Novel approaches to capturing and using continuous cardiorespiratory physiological data in hospitalized children.

Continuous cardiorespiratory physiological monitoring is a cornerstone of care in hospitalized children. The data generated by monitoring devices coupled with machine learning could transform the way we provide care. This scoping review summarizes existing evidence on novel approaches to continuous cardiorespiratory monitoring in hospitalized children. We aimed to identify opportunities for the development of monitoring technology and the use of machine learning to analyze continuous physiological data to improve the outcomes of hospitalized children. We included original research articles published on or after January 1, 2001, involving novel approaches to collect and use continuous cardiorespiratory physiological data in hospitalized children. OVID Medline, PubMed, and Embase databases were searched. We screened 2909 articles and performed full-text extraction of 105 articles. We identified 58 articles describing novel devices or approaches, which were generally small and single-center. In addition, we identified 47 articles that described the use of continuous physiological data in prediction models, but only 7 integrated multidimensional data (e.g., demographics, laboratory results). We identified three areas for development: (1) further validation of promising novel devices; (2) more studies of models integrating multidimensional data with continuous cardiorespiratory data; and (3) further dissemination, implementation, and validation of prediction models using continuous cardiorespiratory data. IMPACT: We performed a comprehensive scoping review of novel approaches to capture and use continuous cardiorespiratory physiological data for monitoring, diagnosis, providing care, and predicting events in hospitalized infants and children, from novel devices to machine learning-based prediction models. We identified three key areas for future development: (1) further validation of promising novel devices; (2) more studies of models integrating multidimensional data with continuous cardiorespiratory data; and (3) further dissemination, implementation, and validation of prediction models using cardiorespiratory data.

Examination of physical activity development in early childhood: protocol for a longitudinal cohort study of mother-toddler dyads.

BACKGROUND: Physical activity (PA) development in toddlers (age 1 and 2 years) is not well understood, partly because of a lack of analytic tools for accelerometer-based data processing that can accurately evaluate PA among toddlers. This has led to a knowledge gap regarding how parenting practices around PA, mothers' PA level, mothers' parenting stress, and child developmental and behavioral problems influence PA development in early childhood. METHODS: The Child and Mother Physical Activity Study is a longitudinal study to observe PA development in toddlerhood and examine the influence of personal and parental characteristics on PA development. The study is designed to refine and validate an accelerometer-based machine learning algorithm for toddler activity recognition (Aim 1), apply the algorithm to compare the trajectories of toddler PA levels in males and females age 1-3 years (Aim 2), and explore the association between gross motor development and PA development in toddlerhood, as well as how parenting practices around PA, mothers' PA, mothers' parenting stress, and child developmental and behavioral problems are associated with toddlerhood PA development (Exploratory Aims 3a-c). DISCUSSION: This study will be one of the first to use longitudinal data to validate a machine learning activity recognition algorithm and apply the algorithm to quantify free-living ambulatory movement in toddlers. The study findings will help fill a significant methodological gap in toddler PA measurement and expand the body of knowledge on the factors influencing early childhood PA development.

Idiosyncratic neural coding and neuromodulation of olfactory individuality in Drosophila.

Innate behavioral biases and preferences can vary significantly among individuals of the same genotype. Though individuality is a fundamental property of behavior, it is not currently understood how individual differences in brain structure and physiology produce idiosyncratic behaviors. Here we present evidence for idiosyncrasy in olfactory behavior and neural responses in Drosophila We show that individual female Drosophila from a highly inbred laboratory strain exhibit idiosyncratic odor preferences that persist for days. We used in vivo calcium imaging of neural responses to compare projection neuron (second-order neurons that convey odor information from the sensory periphery to the central brain) responses to the same odors across animals. We found that, while odor responses appear grossly stereotyped, upon closer inspection, many individual differences are apparent across antennal lobe (AL) glomeruli (compact microcircuits corresponding to different odor channels). Moreover, we show that neuromodulation, environmental stress in the form of altered nutrition, and activity of certain AL local interneurons affect the magnitude of interfly behavioral variability. Taken together, this work demonstrates that individual Drosophila exhibit idiosyncratic olfactory preferences and idiosyncratic neural responses to odors, and that behavioral idiosyncrasies are subject to neuromodulation and regulation by neurons in the AL.

Idiosyncratic learning performance in flies.

Individuals vary in their innate behaviours, even when they have the same genome and have been reared in the same environment. The extent of individuality in plastic behaviours, like learning, is less well characterized. Also unknown is the extent to which intragenotypic differences in learning generalize: if an individual performs well in one assay, will it perform well in other assays? We investigated this using the fruit fly Drosophila melanogaster, an organism long-used to study the mechanistic basis of learning and memory. We found that isogenic flies, reared in identical laboratory conditions, and subject to classical conditioning that associated odorants with electric shock, exhibit clear individuality in their learning responses. Flies that performed well when an odour was paired with shock tended to perform well when the odour was paired with bitter taste or when other odours were paired with shock. Thus, individuality in learning performance appears to be prominent in isogenic animals reared identically, and individual differences in learning performance generalize across some aversive sensory modalities. Establishing these results in flies opens up the possibility of studying the genetic and neural circuit basis of individual differences in learning in a highly suitable model organism.

Imaging a population code for odor identity in the Drosophila mushroom body.

The brain represents sensory information in the coordinated activity of neuronal ensembles. Although the microcircuits underlying olfactory processing are well characterized in Drosophila, no studies to date have examined the encoding of odor identity by populations of neurons and related it to the odor specificity of olfactory behavior. Here we used two-photon Ca(2+) imaging to record odor-evoked responses from >100 neurons simultaneously in the Drosophila mushroom body (MB). For the first time, we demonstrate quantitatively that MB population responses contain substantial information on odor identity. Using a series of increasingly similar odor blends, we identified conditions in which odor discrimination is difficult behaviorally. We found that MB ensemble responses accounted well for olfactory acuity in this task. Kenyon cell ensembles with as few as 25 cells were sufficient to match behavioral discrimination accuracy. Using a generalization task, we demonstrated that the MB population code could predict the flies' responses to novel odors. The degree to which flies generalized a learned aversive association to unfamiliar test odors depended upon the relative similarity between the odors' evoked MB activity patterns. Discrimination and generalization place different demands on the animal, yet the flies' choices in these tasks were reliably predicted based on the amount of overlap between MB activity patterns. Therefore, these different behaviors can be understood in the context of a single physiological framework.

Cellular-resolution population imaging reveals robust sparse coding in the Drosophila mushroom body.

Sensory stimuli are represented in the brain by the activity of populations of neurons. In most biological systems, studying population coding is challenging since only a tiny proportion of cells can be recorded simultaneously. Here we used two-photon imaging to record neural activity in the relatively simple Drosophila mushroom body (MB), an area involved in olfactory learning and memory. Using the highly sensitive calcium indicator GCaMP3, we simultaneously monitored the activity of >100 MB neurons in vivo (∼5% of the total population). The MB is thought to encode odors in sparse patterns of activity, but the code has yet to be explored either on a population level or with a wide variety of stimuli. We therefore imaged responses to odors chosen to evaluate the robustness of sparse representations. Different odors activated distinct patterns of MB neurons; however, we found no evidence for spatial organization of neurons by either response probability or odor tuning within the cell body layer. The degree of sparseness was consistent across a wide range of stimuli, from monomolecular odors to artificial blends and even complex natural smells. Sparseness was mainly invariant across concentrations, largely because of the influence of recent odor experience. Finally, in contrast to sensory processing in other systems, no response features distinguished natural stimuli from monomolecular odors. Our results indicate that the fundamental feature of odor processing in the MB is to create sparse stimulus representations in a format that facilitates arbitrary associations between odor and punishment or reward.

Physical Activity among U.S. Preschool-Aged Children: Application of Machine Learning Physical Activity Classification to the 2012 National Health and Nutrition Examination Survey National Youth Fitness Survey.

Early childhood is an important development period for establishing healthy physical activity (PA) habits. The objective of this study was to evaluate PA levels in a representative sample of U.S. preschool-aged children. The study sample included 301 participants (149 girls, 3-5 years of age) in the 2012 U.S. National Health and Examination Survey National Youth Fitness Survey. Participants were asked to wear an ActiGraph accelerometer on their wrist for 7 days. A machine learning random forest classification algorithm was applied to accelerometer data to estimate daily time spent in moderate- and vigorous-intensity PA (MVPA; the sum of minutes spent in running, walking, and other moderate- and vigorous-intensity PA) and total PA (the sum of MVPA and light-intensity PA). We estimated that U.S. preschool-aged children engaged in 28 min/day of MVPA and 361 min/day of total PA, on average. MVPA and total PA levels were not significantly different between males and females. This study revealed that U.S. preschool-aged children engage in lower levels of MVPA and higher levels of total PA than the minimum recommended by the World Health Organization.

Ectopic growth of hippocampal mossy fibers in a mutated GAP-43 transgenic mouse with impaired spatial memory retention.

In a previous study, it was shown that transgenic mice, designated G-NonP, forget the location of a water maze hidden platform when tested 7 days after the last training day (Holahan and Routtenberg (2008) Hippocampus 18:1099-1102). The memory loss in G-NonP mice might be related to altered hippocampal architecture suggested by the fact that in the rat, 7 days after water maze training, there is discernible mossy fiber (MF) growth (Holahan et al. (2006) Hippocampus 16:560-570; Rekart et al. (2007) Learn Mem 14:416-421). In the present report, we studied the distribution of the MF system within the hippocampus of naïve, untrained, G-NonP mouse. In WT mice, the MF projection was restricted to the stratum lucidum of CA3 with no detectable MF innervation in distal stratum oriens (dSO). In G-NonP mice, in contrast, there was an ectopic projection terminating in the CA3 dSO. Unexpectedly, there was nearly a complete loss of immunostaining for the axonal marker Tau1 in the G-NonP transgenic mice in the MF terminal fields indicating that transgenesis itself leads to off-target consequences (Routtenberg (1996) Trends Neurosci 19:471-472). Because transgenic mice overexpressing nonmutated, wild type GAP-43 do not show this ectopic growth (Rekart et al., in press) and the G-NonP mice overexpress a mutated form of GAP-43 precluding its phosphorylation by protein kinase C (PKC), the possibility exists that permanently dephosphorylated GAP-43 disrupts normal axonal fasciculation which gives rise to the ectopic growth into dSO.

Daily Physical Activity Among Toddlers: Hip and Wrist Accelerometer Assessments.

Physical activity (PA) habits seem to track over time from as young as early childhood. For children under age 3 years, wearable sensor-measured PA levels have begun to be investigated. The aims of this study were to evaluate the feasibility of using hip- vs. wrist-worn accelerometers, and to report accelerometer-derived PA metrics among toddlers. A convenience sample of 22 toddlers aged 13 to 35 months and their mothers were recruited for this study. ActiGraph wGT3X-BT accelerometers were attached to wrist bands and waist belts. The mothers were asked to affix a wrist band and a waist belt to their participating children during waking hours for four days. They also completed an acceptability survey. Of the 22 toddlers, 19 (86%) had ≥ 3 valid days of hip data, while only 14 (64%) did so for wrist data (p = 0.16). In terms of acceptability, 18 mothers (82%) responded that the 4-day hip wear was easy, while only 13 (59%) responded that the 4-day wrist wear was easy (p = 0.19). Daily light-intensity PA (LPA) was on average 161 min, and daily moderate- and vigorous-intensity PA (MVPA) was on average 47 min, as determined using published hip accelerometer cut-points. There were no significant differences in LPA or MVPA by age or by sex. In conclusion, this study suggests that hip placement of an ActiGraph accelerometer is more feasible than wrist placement among toddlers.

GAP-43 gene expression regulates information storage.

Previous reports have shown that overexpression of the growth- and plasticity-associated protein GAP-43 improves memory. However, the relation between the levels of this protein to memory enhancement remains unknown. Here, we studied this issue in transgenic mice (G-Phos) overexpressing native, chick GAP-43. These G-Phos mice could be divided at the behavioral level into "spatial bright" and "spatial dull" groups based on their performance on two hidden platform water maze tasks. G-Phos dull mice showed both acquisition and retention deficits on the fixed hidden platform task, but were able to learn a visible platform task. G-Phos bright mice showed memory enhancement relative to wild type on the more difficult movable hidden platform spatial memory task. In the hippocampus, the G-Phos dull group showed a 50% greater transgenic GAP-43 protein level and a twofold elevated transgenic GAP-43 mRNA level than that measured in the G-Phos bright group. Unexpectedly, the dull group also showed an 80% reduction in hippocampal Tau1 staining. The high levels of GAP-43 seen here leading to memory impairment find its histochemical and behavioral parallel in the observation of Rekart et al. (Neuroscience 126: 579-584) who described elevated levels of GAP-43 protein in the hippocampus of Alzheimer's patients. The present data suggest that moderate overexpression of a phosphorylatable plasticity-related protein can enhance memory, while excessive overexpression may produce a "neuroplasticity burden" leading to degenerative and hypertrophic events culminating in memory dysfunction.

Stochasticity, individuality and behavior.

No two individuals are exactly alike. More than a simple platitude, this observation reflects the fundamentally stochastic nature of biological systems. The term 'stochastic' describes features that cannot be predicted a priori from readily measurable variables. In the dichotomous framework in which biological variation arises from genetic or environmental effects, stochastic effects are classified as environmental because they are not passed on to offspring - any non-heritable cause is, by definition, environmental. But non-heritable effects can be subdivided into those which can be predicted from measurable variables, and those that cannot. These latter effects are stochastic.

Expansion and retraction of hippocampal mossy fibers during postweaning development: strain-specific effects of NMDA receptor blockade.

We have recently discovered differences in the distribution of the mossy fiber terminal field (MFTF) between adult Long-Evans rats (LER) and Wistar rats(WR): the suprapyramidal MFTF extends into distal stratum oriens (dSO) in LER, but is nearly absent in WR (Holahan et al.,2006, Hippocampus 16:560-570). To our knowledge, there is no developmental evidence that sheds light on how this strain-dependent MFTF innervation in the adult is achieved. Accordingly, the present study examined the time course of MFTF development from postnatal days 0 to 40 and the effect of NMDA-receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) on this developmental organization. In both LER and WR, a MFTF projection to dSO was observed between P18 and P21. By P24, the dSO projection in WR was no longer detectable whereas in LER, the dSO projection seen on P21 remained. We suggest that in WR a retraction of the MFTF projection from dSO to stratum lucidum between P21 and P24 leads to its adult pattern. In WR, CPP administration enhanced the dSO projection, possibly by blocking the retraction process. In LER, CPP administration reduced the dSO projection. Thus, in each strain, NMDA receptor blockade effectively reversed the developmental course of MFTF pattern of innervation. The present results lend strong support to the view that NMDA receptor regulation of input-dependent processes during development is of critical importance in promoting the motility and target selection of presynaptic MF axons. This regulation extends later into development than had previously been thought.