetyl aspartate (NAA), but similar hippocampal volume compared to veteran normal comparison participants (n = 23). Healthy, well-educated males with combatrelated PTSD without current depression or recent alcohol/drug abuse did not perform differently on tests of attention, learning, and memory compared to normal comparison participants. Further, hippocampal volume, NAA, or NAA/Creatine ratios did not significantly correlate with any of the cognitive measures when adjustments for multiple comparisons were made. In this study, reduced hippocampal NAA did not appear to be associated with impaired declarative memory. Keywordsposttraumatic stress disorder; memory; hippocampus; alcoholism; N-acetyl aspartate Patients with posttraumatic stress disorder (PTSD) often describe difficulties with concentration, attention, and memory. Poorer performance on tests of attention, declarative memory, and other cognitive domains attributable to PTSD status have been found in many but not all studies (e.g. Crowell, Kieffer, Siders, & Vanderploeg, 2002). Decreased performance on neurocognitive tasks may be of particular relevance to PTSD because multiple studies have documented decreases in hippocampal volume (Bremner et al., 1997;Bremner, Randall, Scott, Bronen, et al., 1995;Gilbertson et al., 2002;Gurvits et al., 1996;Stein, Koverola, Hanna, Torchia, & McClarty, 1997;Villarreal et al., 2002) and decreased reduced concentrations of the neuronal marker N-acetyl aspartate (NAA; Freeman, Cardwell, Karson, & Komoroski, 1998;Schuff et al., 2001). Hippocampal atrophy in PTSD was associated with decreased function in explicit memory in a sample of combat veterans (Bremner, Randall, Scott, Bronen, et al., 1995), though not in women with history of childhood sexual assault (Stein et al., 1997).

Magnetic resonance spectroscopic imaging (MRSI) studies suggest hippocampal abnormalities in posttraumatic stress disorder (PTSD), whereas findings of volume deficits in the hippocampus, as revealed with magnetic resonance imaging (MRI), have been inconsistent. Co-morbidities of PTSD, notably alcohol abuse, may have contributed to the inconsistency. The objective was to determine whether volumetric and metabolic abnormalities in the hippocampus and other brain regions are present in PTSD, independent of alcohol abuse. Four groups of subjects, PTSD patients with (n=28) and without (n=27) alcohol abuse and subjects negative for PTSD with (n=23) and without (n=26) alcohol abuse, were enrolled in this observational MRI and MRSI study of structural and metabolic brain abnormalities in PTSD. PTSD was associated with reduced N-acetylaspartate (NAA) in both the left and right hippocampus, though only when normalized to creatine levels in the absence of significant hippocampal volume reduction. Furthermore, PTSD was associated with reduced NAA in the right anterior cingulate cortex regardless of creatine. NAA appears to be a more sensitive marker for neuronal abnormality in PTSD than brain volume. The alteration in the anterior cingulate cortex in PTSD has implications for fear conditioning and extinction.

Metyrapone blocks cortisol synthesis, which results in the stimulation of hypothalamic cortiocotropin-releasing factor (CRF) and a reduction in delta sleep. We examined the effect of metyrapone administration on endocrine and sleep measures in male subjects with and without chronic PTSD. We hypothesized that metyrapone would result in a decrease in delta sleep and that the magnitude of this decrease would be correlated with the endocrine response. Finally, we utilized the delta sleep response to metyrapone as an indirect measure of hypothalamic CRF activity and hypothesized that PTSD subjects would have decreased delta sleep at baseline and a greater decrease in delta sleep induced by metyrapone. Three nights of polysomnography were obtained in 24 male subjects with combatrelated PTSD and 18 male combat-exposed normal controls. On day 3, metyrapone was administered during normal waking hours until habitual sleep onset preceding night 3. Endocrine responses to metyrapone were measured in plasma obtained the morning following sleep recordings, the day before and after administration. Repeated measures ANOVAs were conducted to compare the endocrine and sleep response to metyrapone in PTSD and controls. PTSD subjects had significantly less delta sleep as indexed by stages 3 and 4, and total delta integrated amplitude prior to metyrapone administration. There were no differences in premetyrapone cortisol or ACTH levels in PTSD vs controls. PTSD subjects had a significantly decreased ACTH response to metyrapone compared to controls. Metyrapone caused an increase in awakenings and a marked decrease in quantitative measures of delta sleep that was significantly greater in controls compared to PTSD. The decline in delta sleep was significantly associated with the magnitude of increase in both 11-deoxycortisol and ACTH. The results suggest that the delta sleep response to metyrapone is a measure of the brain response to increases in hypothalamic CRF. These data also suggest that the ACTH and sleep EEG response to hypothalamic CRF is decreased in PTSD.