Reduced hypothalamic-pituitary-adrenal axis activity in chronic multi-site musculoskeletal pain : partly masked by depressive and anxiety disorders

Peer reviewedPublisher PD

A quantitative approach to neuropsychiatry: The why and the how

The current nosology of neuropsychiatric disorders allows for a pragmatic approach to treatment choice, regulation and clinical research. However, without a biological rationale for these disorders, drug development has stagnated. The recently EU-funded PRISM project aims to develop a quantitative biological approach to the understanding and classification of neuropsychiatric diseases to accelerate the discovery and development of better treatments. By combining clinical data sets from major worldwide disease cohorts and by applying innovative technologies to deeply phenotype stratified patient groups, we will define a set of quantifiable biological parameters for social withdrawal and cognitive deficits common to Schizophrenia (SZ), Major Depression (MD), and Alzheimer's Disease (AD). These studies aim to provide new classification and assessment tools for social and cognitive performance across neuropsychiatric disorders, clinically relevant substrates for treatment development, and predictive, preclinical animal systems. With patients and regulatory agencies, we seek to provide clear routes for the future translation and regulatory approval for new treatments and provide solutions to the growing public health challenges of psychiatry and neurology

Evaluating Spectral Models and the X-ray States of Neutron-Star X-ray Transients

We propose a hybrid model to fit the X-ray spectra of atoll-type X-ray transients in the soft and hard states. This model uniquely produces luminosity tracks that are proportional to T^4 for both the accretion disk and boundary layer. The model also indicates low Comptonization levels for the soft state, gaining a similarity to black holes in the relationship between Comptonization level and the strength of integrated rms variability in the power density spectrum. The boundary layer appears small, with a surface area that is roughly constant across soft and hard states. This result may suggestion that the NS radius is smaller than its inner-most stable circular orbit.Comment: 15 pages, 15 figures, accepted for publication in the Ap

Simultaneous radio and X-ray observations of Galactic Centre low mass X-ray binaries

We have performed simultaneous X-ray and radio observations of thirteen Galactic centre low-mass X-ray binaries in 1998 April using the Wide-Field Cameras onboard BeppoSAX and the Australia Telescope Compact Array, the latter simultaneously at 4.8 and 8.64 GHz. We detect two Z sources, GX 17+2 and GX 5-1, and the unusual `hybrid' source GX 13+1. Upper limits, which are significantly deeper than previous non-detections, are placed on the radio emission from two more Z sources and seven atoll sources. Hardness-Intensity diagrams constructed from the Wide-Field Camera data reveal GX 17+2 and GX 5-1 to have been on the lower part of the horizontal branch and/or the upper part of the normal branch, at the time of the observations, and the two non-detected Z sources, GX 340+0 and GX 349+2, to have been on the lower part of the normal branch. This is consistent with the previous empirically-determined relation between radio and X-ray emission from Z sources, in which radio emission is strongest on the Horizontal branch and weakest on the Flaring branch. For the first time we have information on the X-ray state of atoll sources, which are clearly radio-quiet relative to the Z sources, during periods of observed radio upper limits. We place limits on the linear polarisation from the three detected sources, and use accurate radio astrometry of GX 17+2 to confirm that it is probably not associated with the optical star NP Ser. Additionally we place strong upper limits on the radio emission from the X-ray binary 2S 0921-630, disagreeing with suggestions that it is a Z-source viewed edge-on.Comment: Accepted for publication in MNRA

Circulating insulin-like growth factor I modulates mood and is a biomarker of vulnerability to stress:from mouse to man

Individual susceptibility to anxiety disorders after maladaptive responses to stress is not well understood. We now report that while exploring stress responses in mice after traumatic brain injury (TBI), a condition associated to stress susceptibility, we observed that the anxiogenic effects of either TBI or exposure to life-threatening experiences (predator) were blocked when both stressors were combined. Because TBI increases the entrance into the brain of serum insulin-like growth factor I (IGF-I), a known modulator of anxiety with a wide range of concentrations in the human population, we then determined whether circulating IGF-I is related to anxiety measures. In mice, anxiety-like responses to predator were inversely related to circulating IGF-I levels. Other indicators of mood regulation such as sensitivity to dexamethasone suppression and expression levels of blood and brain FK506 binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor that regulates its activity, were also associated to circulating IGF-I. Indeed, brain FKBP5 expression in mice was stimulated by IGF-I. In addition, we observed in a large human cohort (n = 2686) a significant relationship between plasma IGF-I and exposure to recent stressful life events, while FKBP5 expression in blood cells was significantly associated to plasma IGF-I levels. Collectively, these data indicate that circulating IGF-I appears to be involved in mood homeostasis across different species. Furthermore, the data in mice allow us to indicate that IGF-I may be acting at least in part by modulating FKBP5 expression

The association of childhood maltreatment with depression and anxiety is not moderated by the oxytocin receptor gene

Background: The oxytocin receptor (OXTR) gene may be involved in resilience or vulnerability towards stress, and hence in the development of stress-related disorders. There are indications that OXTR single nucleotide polymorphisms (SNPs) interact with early life stressors in predicting levels of depression and anxiety. To replicate and extend these findings, we examined whether three literature-based OXTR SNPs (rs2254298, rs53576, rs2268498) interact with childhood maltreatment in the development of clinically diagnosed depression and anxiety disorders. Methods: We included 2567 individuals from the Netherlands Study of Depression and Anxiety. This sample consisted of 387 healthy controls, 428 people with a current or past depressive disorder, 243 people with a current or past anxiety disorder, and 1509 people with both lifetime depression and anxiety diagnoses. Childhood maltreatment was measured with both an interview and via self-report. Additional questionnaires measured depression and anxiety sensitivity. Results: Childhood maltreatment was strongly associated with both lifetime depression and anxiety diagnoses, as well as with depression and anxiety sensitivity. However, the OXTR SNPs did not moderate these associations nor had main effects on outcomes. Conclusions: The three OXTR gene SNPs did not interact with childhood maltreatment in predicting lifetime depression and anxiety diagnoses or sensitivity. This stresses the importance of replication studies with regard to OXTR gene variants in general populations as well as in clearly established clinical samples