The neuroendocrinology of childhood trauma in personality disorder.

BACKGROUND: Childhood trauma has been associated with elevated central corticotropin releasing hormone (CRH) drive in adults meeting general DSM-IV criteria for personality disorder. It is not clear how this may be related to pituitary or adrenal responsiveness in personality disorder. It was hypothesized that high levels of childhood trauma would be associated with blunted cortisol and adrenocorticotropin releasing hormone (ACTH) response to the combined dexamethasone(DEX)/CRH test in adults meeting general DSM-IV criteria for personality disorder. METHOD: 24 healthy, medication free adults with personality disorder (N=16) and a group of healthy controls (N=8) underwent semi-structured diagnostic interviews and completed the Childhood Trauma Questionnaire (CTQ). Across two separate study sessions separated by at least a week, cerebrospinal fluid (CSF) was sampled by lumbar puncture for measurement of CRH concentration (N=17), and peripheral blood cortisol and ACTH levels were measured after challenge with DEX/CRH (N=24). RESULTS: As hypothesized, high CTQ score was associated with a blunted cortisol and ACTH response to DEX/CRH challenge. Indices of cortisol and ACTH response (peak level and area under the curve (AUC)) to DEX/CRH were in turn significantly negatively correlated with CSF CRH concentration. CONCLUSION: Childhood trauma in adults with personality disorder is associated with blunted cortisol and ACTH secretion following DEX/CRH challenge. These effects are independent of depression or posttraumatic stress disorder. Previous work would suggest that blunted pituitary-adrenal response is related to elevated central CRH drive. Corroborating this, CSF CRH levels were significantly and negatively correlated with peak level and AUC of both cortisol and ACTH.

Predicting white matter targets for direct neurostimulation therapy.

A novel depth electrode placement planning strategy is presented for propagating current to distant epileptic tissue during direct neurostimulation therapy. Its goal is to predict optimal lead placement in cortical white matter for influencing the maximal extent of the epileptic circuit. The workflow consists of three fundamental techniques to determine responsive neurostimulation depth lead placement in a patient with bilaterally independent temporal lobe epileptogenic regions. (1) Pre-implantation finite element modeling was used to predict the volume of cortical activation (VOCA). This model estimated the electric field and neural tissue influenced surrounding two adjacent active depth contacts prior to implantation. The calculations included anticipated stimulation parameters. (2) Propagation of stimulation therapy was simulated pre-implantation using the VOCA model positioned in the subject's diffusion tensor imaging (DTI) determined 8h post-ictally compared to an interictal DTI. (3) Validation of the predicted stimulated anatomical targets was determined 4.3 months post-implantation using subtracted activated SPECT (SAS). Presurgically, the modeling system predicted white matter connectivity and visual side-effects to stimulation. Post-implantation, SAS validated focal blood flow changes in ipsilateral occipital and frontal regions, and contralateral temporal lobe. This workflow demonstrates the feasibility of planning white matter-electrode placement with individual specificity to predict propagation of electrical current throughout an epileptic circuit.

Acute activation of glucose uptake by glucose deprivation in L929 fibroblast cells.

Glucose is a very important energy source for a wide variety of cells, and the ability of cells to respond to changes in glucose availability or other cell stresses is of critical importance. Many mammalian cells respond to acute stress by increasing the V(max) of transport through GLUT1; the most ubiquitously expressed glucose transporter isoform. This study investigated the acute response of glucose uptake to glucose deprivation in L929 fibroblast cells--a cell line that expresses only the GLUT1 transporter. Results indicated that glucose deprivation of only a minute activated glucose uptake 10-fold and reached a maximum of 20-fold within 10 min. The activation was dose dependent and only partially muted by addition of up to 20mM pyruvate as an alternate energy source. In contrast to the kinetics of acute metabolic stress, glucose deprivation decreased the K(m) of transport, but did not alter the V(max). Maximal activation of glucose transport by glucose deprivation was completely additive to activation of transport by methylene blue--a stimulant that increased the V(max) of transport without a change in the K(m). Glucose-deprived activation of glucose transport was not inhibited by wortmannin or herbimycin A, but was completely inhibited by phenylarsine oxide. Altogether, the data indicate that L929 fibroblast cells respond quickly and robustly to the cell stress of glucose deprivation and methylene blue treatment by two distinct activation pathways.

Methylene blue stimulates 2-deoxyglucose uptake in L929 fibroblast cells.

Methylene blue (MB), a common cell stain, has been shown to inhibit nitric oxide synthase and guanylate cyclase, which has led to the recent use of MB in nitric oxide signaling studies. This study documents the effects of MB on 2-deoxyglucose (2DG) uptake in L929 fibroblast cells where uptake is controlled by a single glucose transporter, GLUT 1. MB significantly activates cytochalasin B-inhibitable glucose transport in a dose dependent fashion within 10 min. A maximal stimulation of up to 800% was achieved by 50 microM MB after a 45-min exposure. The Vmax of transport increased without a change in the Km, which was accomplished without a significant change in the GLUT 1 content. The reduced form of MB, did not stimulate 2DG uptake and potassium ferricyanide, an extracellular redox agent, prevented both the staining and stimulatory effects of MB suggesting MB is reduced at the cell surface before it enters L929 cells. Phenylarsine oxide did not block cell staining as noted in other cells lines, but it did inhibit both basal and MB-stimulated 2DG uptake. Likewise, methyl-beta-cyclodextrin, an agent used to remove membrane cholesterol, blocked both the staining and stimulatory effects of MB. The AMP analog, AICAR, inhibited rather than activated basal 2DG uptake, and it did not alter MB-stimulated uptake suggesting that AMP kinase activation is not critical to the MB effect. Wortmannin, an inhibitor of PI kinase, had no effect on MB-stimulated 2DG uptake. These data provide additional insight into the acute regulation of GLUT 1 transport activity in L929 cells.