Postnatal neurogenesis of granule cells (GCs) in the dentate gyrus (DG) produces GCs that normally migrate from the subgranular zone to the GC layer. However, GCs can mismigrate into the hilus, the ...opposite direction. Previous descriptions of these hilar ectopic GCs (hEGCs) suggest that they are rare unless there are severe seizures. However, it is not clear if severe seizures are required, and it also is unclear if severe seizures are responsible for the abnormalities of hEGCs, which include atypical dendrites and electrophysiological properties. Here we show that large numbers of hEGCs develop in a transgenic mouse without severe seizures. The mice have a deletion of BAX, which normally regulates apoptosis. Surprisingly, we show that hEGCs in the BAX(-/-) mouse have similar abnormalities as hEGCs that arise after severe seizures. We next asked if there are selective effects of hEGCs, i.e., whether a robust population of hEGCs would have any effect on the DG if they were induced without severe seizures. Indeed, this appears to be true, because it has been reported that BAX(-/-) mice have defects in a behavior that tests pattern separation, which depends on the DG. However, inferring functional effects of hEGCs is difficult in mice with a constitutive BAX deletion because there is decreased apoptosis in and outside the DG. Therefore, a computational model of the normal DG and hippocampal subfield CA3 was used. Adding a small population of hEGCs (5% of all GCs), with characteristics defined empirically, was sufficient to disrupt a simulation of pattern separation and completion. Modeling results also showed that effects of hEGCs were due primarily to "backprojections" of CA3 pyramidal cell axons to the hilus. The results suggest that hEGCs can develop for diverse reasons, do not depend on severe seizures, and a small population of hEGCs may impair DG-dependent function.
Researchers have exerted tremendous efforts to empirically study how habits form and dominate at the expense of deliberation, yet we know very little about breaking these rigid habits to restore ...goal-directed control. In a three-experiment study, we first illustrate a novel approach of studying well-learned habits, in order to effectively demonstrate habit disruption. In Experiment 1, we use a Go/NoGo task with familiar color-response associations to demonstrate outcome-insensitivity when compared to novel, more flexible associations. Specifically, subjects perform more accurately when the required mapping is the familiar association of green-Go/red-NoGo than when it is red-Go/green-NoGo, confirming outcome-insensitive, habitual control. As a control condition, subjects show equivalent performance with unfamiliar color-response mappings (using the colors blue and purple mapped to Go and NoGo responses). Next, in Experiments 2 and 3, we test a motivation-based feedback manipulation in varying magnitudes (i.e., performance feedback with and without monetary incentives) to break the well-established habits elicited by our familiar stimuli. We find that although performance feedback prior to the contingency reversal test is insufficient to disrupt outcome-insensitivity in Experiment 2, a combination of performance feedback and monetary incentive is able to restore goal-directed control in Experiment 3, effectively breaking the habits. As the first successful demonstration of well-learned habit disruption in the laboratory, these findings provide new insights into how we execute and modify habits, while fostering new and translational research avenues that may be applicable to treating habit-based pathologies.
Temporal orienting improves sensory processing, akin to other top-down biases. However, it is unknown whether these improvements reflect increased neural gain to any stimuli presented at expected ...time points, or specific tuning to task-relevant stimulus aspects. Furthermore, while other top-down biases are selective, the extent of trade-offs across time is less well characterized. Here, we tested whether gain and/or tuning of auditory frequency processing in humans is modulated by rhythmic temporal expectations, and whether these modulations are specific to time points relevant for task performance. Healthy participants (
= 23) of either sex performed an auditory discrimination task while their brain activity was measured using magnetoencephalography/electroencephalography (M/EEG). Acoustic stimulation consisted of sequences of brief distractors interspersed with targets, presented in a rhythmic or jittered way. Target rhythmicity not only improved behavioral discrimination accuracy and M/EEG-based decoding of targets, but also of irrelevant distractors preceding these targets. To explain this finding in terms of increased sensitivity and/or sharpened tuning to auditory frequency, we estimated tuning curves based on M/EEG decoding results, with separate parameters describing gain and sharpness. The effect of rhythmic expectation on distractor decoding was linked to gain increase only, suggesting increased neural sensitivity to any stimuli presented at relevant time points.
Being able to predict when an event may happen can improve perception and action related to this event, likely due to the alignment of neural activity to the temporal structure of stimulus streams. However, it is unclear whether rhythmic increases in neural sensitivity are specific to task-relevant targets, and whether they competitively impair stimulus processing at unexpected time points. By combining magnetoencephalography and encephalographic recordings, neural decoding of auditory stimulus features, and modeling, we found that rhythmic expectation improved neural decoding of both relevant targets and irrelevant distractors presented and expected time points, but did not competitively impair stimulus processing at unexpected time points. Using a quantitative model, these results were linked to nonspecific neural gain increases due to rhythmic expectation.
Background & Aims We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage. Methods We collected data from the ...Surveillance, Epidemiology, and End Results–Medicare database and identified 6190 black and 61,951 white patients with colon cancer diagnosed from 1998 through 2009 and followed up through 2011. Three sets of 6190 white patients were matched sequentially, using a minimum distance strategy, to the same set of 6190 black patients based on demographic (age; sex; diagnosis year; and Surveillance, Epidemiology, and End Results registry), tumor presentation (demographic plus comorbidities, tumor stage, grade, and size), and treatment (presentation plus therapies) variables. We conducted sensitivity analyses to explore the effects of socioeconomic status in a subcohort that included 2000 randomly selected black patients. Racial differences in treatment were assessed using a logistic regression model; their effects on racial survival disparity were evaluated using the Kaplan–Meier method and the Cox proportional hazards model. Results After patients were matched for demographic variables, the absolute 5-year difference in survival between black and white patients was 8.3% (white, 59.2% 5-y survival; blacks, 50.9% 5-y survival) ( P < .0001); this value decreased significantly, to 5.0% ( P < .0001), after patients were matched for tumor presentation, and decreased to 4.9% ( P < .0001) when patients were matched for treatment. Differences in treatment therefore accounted for 0.1% of the 8.3% difference in survival between black and white patients. After patients were matched for tumor presentation, racial disparities were observed in almost all types of treatment; the disparities were most prominent for patients with advanced-stage cancer (stages III or IV, up to an 11.1% difference) vs early stage cancer (stages I or II, up to a 4.3% difference). After patients were matched for treatment, there was a greater reduction in disparity for black vs white patients with advanced-stage compared with early stage cancer. In sensitivity analyses, the 5-year racial survival disparity was 7.7% after demographic match, which was less than the 8.3% observed in the complete cohort. This reduction likely was owing to the differences between the subcohort and the complete cohort in those variables that were not included in the demographic match. This value was reduced to 6.5% ( P = .0001) after socioeconomic status was included in the demographic match. The difference decreased significantly to 2.8% ( P = .090) after tumor presentation match, but was not reduced further after treatment match. Conclusions We observed significant disparities in treatment and survival of black vs white patients with colon cancer. The disparity in survival appears to have been affected more strongly by tumor presentation at diagnosis than treatment. The effects of treatment differences on disparities in survival were greater for patients with advanced-stage vs early stage cancer.
To explore the association between cryopreserved embryo transfer (CET) and risk of placenta accreta among patients utilizing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection ...(ICSI).
Case-control study.
Academic medical center.
All patients using IVF and/or ICSI, with autologous or donor oocytes, undergoing fresh or cryopreserved transfer, who delivered a live-born fetus at ≥24 weeks of gestation at our center, from 2005 to 2011 (n = 1,571), were reviewed for placenta accreta at delivery.
Cases of accreta (n = 50) were matched by age and prior cesarean section to controls (1:3) without accreta. The association between CET and accreta was modeled using conditional logistic regression, controlling a priori for age and placenta previa. Receiver operating characteristic curves were used to determine thresholds of endometrial thickness and peak serum E2 levels related to accreta.
Placenta accreta.
Univariate predictors of accreta were non-Caucasian race (odds ratio OR 2.85, 95% confidence interval CI 1.25-6.47); uterine factor infertility (OR 5.80, 95% CI 2.49-13.50); prior abdominal or laparoscopic myomectomy (OR 7.24, 95% CI 1.92-27.28); and persistent or resolved placenta previa (OR 4.25, 95% CI 1.94-9.33). In multivariate analysis, we observed a significant association between CET and accreta (adjusted OR 3.20, 95% CI 1.14-9.02), which remained when analyses were restricted to cases of accreta with morbid complications (adjusted OR 3.87, 95% CI 1.08-13.81). Endometrial thickness and peak serum E2 level were each significantly lower in CET cycles and those with accreta.
Cryopreserved ET is a strong independent risk factor for accreta among patients using IVF and/or ICSI. A threshold endometrial thickness and a "safety window" of optimal peak E2 level are proposed for external validation.
It is often assumed that information in visual working memory (vWM) is maintained via persistent activity. However, recent evidence indicates that information in vWM could be maintained in an ...effectively "activity-silent" neural state. Silent vWM is consistent with recent cognitive and neural models, but poses an important experimental problem: how can we study these silent states using conventional measures of brain activity? We propose a novel approach that is analogous to echolocation: using a high-contrast visual stimulus, it may be possible to drive brain activity during vWM maintenance and measure the vWM-dependent impulse response. We recorded electroencephalography (EEG) while participants performed a vWM task in which a randomly oriented grating was remembered. Crucially, a high-contrast, task-irrelevant stimulus was shown in the maintenance period in half of the trials. The electrophysiological response from posterior channels was used to decode the orientations of the gratings. While orientations could be decoded during and shortly after stimulus presentation, decoding accuracy dropped back close to baseline in the delay. However, the visual evoked response from the task-irrelevant stimulus resulted in a clear re-emergence in decodability. This result provides important proof-of-concept for a promising and relatively simple approach to decode "activity-silent" vWM content using non-invasive EEG.
We describe a spatially explicit simulation experiment designed to assess relative impacts of macroecological traits on patterns of biological diversification under changing environmental conditions. ...Using a simulation framework, we assessed impacts of species’ niche breadth (i.e., the range of their abiotic tolerances) and dispersal ability on resulting patterns of speciation and extinction and evaluated how these traits, in conjunction with environmental change, shape biological diversification. Simulation results supported both niche breadth and dispersal ability as important drivers of diversification in the face of environmental change, and suggested that the rate of environmental change influences how species interact with the extrinsic environment to generate diversity. Niche breadth had greater effects on speciation and extinction than dispersal ability when climate changed rapidly, whereas dispersal ability effects were elevated when climate changed slowly. Our simulations provide a bottom-up perspective on the generation and maintenance of diversity under climate change, offering a better understanding of potential interactions between species’ intrinsic macroecological characteristics and a dynamic extrinsic environment in the process of biological diversification.
Abstract Palaeontologists have long sought to explain the diversification of individual clades to whole biotas at global scales. Advances in our understanding of the spatial distribution of the ...fossil record through geological time, however, has demonstrated that global trends in biodiversity were a mosaic of regionally heterogeneous diversification processes. Drivers of diversification must presumably have also displayed regional variation to produce the spatial disparities observed in past taxonomic richness. Here, we analyse the fossil record of ammonoids, pelagic shelled cephalopods, through the Late Cretaceous, characterised by some palaeontologists as an interval of biotic decline prior to their total extinction at the Cretaceous-Paleogene boundary. We regionally subdivide this record to eliminate the impacts of spatial sampling biases and infer regional origination and extinction rates corrected for temporal sampling biases using Bayesian methods. We then model these rates using biotic and abiotic drivers commonly inferred to influence diversification. Ammonoid diversification dynamics and responses to this common set of diversity drivers were regionally heterogeneous, do not support ecological decline, and demonstrate that their global diversification signal is influenced by spatial disparities in sampling effort. These results call into question the feasibility of seeking drivers of diversity at global scales in the fossil record.
The ion dynamics in a collisionless magnetic reconnection layer are studied in a laboratory plasma. The measured in-plane plasma potential profile, which is established by electrons accelerated ...around the electron diffusion region, shows a saddle-shaped structure that is wider and deeper towards the outflow direction. This potential structure ballistically accelerates ions near the separatrices toward the outflow direction. Ions are heated as they travel into the high-pressure downstream region.
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