Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

Generalized Functional Additive Mixed Models

We propose a comprehensive framework for additive regression models for non-Gaussian functional responses, allowing for multiple (partially) nested or crossed functional random effects with flexible correlation structures for, e.g., spatial, temporal, or longitudinal functional data as well as linear and nonlinear effects of functional and scalar covariates that may vary smoothly over the index of the functional response. Our implementation handles functional responses from any exponential family distribution as well as many others like Beta- or scaled non-central $t$-distributions. Development is motivated by and evaluated on an application to large-scale longitudinal feeding records of pigs. Results in extensive simulation studies as well as replications of two previously published simulation studies for generalized functional mixed models demonstrate the good performance of our proposal. The approach is implemented in well-documented open source software in the "pffr()" function in R-package "refund"

Emergence of functional sensory subtypes as defined by transient receptor potential channel expression

The existence of heterogeneous populations of dorsal root ganglion (DRG) neurons conveying different somatosensory information is the basis for the perception of touch, temperature, and pain. A differential expression of transient receptor potential (TRP) cation channels contributes to this functional heterogeneity. However, little is known about the development of functionally diverse neuronal subpopulations. Here, we use calcium imaging of acutely dissociated mouse sensory neurons and quantitative reverse transcription PCR to show that TRP cation channels emerge in waves, with the diversification of functional groups starting at embryonic day 12.5 (E12.5) and extending well into the postnatal life. Functional responses of voltage-gated calcium channels were present in DRG neurons at E11.5 and reached adult levels by E14.5. Responses to capsaicin, menthol, and cinnamaldehyde were first seen at E12.5, E16.5, and postnatal day 0 (P0), when the mRNA for TRP cation channel, subfamily V, member 1 (TRPV1), TRP cation channel, subfamily M, member 8 (TRPM8), and TRP cation channel, subfamily A, member 1 (TRPA1), respectively, was first detected. Cold-sensitive neurons were present before the expression or functional responses of TRPM8 or TRPA1. Our data support a lineage relationship in which TRPM8- and TRPA1-expressing sensory neurons derive from the population of TRPV1-expressing neurons. The TRPA1 subpopulation of neurons emerges independently in two distinct classes of nociceptors: around birth in the peptidergic population and after P14 in the nonpeptidergic class. This indicates that neurons with similar receptive properties can be generated in different sublineages at different developmental stages. This study describes for the first time the emergence of functional subtypes of sensory neurons, providing new insight into the development of nociception and thermoreception

Multivariate varying coefficient model for functional responses

Motivated by recent work studying massive imaging data in the neuroimaging literature, we propose multivariate varying coefficient models (MVCM) for modeling the relation between multiple functional responses and a set of covariates. We develop several statistical inference procedures for MVCM and systematically study their theoretical properties. We first establish the weak convergence of the local linear estimate of coefficient functions, as well as its asymptotic bias and variance, and then we derive asymptotic bias and mean integrated squared error of smoothed individual functions and their uniform convergence rate. We establish the uniform convergence rate of the estimated covariance function of the individual functions and its associated eigenvalue and eigenfunctions. We propose a global test for linear hypotheses of varying coefficient functions, and derive its asymptotic distribution under the null hypothesis. We also propose a simultaneous confidence band for each individual effect curve. We conduct Monte Carlo simulation to examine the finite-sample performance of the proposed procedures. We apply MVCM to investigate the development of white matter diffusivities along the genu tract of the corpus callosum in a clinical study of neurodevelopment.Comment: Published in at http://dx.doi.org/10.1214/12-AOS1045 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Functional responses can’t unify invasion ecology

Dick et al. (Biol Invasions, 2017) propose that the comparative functional response framework provides a unifying approach for the study of invasive species. We agree that functional responses are an important and powerful quantitative description of consumer effects on resources, and co-opting classical ecological theory to better predict invasive species impacts is a laudable move for invasion biology. However, we fear that the early successes of select examples of the comparative functional response (CFR) approach has led Dick et al. to exaggerate the generality of its utility, and about its ability to unify the field. Further, they fail to provide a convincing argument why CFR is better than existing tools such as invasion history or impact indices, even when considering emerging or potential invaders. In this response we provide details of three conceptual issues stemming from classical ecological theoretical frameworks and two practical problems that Dick et al. and other CFR proponents need to address

Choosing the lesser of two evils, the better of two goods: Specifying the roles of ventromedial prefrontal cortex and dorsal anterior cingulate in object choice

The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning

Tumor-Targeting Anti-CD20 Antibodies Mediate In Vitro Expansion of Memory Natural Killer Cells: Impact of CD16 Affinity Ligation Conditions and In Vivo Priming

Natural Killer (NK) cells represent a pivotal player of innate anti-tumor immune responses. The impact of environmental factors in shaping the representativity of different NK cell subsets is increasingly appreciated. Human Cytomegalovirus (HCMV) infection profoundly affects NK cell compartment, as documented by the presence of a CD94/NKG2C+Fc∝RI≥- long-lived “memory” NK cell subset, endowed with enhanced CD16-dependent functional capabilities, in a fraction of HCMV seropositive subjects. However, the requirements for memory NK cell pool establishment/maintenance and activation have not been fully characterised yet. Here we describe the capability of anti-CD20 tumor-targeting therapeutic monoclonal antibodies (mAbs) to drive the selective in vitro expansion of memory NK cells, and we show the impact of donor' HCMV serostatus and CD16 affinity ligation conditions on this event. In vitro expanded memory NK cells maintain the phenotypic and functional signature of their freshly isolated counterpart; furthermore, our data demonstrate that CD16 affinity ligation conditions differently affect memory NK cell proliferation and functional activation, as rituximab-mediated low-affinity ligation represents a superior proliferative stimulus, while high-affinity aggregation mediated by glycoengineered obinutuzumab results in improved multifunctional responses. Our work also expands the molecular and functional characterization of memory NK cells, and investigates the possible impact of CD16 functional allelic variants on their in vivo and in vitro expansion. These results reveal new insights in Ab-driven memory NK cell responses in a therapeutic setting, and may ultimately inspire new NK cell-based intervention strategies against cancer, in which the enhanced responsiveness to mAb-bound target could significantly impact therapeutic efficacy