Multifactoriality in Psychiatric Disorders: A Computational Study of Schizophrenia

The search for biological causes of mental disorders has up to now met with limited success, leading to growing dissatisfaction with diagnostic classifications. However, it is questionable whether most clinical syndromes should be expected to correspond to specific microscale brain alterations, as multiple low-level causes could lead to similar symptoms in different individuals. In order to evaluate the potential multifactoriality of alterations related to psychiatric illness, we performed a parametric exploration of published computational models of schizophrenia. By varying multiple parameters simultaneously, such as receptor conductances, connectivity patterns, and background excitation, we generated 5625 different versions of an attractor-based network model of schizophrenia symptoms. Among networks presenting activity within valid ranges, 154 parameter combinations out of 3002 (5.1%) presented a phenotype reminiscent of schizophrenia symptoms as defined in the original publication. We repeated this analysis in a model of schizophrenia-related deficits in spatial working memory, building 3125 different networks, and found that 41 (4.9%) out of 834 networks with valid activity presented schizophrenia-like alterations. In isolation, none of the parameters in either model showed adequate sensitivity or specificity to identify schizophrenia-like networks. Thus, in computational models of schizophrenia, even simple network phenotypes related to the disorder can be produced by a myriad of causes at the molecular and circuit levels. This suggests that unified explanations for either the full syndrome or its behavioral and network endophenotypes are unlikely to be expected at the genetic and molecular levels

Patogênese da encefalopatia hepática: um papel para os receptores de benzodiazepínicos?

A encefalopatia hepática (EH) é uma síndrome multifatorial, na qual a função do sistema nervoso central está alterada devido às conseqüências metabólicas da disfunção hepática. Os dois principais componentes das doenças hepáticas que levam à EH são a diminuição no número de hepatócitos funcionantes e o rearranjo vascular, que leva à diminuição na fração de sangue, efetivamente detoxificado pelo fígado. Os sintomas da EH podem variar de déficits cognitivos leves até o coma profundo. Algum grau de morte neuronal pode ser observado em pacientes com EH, como conseqüência da cirrose hepática, ou, na EH avançada, da presença de edema cerebral. No entanto, a maior parte da síndrome neurológica é reversível com a compensação da doença hepática. A etiologia da EH não é totalmente conhecida e trata-se, provavelmente, de um processo multifatorial. Inicialmente, as teorias apontavam para o acúmulo de neurotoxinas que prejudicariam a função neuronal. Mais recentemente, anormalidades em vários sistemas de neurotransmissão foram propostos como causas potencias da EH como, por exemplo, o aumento observado na neurotransmissão GABAérgica. Existe evidência de que este aumento esteja relacionado com o aumento da potenciação GABAérgica por substâncias de ação similar aos benzodiazepínicos, as quais se encontram aumentadas na EH. Com esta evidência em mente, foi tentada a terapia desta síndrome com flumazenil, um antagonista benzodiazepínico, o qual tem mostrado eficácia clínica em uma porcentagem variável de pacientes em estudos recentes. No entanto, ainda não há evidências conclusivas para sustentar uma relação causal entre o aumento de ligantes ao receptor de benzodiazepínicos e os sintomas da EH. É possível que esta relação exista em alguns, mas não em todos os pacientes com esta síndrome.Hepatic encephalopathy (HE) is a multifactorial syndrome in which the function of the central nervous system is impaired due to the metabolic consequences of liver disease. The two main components of liver pathology which lead to HE are the decrease in the number of functioning hepatocytes and the vascular rearrangement causing blood from the portal vein to bypass the liver. The symptoms of HE range from mild cognitive impairment to deep coma. Some degree of neuronal loss may be found in HE patients as a consequence of chronic cirrhosis and, in advanced HE, of brain edema; however, most of the HE syndrome is reversible with compensation of the liver disease. The pathogenesis of HE is not fully understood and  is likely to be multifactorial. The initial theories implicated accumulation of neurotoxins leading to an impairment of neuronal function. With better understanding of the physiology of neuroreceptors, abnormalities in several neurotransmission systems have been put forward as potential causes of HE, such as a reported increase in GABAergic neurotransmission. There is evidence that this enhancement is related to an increase in the potentiation of GABAergic action by ligands to the benzodiazepine receptor (BZR), which are known to be increased in liver disease. With this evidence in mind, therapy with the benzodiazepine antagonist flumazenil has been attempted in HE, yielding clinical benefit in a variable percentage of patients in recent studies. However, there is still a lack of evidence to support a causal relationship between increased levels of benzodiazepine agonist ligands and HE symptoms. It is feasible to think that this relationship exists in some but not all HE patients

On the transition from reconsolidation to extinction of contextual fear memories.

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions

A construção do cérebro dependente: uma análise da mídia brasileira e da literatura científica sobre adição a tecnologias

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 scientistsA neurociência é frequentemente usada como um argumento em diversos debates sobre saúde mental, tais como a definição de alguns comportamentos como patológicos. Para compreender como isto ocorre na mídia brasileira, analisamos fatos neurocientíficos mencionados em artigos sobre um diagnóstico ainda controverso, a dependência de jogos eletrônicos e/ou internet. Dos 85 artigos localizados em 7 grandes veículos de imprensa online, 25% faziam alusões à neurociência. A análise de dois fatos frequentemente mencionados (a similaridade das alterações cerebrais observadas nas dependências de tecnologia e drogas e a liberação de dopamina como mediador de recompensa e adição a jogos eletrônicos) demonstra inconsistências entre as afirmações na mídia e a evidência empírica disponível. No entanto, vieses semelhantes foram encontrados na própria literatura científica, sugerindo que interpretações relacionadas à existência de um “cérebro dependente” em adições químicas e comportamentais parecem ser favorecidas tanto entre jornalistas quanto entre cientista

Effect size and statistical power in the rodent fear conditioning literature - A systematic review

<div><p>Proposals to increase research reproducibility frequently call for focusing on effect sizes instead of p values, as well as for increasing the statistical power of experiments. However, it is unclear to what extent these two concepts are indeed taken into account in basic biomedical science. To study this in a real-case scenario, we performed a systematic review of effect sizes and statistical power in studies on learning of rodent fear conditioning, a widely used behavioral task to evaluate memory. Our search criteria yielded 410 experiments comparing control and treated groups in 122 articles. Interventions had a mean effect size of 29.5%, and amnesia caused by memory-impairing interventions was nearly always partial. Mean statistical power to detect the average effect size observed in well-powered experiments with significant differences (37.2%) was 65%, and was lower among studies with non-significant results. Only one article reported a sample size calculation, and our estimated sample size to achieve 80% power considering typical effect sizes and variances (15 animals per group) was reached in only 12.2% of experiments. Actual effect sizes correlated with effect size inferences made by readers on the basis of textual descriptions of results only when findings were non-significant, and neither effect size nor power correlated with study quality indicators, number of citations or impact factor of the publishing journal. In summary, effect sizes and statistical power have a wide distribution in the rodent fear conditioning literature, but do not seem to have a large influence on how results are described or cited. Failure to take these concepts into consideration might limit attempts to improve reproducibility in this field of science.</p></div

Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus

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-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. 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 reexposure 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 reexposure, 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

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation