Classical studies have related the spiking of selected neocortical neurons to behavior, but little is known about activity sampled from the entire neural population. We recorded from neurons selected ...independent of spiking, using cell-attached recordings and two-photon calcium imaging, in the barrel cortex of mice performing an object localization task. Spike rates varied across neurons, from silence to >60 Hz. Responses were diverse, with some neurons showing large increases in spike rate when whiskers contacted the object. Nearly half the neurons discriminated object location; a small fraction of neurons discriminated perfectly. More active neurons were more discriminative. Layer (L) 4 and L5 contained the highest fractions of discriminating neurons (∼63% and 79%, respectively), but a few L2/3 neurons were also highly discriminating. Approximately 13,000 spikes per activated barrel column were available to mice for decision making. Coding of object location in the barrel cortex is therefore highly redundant.
► During tactile localization, 10% of barrel cortex neurons fire ∼50% of all spikes ► Nearly half of all single neurons discriminate object location; coding is redundant ► Cortical layers 4 and 5 discriminate best on average ► Discriminative neurons in layer 2/3 are sparse and include excitatory neurons
Summary
The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, ...definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long‐term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1) beyond which the seizure should be regarded as “continuous seizure activity.” The second time point (t2) is the time of ongoing seizure activity after which there is a risk of long‐term consequences. In the case of convulsive (tonic–clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time‐related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.
Since initial reports regarding the impact of motion artifact on measures of functional connectivity, there has been a proliferation of participant-level confound regression methods to limit its ...impact. However, many of the most commonly used techniques have not been systematically evaluated using a broad range of outcome measures. Here, we provide a systematic evaluation of 14 participant-level confound regression methods in 393 youths. Specifically, we compare methods according to four benchmarks, including the residual relationship between motion and connectivity, distance-dependent effects of motion on connectivity, network identifiability, and additional degrees of freedom lost in confound regression. Our results delineate two clear trade-offs among methods. First, methods that include global signal regression minimize the relationship between connectivity and motion, but result in distance-dependent artifact. In contrast, censoring methods mitigate both motion artifact and distance-dependence, but use additional degrees of freedom. Importantly, less effective de-noising methods are also unable to identify modular network structure in the connectome. Taken together, these results emphasize the heterogeneous efficacy of existing methods, and suggest that different confound regression strategies may be appropriate in the context of specific scientific goals.
•We evaluate 14 participant-level de-noising pipelines for functional connectivity.•Pipeline performance is markedly heterogeneous.•GSR minimizes the impact of motion but introduces distance dependence.•Censoring reduces motion and improves network identifiability.
Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have ...reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.
We examine if and how incumbent firms respond to entry and entry threats using nonprice modes of competition. Our analysis focuses on airline service quality. We find that incumbent on-time ...performance (OTP) actually
worsens
in response to entry, and even entry threats, by Southwest Airlines. Since Southwest is both a top-performing airline in OTP and a low-cost carrier (LCC), we conjecture that this response by incumbents may be due to a cost-cutting strategy that allows for intense postentry price competition along with preentry deterrence, or it may be due to a postentry differentiation strategy along with preentry accommodation. Further analysis of entry and entry threats by other airlines is inconclusive, providing evidence that is partially consistent with both hypotheses. Nonetheless, the phenomenon of worsening OTP can only be observed when the (potential) entrant is a LCC (Southwest, Jet Blue, and AirTran).
Data, as supplemental material, are available at
http://dx.doi.org/10.1287/mnsc.2014.1918
.
This paper was accepted by by Bruno Cassiman, business strategy
.
Neurobiological abnormalities associated with psychiatric disorders do not map well to existing diagnostic categories. High co-morbidity suggests dimensional circuit-level abnormalities that cross ...diagnoses. Here we seek to identify brain-based dimensions of psychopathology using sparse canonical correlation analysis in a sample of 663 youths. This analysis reveals correlated patterns of functional connectivity and psychiatric symptoms. We find that four dimensions of psychopathology - mood, psychosis, fear, and externalizing behavior - are associated (r = 0.68-0.71) with distinct patterns of connectivity. Loss of network segregation between the default mode network and executive networks emerges as a common feature across all dimensions. Connectivity linked to mood and psychosis becomes more prominent with development, and sex differences are present for connectivity related to mood and fear. Critically, findings largely replicate in an independent dataset (n = 336). These results delineate connectivity-guided dimensions of psychopathology that cross clinical diagnostic categories, which could serve as a foundation for developing network-based biomarkers in psychiatry.
Recent research has suggested that increases in mortality among middle-aged US Whites are being driven by suicides and poisonings from alcohol and drug use. Increases in these 'despair' deaths have ...been argued to reflect a cohort-based epidemic of pain and distress among middle-aged US Whites.
We examine trends in all-cause and cause-specific mortality rates among younger and middle-aged US White men and women between 1980 and 2014, using official US mortality data. We estimate trends in cause-specific mortality from suicides, alcohol-related deaths, drug-related deaths, 'metabolic diseases' (i.e. deaths from heart diseases, diabetes, obesity and/or hypertension), and residual deaths from extrinsic causes (i.e. causes external to the body). We examine variation in mortality trends by gender, age and cause of death, and decompose trends into period- and cohort-based variation.
Trends in middle-aged US White mortality vary considerably by cause and gender. The relative contribution to overall mortality rates from drug-related deaths has increased dramatically since the early 1990s, but the contributions from suicide and alcohol-related deaths have remained stable. Rising mortality from drug-related deaths exhibit strong period-based patterns. Declines in deaths from metabolic diseases have slowed for middle-aged White men and have stalled for middle-aged White women, and exhibit strong cohort-based patterns.
We find little empirical support for the pain- and distress-based explanations for rising mortality in the US White population. Instead, recent mortality increases among younger and middle-aged US White men and women have likely been shaped by the US opiate epidemic and an expanding obesogenic environment.
Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations ...of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP-chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.
The mouse is an increasingly prominent model for the analysis of mammalian neuronal circuits. Neural circuits ultimately have to be probed during behaviors that engage the circuits. Linking circuit ...dynamics to behavior requires precise control of sensory stimuli and measurement of body movements. Head-fixation has been used for behavioral research, particularly in non-human primates, to facilitate precise stimulus control, behavioral monitoring and neural recording. However, choice-based, perceptual decision tasks by head-fixed mice have only recently been introduced. Training mice relies on motivating mice using water restriction. Here we describe procedures for head-fixation, water restriction and behavioral training for head-fixed mice, with a focus on active, whisker-based tactile behaviors. In these experiments mice had restricted access to water (typically 1 ml/day). After ten days of water restriction, body weight stabilized at approximately 80% of initial weight. At that point mice were trained to discriminate sensory stimuli using operant conditioning. Head-fixed mice reported stimuli by licking in go/no-go tasks and also using a forced choice paradigm using a dual lickport. In some cases mice learned to discriminate sensory stimuli in a few trials within the first behavioral session. Delay epochs lasting a second or more were used to separate sensation (e.g. tactile exploration) and action (i.e. licking). Mice performed a variety of perceptual decision tasks with high performance for hundreds of trials per behavioral session. Up to four months of continuous water restriction showed no adverse health effects. Behavioral performance correlated with the degree of water restriction, supporting the importance of controlling access to water. These behavioral paradigms can be combined with cellular resolution imaging, random access photostimulation, and whole cell recordings.
Abstract
Life expectancy for US White men and women declined between 2013 and 2017. Initial explanations for the decline focused on increases in “deaths of despair” (i.e., deaths from suicide, drug ...use, and alcohol use), which have been interpreted as a cohort-based phenomenon afflicting middle-aged White Americans. There has been less attention on Black mortality trends from these same causes, and whether the trends are similar or different by cohort and period. We complement existing research and contend that recent mortality trends in both the US Black and White populations most likely reflect period-based exposures to 1) the US opioid epidemic and 2) the Great Recession. We analyzed cause-specific mortality trends in the United States for deaths from suicide, drug use, and alcohol use among non-Hispanic Black and non-Hispanic White Americans, aged 20–64 years, over 1990–2017. We employed sex-, race-, and cause-of-death–stratified Poisson rate models and age-period-cohort models to compare mortality trends. Results indicate that rising “deaths of despair” for both Black and White Americans are overwhelmingly driven by period-based increases in drug-related deaths since the late 1990s. Further, deaths related to alcohol use and suicide among both White and Black Americans changed during the Great Recession, despite some racial differences across cohorts.
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