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This review examines the putative link between glucocorticoid and hippocampal abnormalities in posttraumatic stress disorder (PTSD). Increased glucocorticoid receptor (GR) sensitivity in PTSD may permit enhanced negative feedback inhibition of cortisol at the pituitary, hypothalamus, or other brain regions comprising the hypothalamic-pituitary-adrenal (HPA) axis and would be expected to affect other physiological systems that are regulated by glucocorticoids. Molecular and transcriptional studies of cortisol are consistent with the hypothesis that cortisol actions may be amplified in PTSD as a result of enhanced GR sensitivity in monocytes and some brain regions, although cortisol levels themselves are unchanged and oftentimes lower than normal. Concurrently, magnetic resonance imaging studies have demonstrated that individuals with PTSD have smaller hippocampal volume than individuals without PTSD. Initial hypotheses regarding the mechanism underlying hippocampal alterations in PTSD focused on elevated glucocorticoid levels in combination with extreme stress as the primary cause, but this explanation has not been well supported in human studies. Lack of data from neuroimaging studies preclude a firm link between PTSD onset and hippocampal volume changes. Rather, the available evidence is consistent with the possibility that smaller hippocampal volume (like reduced cortisol levels and enhanced GR sensitivity) may be a vulnerability factor for developing the disorder; limitations of hippocampal-based models of PTSD are described. We further review neuroimaging studies examining hippocampal structure and function following manipulation of glucocorticoid levels and also examining changes in the hippocampus in relationship to other brain regions. Evidence that the GR may be an important therapeutic target for the treatment of PTSD, especially for functions subserved by the hippocampus, is discussed. Implications of the current review for future research are described, with an emphasis on the need to integrate findings of glucocorticoid abnormalities with functional-imaging paradigms to formulate a comprehensive model of HPA-axis functioning in PTSD.

Earlier studies are inconsistent regarding the structural basis of obsessive-compulsive disorder (OCD), and few studies have investigated whether patients with OCD have cortical thickness abnormalities compared with healthy volunteers. Using magnetic resonance imaging we compared regional differences in cortical thickness among 21 patients with OCD and 21 demographically matched healthy volunteers. Our findings indicate that the right inferior frontal cortex and posterior middle temporal gyrus are thicker in patients with OCD compared with healthy controls, which may contribute to response inhibition deficits and other aspects of phenomenology related to the disorder.

Sex, handedness, and disease processes in schizophrenia may affect the magnitude and/or direction of structural brain asymmetries. Using MRI data from 67 healthy (30 men, 10 nondextral) and 84 schizophrenia patients (60 men, 16 nondextral), cortical thickness asymmetries were compared at high spatial resolution. Within-group asymmetries were observed in sensorimotor, perisylvian, and parahippocampal cortices (leftward) and in anterior mesial frontal cortices (rightward). Asymmetry patterns were similar across diagnosis and sex, although some regional asymmetry increases were observed in men. Hand preference (dextrality) significantly influenced regional asymmetries in parietal association and dorsomedial frontal cortices (false discovery rate-corrected), where medial-frontal regions showed diagnosis by dextrality effects (uncorrected). Thus, dextrality relates to cortical thickness asymmetries, although schizophrenia may differentially affect asymmetry patterns across handedness.

Animal studies indicate that stress negatively impacts hippocampal structure; little is known, however, regarding the relationship between stress and hippocampal morphology in healthy humans. Twenty-one healthy adults underwent structural magnetic resonance imaging examinations and completed the Derogatis Stress Profile. Greater psychological stress at the time of the scan correlated significantly and more strongly with anterior than posterior hippocampal volume. These findings suggest that psychological stress may be associated with structural alterations in the anterior hippocampal formation and that this relationship may differ along the rostrocaudal axis of the hippocampus. Our results may also have implications for neuropsychiatric disorders that have implicated stress and hippocampal abnormalities in their pathogenesis.

Loss of cortical gray matter is accompanied by a commensurate increase in the sulcal and intraventricular cerebrospinal fluid volume. On diffusion-weighted magnetic resonance imaging, this would be reflected as a higher apparent diffusion coefficient in affected brain regions. On the basis of the above premise, we suggest that the apparent diffusion coefficient may be used as a surrogate marker for the assessment of regional brain volume deficits. We demonstrate this approach by voxelwise analysis of registered apparent diffusion coefficient images from a group of 15 patients with schizophrenia and 15 age-matched healthy controls. We found widespread regional apparent diffusion coefficient increases in patients. Affected areas included the bilateral insular cortex, hippocampus, temporal lobe, and occipital areas. These results largely concur with previous findings of cortical volume deficits in schizophrenia.

We recently reported an association between DISC1 and schizophrenia, schizoaffective disorder, and bipolar disorder. Convergent evidence suggests that DISC1 has a direct effect on central nervous system functioning. However, there is a paucity of data investigating the effects of DISC1 on neurocognition. Thus, we analyzed the relationship between five single-nucleotide polymorphisms that influenced risk for schizophrenia in our previous study and neurocognition in 250 patients with schizophrenia. DISC1 genotype was related to neurocognitive performance on measures of rapid visual search and verbal working memory, when controlling for age and premorbid intellectual capacity, and explained 3%-4% of the variance. These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia.

There is evidence that the brains of men and women are structurally different, but there are few data regarding possible sex differences in white matter microstructure. Using diffusion tensor imaging we assessed fractional anisotropy (FA) in the frontal lobe white matter on contiguous 5 mm slices in nine healthy male and 11 healthy female adults. Overall, women had higher FA in the left frontal lobe compared to men and a leftward asymmetry of FA in contrast to men, who showed no hemispheric asymmetry. Among women, greater leftward asymmetry of frontal lobe FA correlated significantly with better verbal comprehension and memory functioning. Our findings may be indicative of increased directional coherence and/or density of left hemisphere white matter fibers and a leftward asymmetry of this structural integrity among women compared to men.