Jing Lei.

Source: Bernoulli, Volume 26, Number 1, 767--798.

Abstract:
We provide upper bounds of the expected Wasserstein distance between a probability measure and its empirical version, generalizing recent results for finite dimensional Euclidean spaces and bounded functional spaces. Such a generalization can cover Euclidean spaces with large dimensionality, with the optimal dependence on the dimensionality. Our method also covers the important case of Gaussian processes in separable Hilbert spaces, with rate-optimal upper bounds for functional data distributions whose coordinates decay geometrically or polynomially. Moreover, our bounds of the expected value can be combined with mean-concentration results to yield improved exponential tail probability bounds for the Wasserstein error of empirical measures under Bernstein-type or log Sobolev-type conditions.

Zhuang Ma, Xiaodong Li.

Source: Bernoulli, Volume 26, Number 1, 432--470.

Abstract:
Canonical correlation analysis (CCA) is a fundamental statistical tool for exploring the correlation structure between two sets of random variables. In this paper, motivated by the recent success of applying CCA to learn low dimensional representations of high dimensional objects, we propose two losses based on the principal angles between the model spaces spanned by the sample canonical variates and their population correspondents, respectively. We further characterize the non-asymptotic error bounds for the estimation risks under the proposed error metrics, which reveal how the performance of sample CCA depends adaptively on key quantities including the dimensions, the sample size, the condition number of the covariance matrices and particularly the population canonical correlation coefficients. The optimality of our uniform upper bounds is also justified by lower-bound analysis based on stringent and localized parameter spaces. To the best of our knowledge, for the first time our paper separates $p_{1}$ and $p_{2}$ for the first order term in the upper bounds without assuming the residual correlations are zeros. More significantly, our paper derives $(1-lambda_{k}^{2})(1-lambda_{k+1}^{2})/(lambda_{k}-lambda_{k+1})^{2}$ for the first time in the non-asymptotic CCA estimation convergence rates, which is essential to understand the behavior of CCA when the leading canonical correlation coefficients are close to $1$.

Jami J. Mulgrave, Subhashis Ghosal.

Source: Bayesian Analysis, Volume 15, Number 2, 449--475.

Abstract:
Gaussian graphical models have been used to study intrinsic dependence among several variables, but the Gaussianity assumption may be restrictive in many applications. A nonparanormal graphical model is a semiparametric generalization for continuous variables where it is assumed that the variables follow a Gaussian graphical model only after some unknown smooth monotone transformations on each of them. We consider a Bayesian approach in the nonparanormal graphical model by putting priors on the unknown transformations through a random series based on B-splines where the coefficients are ordered to induce monotonicity. A truncated normal prior leads to partial conjugacy in the model and is useful for posterior simulation using Gibbs sampling. On the underlying precision matrix of the transformed variables, we consider a spike-and-slab prior and use an efficient posterior Gibbs sampling scheme. We use the Bayesian Information Criterion to choose the hyperparameters for the spike-and-slab prior. We present a posterior consistency result on the underlying transformation and the precision matrix. We study the numerical performance of the proposed method through an extensive simulation study and finally apply the proposed method on a real data set.

Xuan Cao, Kshitij Khare, Malay Ghosh.

Source: Bayesian Analysis, Volume 15, Number 1, 241--262.

Abstract:
The choice of tuning parameters in Bayesian variable selection is a critical problem in modern statistics. In particular, for Bayesian linear regression with non-local priors, the scale parameter in the non-local prior density is an important tuning parameter which reflects the dispersion of the non-local prior density around zero, and implicitly determines the size of the regression coefficients that will be shrunk to zero. Current approaches treat the scale parameter as given, and suggest choices based on prior coverage/asymptotic considerations. In this paper, we consider the fully Bayesian approach introduced in (Wu, 2016) with the pMOM non-local prior and an appropriate Inverse-Gamma prior on the tuning parameter to analyze the underlying theoretical property. Under standard regularity assumptions, we establish strong model selection consistency in a high-dimensional setting, where $p$ is allowed to increase at a polynomial rate with $n$ or even at a sub-exponential rate with $n$ . Through simulation studies, we demonstrate that our model selection procedure can outperform other Bayesian methods which treat the scale parameter as given, and commonly used penalized likelihood methods, in a range of simulation settings.

Andrea Cremaschi, Raffaele Argiento, Katherine Shoemaker, Christine Peterson, Marina Vannucci.

Source: Bayesian Analysis, Volume 14, Number 4, 1271--1301.

Abstract:
Gaussian graphical models are useful tools for exploring network structures in multivariate normal data. In this paper we are interested in situations where data show departures from Gaussianity, therefore requiring alternative modeling distributions. The multivariate $t$ -distribution, obtained by dividing each component of the data vector by a gamma random variable, is a straightforward generalization to accommodate deviations from normality such as heavy tails. Since different groups of variables may be contaminated to a different extent, Finegold and Drton (2014) introduced the Dirichlet $t$ -distribution, where the divisors are clustered using a Dirichlet process. In this work, we consider a more general class of nonparametric distributions as the prior on the divisor terms, namely the class of normalized completely random measures (NormCRMs). To improve the effectiveness of the clustering, we propose modeling the dependence among the divisors through a nonparametric hierarchical structure, which allows for the sharing of parameters across the samples in the data set. This desirable feature enables us to cluster together different components of multivariate data in a parsimonious way. We demonstrate through simulations that this approach provides accurate graphical model inference, and apply it to a case study examining the dependence structure in radiomics data derived from The Cancer Imaging Atlas.

Lutz F. Gruber, Erica F. Stuber, Lyndsie S. Wszola, Joseph J. Fontaine.

Source: Bayesian Analysis, Volume 14, Number 4, 1173--1199.

Abstract:
We present an integrated open population model where the population dynamics are defined by a differential equation, and the related statistical model utilizes a Poisson binomial convolution likelihood. Key advantages of the proposed approach over existing open population models include the flexibility to predict related, but unobserved quantities such as total immigration or emigration over a specified time period, and more computationally efficient posterior simulation by elimination of the need to explicitly simulate latent immigration and emigration. The viability of the proposed method is shown in an in-depth analysis of outdoor recreation participation on public lands, where the surveyed populations changed rapidly and demographic population closure cannot be assumed even within a single day.

Ioannis Ntzoufras, Claudia Tarantola, Monia Lupparelli.

Source: Bayesian Analysis, Volume 14, Number 3, 797--823.

Abstract:
We introduce a novel Bayesian approach for quantitative learning for graphical log-linear marginal models. These models belong to curved exponential families that are difficult to handle from a Bayesian perspective. The likelihood cannot be analytically expressed as a function of the marginal log-linear interactions, but only in terms of cell counts or probabilities. Posterior distributions cannot be directly obtained, and Markov Chain Monte Carlo (MCMC) methods are needed. Finally, a well-defined model requires parameter values that lead to compatible marginal probabilities. Hence, any MCMC should account for this important restriction. We construct a fully automatic and efficient MCMC strategy for quantitative learning for such models that handles these problems. While the prior is expressed in terms of the marginal log-linear interactions, we build an MCMC algorithm that employs a proposal on the probability parameter space. The corresponding proposal on the marginal log-linear interactions is obtained via parameter transformation. We exploit a conditional conjugate setup to build an efficient proposal on probability parameters. The proposed methodology is illustrated by a simulation study and a real dataset.

Marcos Oliveira Prates, Renato Martins Assunção, Erica Castilho Rodrigues.

Source: Bayesian Analysis, Volume 14, Number 2, 623--647.

Abstract:
Spatial confounding between the spatial random effects and fixed effects covariates has been recently discovered and showed that it may bring misleading interpretation to the model results. Techniques to alleviate this problem are based on decomposing the spatial random effect and fitting a restricted spatial regression. In this paper, we propose a different approach: a transformation of the geographic space to ensure that the unobserved spatial random effect added to the regression is orthogonal to the fixed effects covariates. Our approach, named SPOCK, has the additional benefit of providing a fast and simple computational method to estimate the parameters. Also, it does not constrain the distribution class assumed for the spatial error term. A simulation study and real data analyses are presented to better understand the advantages of the new method in comparison with the existing ones.

Suprateek Kundu, Bani K. Mallick, Veera Baladandayuthapani.

Source: Bayesian Analysis, Volume 14, Number 2, 449--476.

Abstract:
There has been an intense development in the Bayesian graphical model literature over the past decade; however, most of the existing methods are restricted to moderate dimensions. We propose a novel graphical model selection approach for large dimensional settings where the dimension increases with the sample size, by decoupling model fitting and covariance selection. First, a full model based on a complete graph is fit under a novel class of mixtures of inverse–Wishart priors, which induce shrinkage on the precision matrix under an equivalence with Cholesky-based regularization, while enabling conjugate updates. Subsequently, a post-fitting model selection step uses penalized joint credible regions to perform model selection. This allows our methods to be computationally feasible for large dimensional settings using a combination of straightforward Gibbs samplers and efficient post-fitting inferences. Theoretical guarantees in terms of selection consistency are also established. Simulations show that the proposed approach compares favorably with competing methods, both in terms of accuracy metrics and computation times. We apply this approach to a cancer genomics data example.

Luis Gutiérrez, Eduardo Gutiérrez-Peña, Ramsés H. Mena.

Source: Bayesian Analysis, Volume 14, Number 2, 427--447.

Abstract:
This work presents a Bayesian predictive approach to statistical shape analysis. A modeling strategy that starts with a Gaussian distribution on the configuration space, and then removes the effects of location, rotation and scale, is studied. This boils down to an application of the projected normal distribution to model the configurations in the shape space, which together with certain identifiability constraints, facilitates parameter interpretation. Having better control over the parameters allows us to generalize the model to a regression setting where the effect of predictors on shapes can be considered. The methodology is illustrated and tested using both simulated scenarios and a real data set concerning eight anatomical landmarks on a sagittal plane of the corpus callosum in patients with autism and in a group of controls.

Daniela Pauger, Helga Wagner.

Source: Bayesian Analysis, Volume 14, Number 2, 341--369.

Abstract:
We propose a Bayesian approach to obtain a sparse representation of the effect of a categorical predictor in regression type models. As this effect is captured by a group of level effects, sparsity cannot only be achieved by excluding single irrelevant level effects or the whole group of effects associated to this predictor but also by fusing levels which have essentially the same effect on the response. To achieve this goal, we propose a prior which allows for almost perfect as well as almost zero dependence between level effects a priori. This prior can alternatively be obtained by specifying spike and slab prior distributions on all effect differences associated to this categorical predictor. We show how restricted fusion can be implemented and develop an efficient MCMC (Markov chain Monte Carlo) method for posterior computation. The performance of the proposed method is investigated on simulated data and we illustrate its application on real data from EU-SILC (European Union Statistics on Income and Living Conditions).

Lloyd T. Elliott, Maria De Iorio, Stefano Favaro, Kaustubh Adhikari, Yee Whye Teh.

Source: Bayesian Analysis, Volume 14, Number 2, 313--339.

Abstract:
We propose a Bayesian nonparametric model to infer population admixture, extending the hierarchical Dirichlet process to allow for correlation between loci due to linkage disequilibrium. Given multilocus genotype data from a sample of individuals, the proposed model allows inferring and classifying individuals as unadmixed or admixed, inferring the number of subpopulations ancestral to an admixed population and the population of origin of chromosomal regions. Our model does not assume any specific mutation process, and can be applied to most of the commonly used genetic markers. We present a Markov chain Monte Carlo (MCMC) algorithm to perform posterior inference from the model and we discuss some methods to summarize the MCMC output for the analysis of population admixture. Finally, we demonstrate the performance of the proposed model in a real application, using genetic data from the ectodysplasin-A receptor (EDAR) gene, which is considered to be ancestry-informative due to well-known variations in allele frequency as well as phenotypic effects across ancestry. The structure analysis of this dataset leads to the identification of a rare haplotype in Europeans. We also conduct a simulated experiment and show that our algorithm outperforms parametric methods.

Khanh N. Dinh, Roman Jaksik, Marek Kimmel, Amaury Lambert, Simon Tavaré.

Source: Statistical Science, Volume 35, Number 1, 129--144.

Abstract:
Recent years have seen considerable work on inference about cancer evolution from mutations identified in cancer samples. Much of the modeling work has been based on classical models of population genetics, generalized to accommodate time-varying cell population size. Reverse-time, genealogical views of such models, commonly known as coalescents, have been used to infer aspects of the past of growing populations. Another approach is to use branching processes, the simplest scenario being the classical linear birth-death process. Inference from evolutionary models of DNA often exploits summary statistics of the sequence data, a common one being the so-called Site Frequency Spectrum (SFS). In a bulk tumor sequencing experiment, we can estimate for each site at which a novel somatic point mutation has arisen, the proportion of cells that carry that mutation. These numbers are then grouped into collections of sites which have similar mutant fractions. We examine how the SFS based on birth-death processes differs from those based on the coalescent model. This may stem from the different sampling mechanisms in the two approaches. However, we also show that despite this, they are quantitatively comparable for the range of parameters typical for tumor cell populations. We also present a model of tumor evolution with selective sweeps, and demonstrate how it may help in understanding the history of a tumor as well as the influence of data pre-processing. We illustrate the theory with applications to several examples from The Cancer Genome Atlas tumors.

Thomas Staudt, Timo Aspelmeier, Oskar Laitenberger, Claudia Geisler, Alexander Egner, Axel Munk.

Source: Statistical Science, Volume 35, Number 1, 92--111.

Abstract:
Super-resolution microscopy is rapidly gaining importance as an analytical tool in the life sciences. A compelling feature is the ability to label biological units of interest with fluorescent markers in (living) cells and to observe them with considerably higher resolution than conventional microscopy permits. The images obtained this way, however, lack an absolute intensity scale in terms of numbers of fluorophores observed. In this article, we discuss state of the art methods to count such fluorophores and statistical challenges that come along with it. In particular, we suggest a modeling scheme for time series generated by single-marker-switching (SMS) microscopy that makes it possible to quantify the number of markers in a statistically meaningful manner from the raw data. To this end, we model the entire process of photon generation in the fluorophore, their passage through the microscope, detection and photoelectron amplification in the camera, and extraction of time series from the microscopic images. At the heart of these modeling steps is a careful description of the fluorophore dynamics by a novel hidden Markov model that operates on two timescales (HTMM). Besides the fluorophore number, information about the kinetic transition rates of the fluorophore’s internal states is also inferred during estimation. We comment on computational issues that arise when applying our model to simulated or measured fluorescence traces and illustrate our methodology on simulated data.

Chao Du, S. C. Kou.

Source: Statistical Science, Volume 35, Number 1, 75--91.

Abstract:
Toward the last quarter of the 20th century, the emergence of single-molecule experiments enabled scientists to track and study individual molecules’ dynamic properties in real time. Unlike macroscopic systems’ dynamics, those of single molecules can only be properly described by stochastic models even in the absence of external noise. Consequently, statistical methods have played a key role in extracting hidden information about molecular dynamics from data obtained through single-molecule experiments. In this article, we survey the major statistical methodologies used to analyze single-molecule experimental data. Our discussion is organized according to the types of stochastic models used to describe single-molecule systems as well as major experimental data collection techniques. We also highlight challenges and future directions in the application of statistical methodologies to single-molecule experiments.

Peter J. Diggle, Emanuele Giorgi, Julienne Atsame, Sylvie Ntsame Ella, Kisito Ogoussan, Katherine Gass.

Source: Statistical Science, Volume 35, Number 1, 42--50.

Abstract:
Vector-borne diseases have long presented major challenges to the health of rural communities in the wet tropical regions of the world, but especially in sub-Saharan Africa. In this paper, we describe the contribution that statistical modelling has made to the global elimination programme for one vector-borne disease, onchocerciasis. We explain why information on the spatial distribution of a second vector-borne disease, Loa loa, is needed before communities at high risk of onchocerciasis can be treated safely with mass distribution of ivermectin, an antifiarial medication. We show how a model-based geostatistical analysis of Loa loa prevalence survey data can be used to map the predictive probability that each location in the region of interest meets a WHO policy guideline for safe mass distribution of ivermectin and describe two applications: one is to data from Cameroon that assesses prevalence using traditional blood-smear microscopy; the other is to Africa-wide data that uses a low-cost questionnaire-based method. We describe how a recent technological development in image-based microscopy has resulted in a change of emphasis from prevalence alone to the bivariate spatial distribution of prevalence and the intensity of infection among infected individuals. We discuss how statistical modelling of the kind described here can contribute to health policy guidelines and decision-making in two ways. One is to ensure that, in a resource-limited setting, prevalence surveys are designed, and the resulting data analysed, as efficiently as possible. The other is to provide an honest quantification of the uncertainty attached to any binary decision by reporting predictive probabilities that a policy-defined condition for action is or is not met.

Michael L. Stein.

Source: Statistical Science, Volume 35, Number 1, 31--41.

Abstract:
Climate science is a field that is arguably both data-rich and data-poor. Data rich in that huge and quickly increasing amounts of data about the state of the climate are collected every day. Data poor in that important aspects of the climate are still undersampled, such as the deep oceans and some characteristics of the upper atmosphere. Data rich in that modern climate models can produce climatological quantities over long time periods with global coverage, including quantities that are difficult to measure and under conditions for which there is no data presently. Data poor in that the correspondence between climate model output to the actual climate, especially for future climate change due to human activities, is difficult to assess. The scope for fruitful interactions between climate scientists and statisticians is great, but requires serious commitments from researchers in both disciplines to understand the scientific and statistical nuances arising from the complex relationships between the data and the real-world problems. This paper describes a small fraction of some of the intellectual challenges that occur at the interface between climate science and statistics, including inferences for extremes for processes with seasonality and long-term trends, the use of climate model ensembles for studying extremes, the scope for using new data sources for studying space-time characteristics of environmental processes and a discussion of non-Gaussian space-time process models for climate variables. The paper concludes with a call to the statistical community to become more engaged in one of the great scientific and policy issues of our time, anthropogenic climate change and its impacts.

Junhui Cai, Avishai Mandelbaum, Chaitra H. Nagaraja, Haipeng Shen, Linda Zhao.

Source: Statistical Science, Volume 34, Number 4, 669--691.

Abstract:
Statisticians are finding their place in the emerging field of data science. However, many issues considered “new” in data science have long histories in statistics. Examples of using statistical thinking are illustrated, which range from exploratory data analysis to measuring uncertainty to accommodating nonrandom samples. These examples are then applied to service networks, baseball predictions and official statistics.

Alessandro Rinaldo, Ryan J. Tibshirani, Larry Wasserman.

Source: Statistical Science, Volume 34, Number 4, 599--603.

Abstract:
What is the meaning of a regression parameter? Why is this the de facto standard object of interest for statistical inference? These are delicate issues, especially when the model is misspecified. We argue that focusing on predictive quantities may be a desirable alternative.

Lei Liu, Ya-Chen Tina Shih, Robert L. Strawderman, Daowen Zhang, Bankole A. Johnson, Haitao Chai.

Source: Statistical Science, Volume 34, Number 2, 253--279.

Abstract:
Zero-inflated nonnegative continuous (or semicontinuous) data arise frequently in biomedical, economical, and ecological studies. Examples include substance abuse, medical costs, medical care utilization, biomarkers (e.g., CD4 cell counts, coronary artery calcium scores), single cell gene expression rates, and (relative) abundance of microbiome. Such data are often characterized by the presence of a large portion of zero values and positive continuous values that are skewed to the right and heteroscedastic. Both of these features suggest that no simple parametric distribution may be suitable for modeling such type of outcomes. In this paper, we review statistical methods for analyzing zero-inflated nonnegative outcome data. We will start with the cross-sectional setting, discussing ways to separate zero and positive values and introducing flexible models to characterize right skewness and heteroscedasticity in the positive values. We will then present models of correlated zero-inflated nonnegative continuous data, using random effects to tackle the correlation on repeated measures from the same subject and that across different parts of the model. We will also discuss expansion to related topics, for example, zero-inflated count and survival data, nonlinear covariate effects, and joint models of longitudinal zero-inflated nonnegative continuous data and survival. Finally, we will present applications to three real datasets (i.e., microbiome, medical costs, and alcohol drinking) to illustrate these methods. Example code will be provided to facilitate applications of these methods.

Bradley Efron.

Source: Statistical Science, Volume 34, Number 2, 234--235.

Yixin Wang, Andrew C. Miller, David M. Blei.

Source: Statistical Science, Volume 34, Number 2, 229--233.

Eitan Greenshtein, Ya’acov Ritov.

Source: Statistical Science, Volume 34, Number 2, 224--228.

Abstract:
We present some personal reflections on empirical Bayes/ compound decision (EB/CD) theory following Efron (2019). In particular, we consider the role of exchangeability in the EB/CD theory and how it can be achieved when there are covariates. We also discuss the interpretation of EB/CD confidence interval, the theoretical efficiency of the CD procedure, and the impact of sparsity assumptions.

Wenhua Jiang.

Source: Statistical Science, Volume 34, Number 2, 219--223.

Abstract:
This is a contribution to the discussion of the enlightening paper by Professor Efron. We focus on empirical Bayes interval estimation. We discuss the oracle interval estimation rules, the empirical Bayes estimation of the oracle rule and the computation. Some numerical results are reported.

Aad van der Vaart.

Source: Statistical Science, Volume 34, Number 2, 214--218.

Nan Laird.

Source: Statistical Science, Volume 34, Number 2, 206--208.

Thomas A. Louis.

Source: Statistical Science, Volume 34, Number 2, 202--205.

Bradley Efron.

Source: Statistical Science, Volume 34, Number 2, 177--201.

Abstract:
This article concerns the Bayes and frequentist aspects of empirical Bayes inference. Some of the ideas explored go back to Robbins in the 1950s, while others are current. Several examples are discussed, real and artificial, illustrating the two faces of empirical Bayes methodology: “oracle Bayes” shows empirical Bayes in its most frequentist mode, while “finite Bayes inference” is a fundamentally Bayesian application. In either case, modern theory and computation allow us to present a sharp finite-sample picture of what is at stake in an empirical Bayes analysis.

The capacity to process information in conceptual form is a fundamental aspect of human cognition, yet little is known about how this type of information is encoded in the brain. Although the role of sensory and motor cortical areas has been a focus of recent debate, neuroimaging studies of concept representation consistently implicate a network of heteromodal areas that seem to support concept retrieval in general rather than knowledge related to any particular sensory-motor content. We used predictive machine learning on fMRI data to investigate the hypothesis that cortical areas in this "general semantic network" (GSN) encode multimodal information derived from basic sensory-motor processes, possibly functioning as convergence–divergence zones for distributed concept representation. An encoding model based on five conceptual attributes directly related to sensory-motor experience (sound, color, shape, manipulability, and visual motion) was used to predict brain activation patterns associated with individual lexical concepts in a semantic decision task. When the analysis was restricted to voxels in the GSN, the model was able to identify the activation patterns corresponding to individual concrete concepts significantly above chance. In contrast, a model based on five perceptual attributes of the word form performed at chance level. This pattern was reversed when the analysis was restricted to areas involved in the perceptual analysis of written word forms. These results indicate that heteromodal areas involved in semantic processing encode information about the relative importance of different sensory-motor attributes of concepts, possibly by storing particular combinations of sensory and motor features.

SIGNIFICANCE STATEMENT The present study used a predictive encoding model of word semantics to decode conceptual information from neural activity in heteromodal cortical areas. The model is based on five sensory-motor attributes of word meaning (color, shape, sound, visual motion, and manipulability) and encodes the relative importance of each attribute to the meaning of a word. This is the first demonstration that heteromodal areas involved in semantic processing can discriminate between different concepts based on sensory-motor information alone. This finding indicates that the brain represents concepts as multimodal combinations of sensory and motor representations.

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Michael N. Shadlen
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02020-02-08: Tropical Cyclone Damien

Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by overstimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterization of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterize a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties of the auditory receptors remain unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialized receptor lymph that bathes the auditory receptors, revealing striking parallels with the mammalian auditory system.

SIGNIFICANCE STATEMENT Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive sound-induced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to, for the first time in any animal, characterize changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something that we show rings true for invertebrate ears too.

Knowledge about objects encompasses not only their prototypical features but also complex, atypical, semantic knowledge (e.g., "Pizza was invented in Naples"). This fMRI study of male and female human participants combines univariate and multivariate analyses to consider the cortical representation of this more complex semantic knowledge. Using the categories of food, people, and places, this study investigates whether access to spatially related geographic semantic knowledge (1) involves the same domain-selective neural representations involved in access to prototypical taste knowledge about food; and (2) elicits activation of neural representations classically linked to places when this geographic knowledge is accessed about food and people. In three experiments using word stimuli, domain-relevant and atypical conceptual access for the categories food, people, and places were assessed. Results uncover two principles of semantic representation: food-selective representations in the left insula continue to be recruited when prototypical taste knowledge is task-irrelevant and under conditions of high cognitive demand; access to geographic knowledge for food and people categories involves the additional recruitment of classically place-selective parahippocampal gyrus, retrosplenial complex, and transverse occipital sulcus. These findings underscore the importance of object category in the representation of a broad range of knowledge, while showing how the cross recruitment of specialized representations may endow the considerable flexibility of our complex semantic knowledge.

SIGNIFICANCE STATEMENT We know not only stereotypical things about objects (an apple is round, graspable, edible) but can also flexibly combine typical and atypical features to form complex concepts (the metaphorical role an apple plays in Judeo-Christian belief). In this fMRI study, we observe that, when atypical geographic knowledge is accessed about food dishes, domain-selective sensorimotor-related cortical representations continue to be recruited, but that regions classically associated with place perception are additionally engaged. This interplay between categorically driven representations, linked to the object being accessed, and the flexible recruitment of semantic stores linked to the content being accessed, provides a potential mechanism for the broad representational repertoire of our semantic system.

Neural plasticity due to hearing loss results in tonotopic map changes. Several studies have suggested a relation between hearing loss-induced tonotopic reorganization and tinnitus. This large fMRI study on humans was intended to clarify the relations between hearing loss, tinnitus, and tonotopic reorganization. To determine the differential effect of hearing loss and tinnitus, both male and female participants with bilateral high-frequency hearing loss, with and without tinnitus, and a control group were included. In a total of 90 participants, bilateral cortical responses to sound stimulation were measured with loudness-matched pure-tone stimuli (0.25-8 kHz). In the bilateral auditory cortices, the high-frequency sound-evoked activation level was higher in both hearing-impaired participant groups, compared with the control group. This was most prominent in the hearing loss group without tinnitus. Similarly, the tonotopic maps for the hearing loss without tinnitus group were significantly different from the controls, whereas the maps of those with tinnitus were not. These results show that higher response amplitudes and map reorganization are a characteristic of hearing loss, not of tinnitus. Both tonotopic maps and response amplitudes of tinnitus participants appear intermediate to the controls and hearing loss without tinnitus group. This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus toward enhancing the cortical plasticity, instead of reversing it.

SIGNIFICANCE STATEMENT Tinnitus, a common and potentially devastating condition, is the presence of a "phantom" sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and subcortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reverse it.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.

SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.

The tuberal hypothalamus is comprised of the dorsomedial, ventromedial, and arcuate nuclei, as well as parts of the lateral hypothalamic area, and it governs a wide range of physiologies. During neurogenesis, tuberal hypothalamic neurons are thought to be born in a dorsal-to-ventral and outside-in pattern, although the accuracy of this description has been questioned over the years. Moreover, the intrinsic factors that control the timing of neurogenesis in this region are poorly characterized. Proneural genes, including Achate-scute-like 1 (Ascl1) and Neurogenin 3 (Neurog3) are widely expressed in hypothalamic progenitors and contribute to lineage commitment and subtype-specific neuronal identifies, but the potential role of Neurogenin 2 (Neurog2) remains unexplored. Birthdating in male and female mice showed that tuberal hypothalamic neurogenesis begins as early as E9.5 in the lateral hypothalamic and arcuate and rapidly expands to dorsomedial and ventromedial neurons by E10.5, peaking throughout the region by E11.5. We confirmed an outside-in trend, except for neurons born at E9.5, and uncovered a rostrocaudal progression but did not confirm a dorsal-ventral patterning to tuberal hypothalamic neuronal birth. In the absence of Neurog2, neurogenesis stalls, with a significant reduction in early-born BrdU⁺ cells but no change at later time points. Further, the loss of Ascl1 yielded a similar delay in neuronal birth, suggesting that Ascl1 cannot rescue the loss of Neurog2 and that these proneural genes act independently in the tuberal hypothalamus. Together, our findings show that Neurog2 functions as a classical proneural gene to regulate the temporal progression of tuberal hypothalamic neurogenesis.

SIGNIFICANCE STATEMENT Here, we investigated the general timing and pattern of neurogenesis within the tuberal hypothalamus. Our results confirmed an outside-in trend of neurogenesis and uncovered a rostrocaudal progression. We also showed that Neurog2 acts as a classical proneural gene and is responsible for regulating the birth of early-born neurons within the ventromedial hypothalamus, acting independently of Ascl1. In addition, we revealed a role for Neurog2 in cell fate specification and differentiation of ventromedial -specific neurons. Last, Neurog2 does not have cross-inhibitory effects on Neurog1, Neurog3, and Ascl1. These findings are the first to reveal a role for Neurog2 in hypothalamic development.