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Freezing behavior is commonly used as a measure of associative fear memory. It can be measured by a trained observer, but this task is time-consuming and subject to variation. Commercially available software packages can also be used to quantify freezing; however, they can be expensive and usually require various parameters to be adjusted by the researcher, leading to additional work and variability in results. With this in mind, we developed Phobos, a freely available, self-calibrating software that measures freezing in a set of videos using a brief manual quantification performed by the user to automatically adjust parameters. To optimize the software, we used four different video sets with different features in order to determine the most relevant parameters, the amount of videos needed for calibration and the minimum criteria to consider it reliable. The results of four different users were compared in order to test intra- and interobserver variability in manual and automated freezing scores. Our results suggest that Phobos can be an inexpensive, simple and reliable tool for measurement of fear-related behavior, with intra- and interuser variability similar to that obtained with manual scoring.

Neuroscience is frequently used as an argument in various debates on mental health, such as the definition of some behaviors as pathological. To understand how this happens in the Brazilian media, we analyzed neuroscientific facts mentioned in articles about a controversial diagnosis: internet and or/video gaming addiction. Of 85 articles located in web searches of seven major press vehicles, 25% made allusions to neuroscience. The analysis of two frequently mentioned facts (the similarity between cerebral alterations observed in drug and technology addictions and the release of dopamine as a mediator of reward and addiction to video games) showed inconsistencies between media claims and the available empirical evidence. However, similar biases were already observable in the scientific literature itself, suggesting that the theory of a “dependent brain” in behavioral and chemical addictions seems to be favored by both journalists and scientists

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-re-exposure interventions, while those in the hippocampus have performed them after re-exposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory re-exposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after re-exposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

The search for biomarkers has been one of the leading endeavours in biological psychiatry; nevertheless, in spite of hundreds of publications, hardly any marker has proved useful in clinical practice. To study how biomarker research has progressed over the years, we performed a systematic review of the literature to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main experimental design features of studies in which they are proposed as biomarkers and (c) whether their patterns of variation are similar across disorders. An automated search revealed that, out of the six molecules most commonly present as keywords in articles studying plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across the three diagnoses. An analysis of the literature on these molecules showed that, whilst 66% of original articles compared their levels between patients and controls, only 35% were longitudinal studies, and only 10% presented an evaluation of diagnostic efficacy, a pattern that has not changed significantly over two decades. Interestingly, these molecules varied similarly across the three disorders, suggesting them to be nonspecific systemic consequences of psychiatric illness rather than diagnostic markers. On the basis of this, we discuss how research fragmentation between diagnoses and publication practices rewarding positive findings may be directing the biomarker literature to nonspecific targets, and what steps could be taken to increase clinical translation in the field.

Histoplasmosis of the central nervous system occurs in a significant percentage of patients with Histoplasma capsulatum infection, but has usually been described in association with immunosuppression and/or disseminated histoplasmosis. We aim to review the clinical and laboratory features of isolated histoplasmosis of the central nervous system in the immunocompetent host by presenting a series of 11 cases with this condition. Most of these patients presented with headache, meningeal irritation signs and mental status changes, comprising a somewhat different picture from that described in immunosuppressed patients. Moreover, almost all patients had signs of ventricular dilatation in neuroimaging studies, and 8 of the 11 patients had a ventriculoperitoneal shunt at the time of diagnosis, suggesting hydrocephalus to be an important feature of this condition and/or the possibility of shunt infection by the fungus. Immunodiffusion analysis of the cerebrospinal fluid appeared to be the most efficient way to reach the diagnosis and should be considered in immunocompetent patients with chronic lymphocytic meningitis, especially in those who have ventricular shunt or live in endemic areas of Histoplasma capsulatum.

Eclampsia is defined as the occurrence of seizures and/or coma resulting from hypertensive encephalopathy on a background of preeclampsia (1). Eclampsia appears to be caused by a failure of the brain’s autoregulatory response to increases in blood pressure, leading to an increase in cerebral perfusion pressure with overperfusion injury similar to that observed in hypertensive encephalopathy (2)(3). Brain edema and hemorrhage ensue, as observed in imaging studies (4)(5), and there is evidence to suggest that these alterations can cause ischemia to brain cells. These events lead to neurologic symptoms (6), including seizures as well as cortical blindness, aphasia, limb weakness, psychosis, coma, and cerebrovascular accidents. Studies have analyzed various diagnostic methods, such as transcranial Doppler measurements, as a way to evaluate neurologic involvement in preeclampsia (3)(7). To date, however, there is no reliable laboratory marker to identify patients at risk for eclampsia or its related complications. S100B is a 21-kDa protein physiologically produced and released primarily by astrocytes in the central nervous system (CNS), where it exerts neurotrophic and gliotrophic actions (8). Because ∼95% of S100B is located in the CNS, the results of several studies have suggested that an increase in S100B in blood and cerebrospinal fluid could be a potential marker of neural injury, indicating reactive gliosis, astrocytic death, and/or blood–brain barrier dysfunction. Accordingly, increased S100B concentrations in cerebrospinal fluid and/or blood have been reported in several pathologic conditions causing acute and chronic brain injury, such as head trauma (9), stroke (10), schizophrenia (11), and human T-lymphotropic virus type 1-associated myelopathy (12). Some studies have also evaluated S100B as a marker of recent seizures. Although S100B has been shown to be increased in both cerebrospinal fluid and brain tissue of patients with temporal lobe epilepsy (13)(14), studies in which …

Benzodiazepines are among the most prescribed and consumed medication groups in the world. Although benzodiazepines are used in the treatment of several psychiatric and non-psychiatric disorders, and are generally safe and well-tolerated, the potential for misuse and abuse is considerable. This makes the study and regulation of benzodiazepine prescription and consumption an item of concern in public health around the world. Most developed countries have consistent data of benzodiazepine sales and consumption; however, data from developing countries is scarce, making health policies on the use of benzodiazepines a much tougher issue in these countries. This article aims to review the epidemiology of benzodiazepine use in Brazil, as well as to analyze how legislation, physician misinformation and economic factors might contribute to making benzodiazepine abuse a problem in the country.

Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.

Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, e Fundação de Apoio à Pesquisa do Estado do Rio Grande do Norte. Journal impact factors have become an important criterion to judge the quality of scientific publications over the years, influencing the evaluation of institutions and individual researchers worldwide. However, they are also subject to a number of criticisms. Here we point out that the calculation of a journal’s impact factor is mainly based on the date of publication of its articles in print form, despite the fact that most journals now make their articles available online before that date. We analyze 61 neuroscience journals and show that delays between online and print publication of articles increased steadily over the last decade. Importantly, such a practice varies widely among journals, as some of them have no delays, while for others this period is longer than a year. Using a modified impact factor based on online rather than print publication dates, we demonstrate that online-to-print delays can artificially raise a journal’s impact factor, and that this inflation is greater for longer publication lags. We also show that correcting the effect of publication delay on impact factors changes journal rankings based on this metric. We thus suggest that indexing of articles in citation databases and calculation of citation metrics should be based on the date of an article’s online appearance, rather than on that of its publication in print.

The gap between basic neuroscience and clinical psychiatry in the treatment of anxiety disorders has been steadily diminishing over recent years. Among the leading advances in this field of translation research is the application of knowledge on the neurobiology of fear memory to the treatment of anxiety disorders in humans. Animal studies have identified N-methyl-D-aspartate (NMDA) receptors as crucial in fear memory acquisition and consolidation, as well as in its extinction and reconsolidation. Based on this, the NMDA receptor partial agonist D-cycloserine, which facilitates fear extinction in rodents, has been shown to increase the effect of exposure therapy in psychiatric patients for conditions such as phobias, social anxiety and obsessive-compulsive disorder. In this article, we review current strategies for targeting the NMDA receptor in the treatment of fear-related disorders, analyzing experimental results, clinical data, and recent patents in the field, while also addressing potential new approaches to explore this field of drug discovery.

The series of disease mongering articles in the April 2006 issue of PLoS Medicine overall seem to define the term as “widening the boundaries of illness” [ 1] by “taking a normal function and implying that there's something wrong with it and that it should be treated” [ 2]. While there is undoubtedly a strong case to be made for this sort of practice by pharmaceutical companies, perhaps we should also question ourselves on what we mean by “disease boundaries.” All of the conditions touched on by the disease mongering series (e.g., bipolar disease, attention deficit hyperactivity disorder, restless legs syndrome, and sexual dysfunctions) share the fact that they represent spectra of symptoms felt by virtually everyone, but which for some people can reach a point at which they become disturbing. However, since the benefit of treating these symptoms is ultimately dependent on their significance in a patient's life, it seems doubtful that anyone but the patient can adequately define the “boundaries” of illness for these conditions. The existence of these large “grey zones” between disease and normality (as well as the difficulty of doctors in dealing with them) might help to explain the increase in “lifestyle drug use” and self-prescription of psychiatric medication [ 3]. While these behaviors undoubtedly carry risks, they might well be an inevitable development in an age where information on anything (including drugs) is so widely available. Moreover, tampering with body chemistry is nothing new (alcohol, coffee, chocolate, and sunlight come to mind as examples), and it is hard to expect people will not do it because of pharmaceutical labels. Therefore, complain as we may, it is unlikely that this trend can be feasibly prevented. Therefore, if we want to prevent disease mongering, perhaps we should start by focusing on our own concept of “disease.” Maybe it is time we start to loosen the grip on our powers to define disease and start working less as diagnosing machines and more as decision facilitators for patients. It seems quite absurd to decide on a “concept” of erectile dysfunction or depression that can define who should be treated. On the contrary, our role should be to inform patients of the benefits and risks of treatment (or nontreatment) for their particular condition. This also means being comfortable with the fact that, no matter which criteria one uses to define disease, there will always be “normal” people who will want treatment as well as “sick” people who will refuse it. And in both cases they are probably entitled to do so, without necessarily receiving a diagnosis of “normal” or “sick.” Moreover, since the trend for self-prescription is not likely to be prevented, and since the pharmaceutical industry will surely try to capitalize on it, perhaps we should also worry about making nonprofit, unbiased scientific information more available to the public. Education on health matters is an important responsibility that traditionally has been overlooked by doctors in most countries. Now, if ever, seems to be the time to change that, because if physicians do not concentrate on it, drug companies will be happy to do it for them. It is obvious that medicine cannot abandon the concept of disease boundaries, since most of our medical knowledge and research is still based on it. Moreover, there are fields in which medical responsibility is sure to remain important in defining these boundaries (e.g., attribution of public funds, research studies, and treatment of children). But after reading so much on disease mongering, it seems to me that if we become a little more flexible in admitting that “disease boundaries” for many conditions are an oxymoron, perhaps the pharmaceutical industry will make less of a fuss in trying to convince people they are ill. My guess is that this would do everybody a favor.

We hereby describe a simple and inexpensive approach to evaluate the position and locomotion of rodents in an arena. The system is based on webcam registering of animal behaviour with subsequent analysis on customized software. Based on black/white differentiation, it provides rapid evaluation of animal position over a period of time, and can be used in a myriad of behavioural tasks in which locomotion, velocity or place preference are variables of interest. A brief review of the results obtained so far with this system and a discussion of other possible applications in behavioural neuroscience are also included. Such a system can be easily implemented in most laboratories and can significantly reduce the time and costs involved in behavioural analysis, especially in developing countries.

Background: Visual evoked potentials (VEPs) and brain stem auditory evoked potentials (BAEPs) have been proposed as tools in the diagnosis of subclinical hepatic encephalopathy (HE). However, little information exists to determine their usefulness in pediatric patients. This study was undertaken to evaluate both methods in the detection of subclinical HE in pediatric liver transplant candidates. Methods: VEPs and BAEPs were recorded in 15 pediatric liver transplant candidates with no clinical signs of HE. The wave latencies found in these examinations were then compared with those in 16 healthy controls of similar age. Laboratory data on liver function and electroencephalographic data from the patients were also recorded to examine their correlation with the evoked potentials results. Results: No differences were found in the BAEP results between patients and controls. However, in the VEPs, the liver transplant candidates had significantly prolonged N1 (N75) latencies when compared with controls; no significant delay was found in the other waves. In contrast, among the children with liver disease, higher BAEP peak latencies correlated positively with electroencephalographic abnormalities, but this correlation was not observed in VEPs. Conclusions: Evoked potentials might be of use in detecting alterations related to HE in children. However, further studies are necessary to determine their sensitivity and specificity in this situation.

The comments voiced by some scientists in response to Brian Nosek's project to systematically replicate studies in social psychology (“Psychology's bold initiative,” S. Carpenter, News Focus, 30 March, p. [1558][1]) are deeply worrisome. Reluctance to replicate data in a given field of science because it might harm the field's public image among other disciplines is symptomatic of a very dangerous logic. If such concerns are deemed valid, it seems natural to assume that scientists should also be worried about replicating their own labs' findings because of their standing among other laboratories, or that postdocs should not try to repeat experiments because it will make them look bad among their lab colleagues. The fact that this logic has spread among scientists is probably a large part of the reason why systematic replication studies have become so urgent in the first place. When the public image of a given field of science (or of science as a whole) becomes more important than establishing the truth of its findings in its value scale, one must conclude that something has gone awry along the way. [1]: pending:yes