Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.FV was supported by the Groupe Pasteur Mutualité. RG was supported by the Fondation pour la Recherche Médicale and the Fondation Bettencourt Schueller. SP is supported by a Marie Curie Intra-European fellowship (FP7-PEOPLE-2012-IEF). AF was supported by National Health and Medical Research Council grants (IDs : 1050504 and 1066779) and an Australian Research Council Future Fellowship (ID: FT130100589). This work was supported by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund.This is the final version of the article. It first appeared from the Nature Publishing Group via http://dx.doi.org/10.1038/mp.2015.7

Bone regeneration in surgically created defects filled with autogenous bone: an epifluorescence microscopy analysis in rats

Although the search for the ideal bone substitute has been the focus of a large number of studies, autogenous bone is still the gold standard for the filling of defects caused by pathologies and traumas, and mainly, for alveolar ridge reconstruction, allowing the titanium implants installation. OBJECTIVES: The aim of this study was to evaluate the dynamics of autogenous bone graft incorporation process to surgically created defects in rat calvaria, using epifluorescence microscopy. MATERIAL AND METHODS: Five adult male rats weighing 200-300 g were used. The animals received two 5-mm-diameter bone defects bilaterally in each parietal bone with a trephine bur under general anesthesia. Two groups of defects were formed: a control group (n=5), in which the defects were filled with blood clot, and a graft group (n=5), in which the defects were filled with autogenous bone block, removed from the contralateral defect. The fluorochromes calcein and alizarin were applied at the 7th and 30th postoperative days, respectively. The animals were killed at 35 days. RESULTS: The mineralization process was more intense in the graft group (32.09%) and occurred mainly between 7 and 30 days, the period labeled by calcein (24.66%). CONCLUSIONS: The fluorochromes showed to be appropriate to label mineralization areas. The interfacial areas between fluorochrome labels are important sources of information about the bone regeneration dynamics

The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease

For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic