Dynamic Electrode-to-Image (DETI) mapping reveals the human brain's spatiotemporal code of visual information.

A number of neuroimaging techniques have been employed to understand how visual information is transformed along the visual pathway. Although each technique has spatial and temporal limitations, they can each provide important insights into the visual code. While the BOLD signal of fMRI can be quite informative, the visual code is not static and this can be obscured by fMRI's poor temporal resolution. In this study, we leveraged the high temporal resolution of EEG to develop an encoding technique based on the distribution of responses generated by a population of real-world scenes. This approach maps neural signals to each pixel within a given image and reveals location-specific transformations of the visual code, providing a spatiotemporal signature for the image at each electrode. Our analyses of the mapping results revealed that scenes undergo a series of nonuniform transformations that prioritize different spatial frequencies at different regions of scenes over time. This mapping technique offers a potential avenue for future studies to explore how dynamic feedforward and recurrent processes inform and refine high-level representations of our visual world.

Towards a state-space geometry of neural responses to natural scenes: A steady-state approach.

Our understanding of information processing by the mammalian visual system has come through a variety of techniques ranging from psychophysics and fMRI to single unit recording and EEG. Each technique provides unique insights into the processing framework of the early visual system. Here, we focus on the nature of the information that is carried by steady state visual evoked potentials (SSVEPs). To study the information provided by SSVEPs, we presented human participants with a population of natural scenes and measured the relative SSVEP response. Rather than focus on particular features of this signal, we focused on the full state-space of possible responses and investigated how the evoked responses are mapped onto this space. Our results show that it is possible to map the relatively high-dimensional signal carried by SSVEPs onto a 2-dimensional space with little loss. We also show that a simple biologically plausible model can account for a high proportion of the explainable variance (~73%) in that space. Finally, we describe a technique for measuring the mutual information that is available about images from SSVEPs. The techniques introduced here represent a new approach to understanding the nature of the information carried by SSVEPs. Crucially, this approach is general and can provide a means of comparing results across different neural recording methods. Altogether, our study sheds light on the encoding principles of early vision and provides a much needed reference point for understanding subsequent transformations of the early visual response space to deeper knowledge structures that link different visual environments.

Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype.

OBJECTIVE: Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions. APPROACH AND RESULTS: In a cohort of patients with metabolic and peripheral artery disease, platelet activity was enhanced, and inhibition with oral antiplatelet agents was impaired compared with platelets from control subjects, suggesting a difference in platelet phenotype caused by the disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O2) had increased expression of some proteins that augment platelet activation compared with platelets in normoxic conditions (21% O2). Using a murine model of critical limb ischemia, platelet activity was increased even 2 weeks postsurgery compared with sham surgery mice. This effect was partly inhibited in platelet-specific ERK5 (extracellular regulated protein kinase 5) knockout mice. CONCLUSIONS: These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses because of changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should, therefore, be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of antiplatelet therapy.

Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth.

OBJECTIVES: To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity. STUDY DESIGN: Geographical, prospective population-based cohort study of 1139 infants born LMPT (320/7 to 366/7 weeks' gestation) and 1255 infants born at term (370/7 to 426/7 weeks' gestation). Parent questionnaires were obtained to identify impaired cognitive and language development, behavioral problems, delayed social-emotional competence, autistic features, and clinically significant eating difficulties at 24 months corrected age for 638 (57%) children born LMPT and 765 (62%) children born at term. RESULTS: Latent class analysis revealed 2 profiles of development among the term group: optimal (84%) and a profile of social, emotional, and behavioral impairments termed "nonoptimal" (16%). These 2 profiles were also identified among the LMPT group (optimal: 67%; nonoptimal: 26%). In the LMPT group, a third profile was identified (7%) that was similar to the phenotype previously identified in infants born very preterm. Nonwhite ethnicity, socioeconomic risk, and not receiving breast milk at hospital discharge were risk factors for nonoptimal outcomes in both groups. Male sex, greater gestational age, and pre-eclampsia were only associated with the preterm phenotype. CONCLUSIONS: Among children born LMPT with parent-reported cognitive or behavioral impairments, most had problems similar to the profile of difficulties observed in children born at term. A smaller proportion of children born LMPT had impairments consistent with the "very preterm phenotype" which are likely to have arisen through a preterm pathway. These results suggest that prematurity may affect development through several etiologic pathways in the late and moderately preterm population.

Selectivity, hyperselectivity, and the tuning of V1 neurons.

In this article, we explore two forms of selectivity in sensory neurons. The first we call classic selectivity, referring to the stimulus that optimally stimulates a neuron. If a neuron is linear, then this stimulus can be determined by measuring the response to an orthonormal basis set (the receptive field). The second type of selectivity we call hyperselectivity; it is either implicitly or explicitly a component of several models including sparse coding, gain control, and some linear-nonlinear models. Hyperselectivity is unrelated to the stimulus that maximizes the response. Rather, it refers to the drop-off in response around that optimal stimulus. We contrast various models that produce hyperselectivity by comparing the way each model curves the iso-response surfaces of each neuron. We demonstrate that traditional sparse coding produces such curvature and increases with increasing degrees of overcompleteness. We demonstrate that this curvature produces a systematic misestimation of the optimal stimulus when the neuron's receptive field is measured with spots or gratings. We also show that this curvature allows for two apparently paradoxical results. First, it allows a neuron to be very narrowly tuned (hyperselective) to a broadband stimulus. Second, it allows neurons to break the Gabor-Heisenberg limit in their localization in space and frequency. Finally, we argue that although gain-control models, some linear-nonlinear models, and sparse coding have much in common, we believe that this approach to hyperselectivity provides a deeper understanding of why these nonlinearities are present in the early visual system.

Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion.

BACKGROUND: Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species-rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species-rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species-mediated mechanisms in ischemic myocardium. METHODS AND RESULTS: Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5(-/-) mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5(-/-) platelets post-MI. CONCLUSIONS: ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment.

Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age.

OBJECTIVES: To assess the prevalence of positive screens using the Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire and follow-up interview in late and moderately preterm (LMPT; 32-36 weeks) infants and term-born controls. STUDY DESIGN: Population-based prospective cohort study of 1130 LMPT and 1255 term-born infants. Parents completed the M-CHAT questionnaire at 2-years corrected age. Parents of infants with positive questionnaire screens were followed up with a telephone interview to clarify failed items. The M-CHAT questionnaire was re-scored, and infants were classified as true or false positives. Neurosensory, cognitive, and behavioral outcomes were assessed using parent report. RESULTS: Parents of 634 (57%) LMPT and 761 (62%) term-born infants completed the M-CHAT questionnaire. LMPT infants had significantly higher risk of a positive questionnaire screen compared with controls (14.5% vs 9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up, significantly more LMPT infants than controls had a true positive screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained significant after excluding infants with neurosensory impairments (2.0% vs 0.5%; RR 3.67; 1.19, 11.3). CONCLUSIONS: LMPT infants are at significantly increased risk for positive autistic screen. An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations. Infants with false positive screens are at risk for cognitive and behavioral problems.

Platelet factor 4 mediates vascular smooth muscle cell injury responses.

Activated platelets release many inflammatory molecules with important roles in accelerating vascular inflammation. Much is known about platelet and platelet-derived mediator interactions with endothelial cells and leukocytes, but few studies have examined the effects of platelets on components of the vascular wall. Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to injury including the production of inflammatory molecules, cell proliferation, cell migration, and a decline in the expression of differentiation markers. In this study, we demonstrate that the platelet-derived chemokine platelet factor 4 (PF4/CXCL4) stimulates VSMC injury responses both in vitro and in vivo in a mouse carotid ligation model. PF4 drives a VSMC inflammatory phenotype including a decline in differentiation markers, increased cytokine production, and cell proliferation. We also demonstrate that PF4 effects are mediated, in part, through increased expression of the transcription factor Krüppel-like factor 4. Our data indicate an important mechanistic role for platelets and PF4 in VSMC injury responses both in vitro and in vivo.

Platelet induction of the acute-phase response is protective in murine experimental cerebral malaria.

Platelets are most recognized as the cellular mediator of thrombosis, but they are increasingly appreciated for their immunomodulatory roles, including responses to Plasmodium infection. Platelet interactions with endothelial cells and leukocytes contribute significantly to the pathogenesis of experimental cerebral malaria (ECM). Recently, it has been suggested that platelets not only have an adverse role in cerebral malaria, but platelets may also be protective in animal models of uncomplicated malaria. We now demonstrate that these diverse and seemingly contradictory roles for platelets extend to cerebral malaria models and are dependent on the timing of platelet activation during infection. Our data show that platelets are activated very early in ECM and have a central role in initiation of the acute-phase response to blood-stage infection. Unlike platelet depletion or inhibition postinfection, preinfection platelet depletion or treatment with a platelet inhibitor is not protective. Additionally, we show that platelet-driven acute-phase responses have a major role in protecting mice from ECM by limiting parasite growth. Our data now suggest that platelets have a complex role in ECM pathogenesis: platelets help limit parasite growth early postinfection, but with continued platelet activation as the disease progresses, platelets contribute to ECM-associated inflammation.

Platelets present antigen in the context of MHC class I.

Platelets are most recognized for their vital role as the cellular mediator of thrombosis, but platelets also have important immune functions. Platelets initiate and sustain vascular inflammation in many disease conditions, including arthritis, atherosclerosis, transplant rejection, and severe malaria. We now demonstrate that platelets express T cell costimulatory molecules, process and present Ag in MHC class I, and directly activate naive T cells in a platelet MHC class I-dependent manner. Using an experimental cerebral malaria mouse model, we also demonstrate that platelets present pathogen-derived Ag to promote T cell responses in vivo, and that platelets can be used in a cell-based vaccine model to induce protective immune responses. Our study demonstrates a novel Ag presentation role for platelets.

Local edge statistics provide information regarding occlusion and nonocclusion edges in natural scenes.

Edges in natural scenes can result from a number of different causes. In this study, we investigated the statistical differences between edges arising from occlusions and nonocclusions (reflectance differences, surface change, and cast shadows). In the first experiment, edges in natural scenes were identified using the Canny edge detection algorithm. Observers then classified these edges as either an occlusion edge (one region of an image occluding another) or a nonocclusion edge. The nonocclusion edges were further subclassified as due to a reflectance difference, a surface change, or a cast shadow. We found that edges were equally likely to be classified as occlusion or nonocclusion edges. Of the nonocclusion edges, approximately 33% were classified as reflectance changes, 9% as cast shadows, and 58% as surface changes. We also analyzed local statistical properties like contrast, average edge profile, and slope of the edges. We found significant differences between the contrast values for each category. Based on the local contrast statistics, we developed a maximum likelihood classifier to label occlusion and nonocclusion edges. An 80%-20% cross validation demonstrated that the human classification could be predicted with 83% accuracy. Overall, our results suggest that for many edges in natural scenes, there exists local statistical information regarding the cause of the edge. We believe that this information can potentially be used by the early visual system to begin the process of segregating objects from their backgrounds.

Local masking in natural images: a database and analysis.

Studies of visual masking have provided a wide range of important insights into the processes involved in visual coding. However, very few of these studies have employed natural scenes as masks. Little is known on how the particular features found in natural scenes affect visual detection thresholds and how the results obtained using unnatural masks relate to the results obtained using natural masks. To address this issue, this paper describes a psychophysical study designed to obtain local contrast detection thresholds for a database of natural images. Via a three-alternative forced-choice experiment, we measured thresholds for detecting 3.7 cycles/° vertically oriented log-Gabor noise targets placed within an 85 × 85-pixels patch (1.9° patch) drawn from 30 natural images from the CSIQ image database (Larson & Chandler, Journal of Electronic Imaging, 2010). Thus, for each image, we obtained a masking map in which each entry in the map denotes the root mean squared contrast threshold for detecting the log-Gabor noise target at the corresponding spatial location in the image. From qualitative observations we found that detection thresholds were affected by several patch properties such as visual complexity, fineness of textures, sharpness, and overall luminance. Our quantitative analysis shows that except for the sharpness measure (correlation coefficient of 0.7), the other tested low-level mask features showed a weak correlation (correlation coefficients less than or equal to 0.52) with the detection thresholds. Furthermore, we evaluated the performance of a computational contrast gain control model that performed fairly well with an average correlation coefficient of 0.79 in predicting the local contrast detection thresholds. We also describe specific choices of parameters for the gain control model. The objective of this database is to provide researchers with a large ground-truth dataset in order to further investigate the properties of the human visual system using natural masks.

Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants.

AIMS: Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants. METHODS: DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement. RESULTS: Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹ kg⁻¹; V = 593 ml kg⁻¹; t(½) = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h⁻¹ kg⁻¹; V = 640-970 ml kg⁻¹; t(½) = 101-144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data. CONCLUSIONS: This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.

Modelling time to death or discharge in neonatal care: an application of competing risks.

BACKGROUND: Understanding length of stay for babies in neonatal care is vital for planning services and for counselling parents. While previous work has focused on the length of stay of babies who survive to discharge, when investigating resource use within neonatal care, it is important to also incorporate information on those babies who die while in care. We present an analysis using competing risks methodology which allows the simultaneous modelling of babies who die in neonatal care and those who survive to discharge. METHODS: Data were obtained on 2723 babies born at 24-28 weeks gestational age in 2006-10 and admitted to neonatal care. Death and discharge alive are two mutually exclusive events and can be treated as competing risks. A flexible parametric modelling approach was used to analyse these two competing events and obtain estimates of the absolute probabilities of death or discharge. RESULTS: The absolute probabilities of death or discharge are presented in graphical form showing the cause-specific cumulative incidence over time by gender, gestational age and birthweight. The discharge of babies alive generally occurred over a longer time period for babies of lower gestational age and smaller birthweight than for bigger babies. CONCLUSION: This study has presented a useful statistical method for modelling the length of stay where there are significant rates of in-unit mortality. In health care systems that are increasingly focusing on costs and resource planning, it is essential to consider not only length of stay of survivors but also for those patients who die before discharge.

Platelets contribute to allograft rejection through glutamate receptor signaling.

Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Platelets have been long described as markers of transplant rejection, but the contribution of platelets to transplant rejection has not been critically examined. We demonstrate in this study that following T cell initiation of allograft rejection, platelets contribute to T cell recruitment and increased plasma inflammatory mediators and accelerate T cell-meditated skin graft rejection. Prior work from our laboratory has shown that platelets secrete glutamate when activated, which then induces platelet thromboxane production by signaling through platelet-expressed ionotropic glutamate receptors. Glutamate receptor antagonists therefore represent, to our knowledge, novel inhibitors of platelet-accelerated inflammation. We have found that plasma glutamate is increased in mice that receive skin grafts and that mice treated with glutamate receptor antagonists have improved graft survival and decreased plasma thromboxane, platelet factor 4 (CXCL4), and IFN-γ. Taken together, our work now demonstrates that subsequent to T cell initiation of skin graft rejection, platelets contribute to further T cell recruitment and that by blunting glutamate-mediated platelet activation, graft survival is improved.

Method for estimating the relative contribution of phase and power spectra to the total information in natural-scene patches.

A wide variety of recent studies have argued that the human visual system provides an efficient means of processing the information in the natural environment. However, the amount of information (entropy) in the signal can be estimated in a number of ways, and it is has been unclear how much of the information is carried by the different sources of redundancy. The primary difficulty is that there has been no rational way to estimate the entropy of such complex scenes. In this paper, we provide a technique that uses a recent approach to estimating the entropy and dimensionality of natural scenes [D. M. Chandler and D. J. Field, J. Opt. Soc. Am. A 24, 922-941 (2007)] to estimate the amount of information attributable to the power and phase spectra in natural-scene patches. By comparing the entropies of patches that have swapped phase spectra and fixed phase spectra, we demonstrate how to estimate both the amount of information in each type of spectrum and the amount of information that is shared by these spectra (mutual information). We applied this technique to small patches (4×4 and 8×8). From our estimates, we show that the power spectrum of 8×8 patches carries approximately 54% of the total information, the phase spectrum carries 56%, and 10% is mutual information (54%+56%-10%=100%). This technique is currently limited to relatively small image patches, due to the number of patches currently in our collection (on the order of 106). However, the technique can, in theory, be extended to larger images. Even with these relatively small patches, we discuss how these results can provide important insights into both compression techniques and efficient coding techniques that work with relatively small image patches (e.g., JPEG, sparse coding, independent components analysis).

Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience.

The aim of this study was to report the birth prevalence and short-term outcome of congenital diaphragmatic hernia (CDH) in a large geographically defined population, and to assess the feasibility of performing a randomised control trial (RCT) in this population. Data were collected on all cases of CDH reported to the East Midlands and South Yorkshire Congenital Anomalies Register between 1997 and 2005. A total of 194 cases of CDH were identified from 547,025 births; a birth prevalence of 3.5/10,000. Overall 1-year survival was 42%. In total, 69% of cases resulted in a live birth, of these 61% survived to 1 year; 73% were diagnosed antenatally and 22% postnatally, with 1-year survivals 30% and 71%, respectively. A total of 54% were isolated cases and 46% associated with another anomaly, with more live births (80% vs. 56%) and better 1-year survival (62% vs. 19%) with isolated CDH. Overall, only 83 babies were born alive with an isolated CDH: the only group suitable for inclusion in a RCT. In conclusion, given the small numbers of live isolated CDH cases it is impossible that any network alone would be able to perform a valid RCT of treatments, highlighting the need for collaborative international trials to address this complex condition.

On the Role of LGN/V1 Spontaneous Activity as an Innate Learning Pattern for Visual Development.

Correlated, spontaneous neural activity is known to play a necessary role in visual development, but the higher-order statistical structure of these coherent, amorphous patterns has only begun to emerge in the past decade. Several computational studies have demonstrated how this endogenous activity can be used to train a developing visual system. Models that generate spontaneous activity analogous to retinal waves have shown that these waves can serve as stimuli for efficient coding models of V1. This general strategy in development has one clear advantage: The same learning algorithm can be used both before and after eye-opening. This same insight can be applied to understanding LGN/V1 spontaneous activity. Although lateral geniculate nucleus (LGN) activity has been less discussed in the literature than retinal waves, here we argue that the waves found in the LGN have a number of properties that fill the role of a training pattern. We make the case that the role of "innate learning" with spontaneous activity is not only possible, but likely in later stages of visual development, and worth pursuing further using an efficient coding paradigm.