Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: The influence of maternal HPA function

In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother's ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1-21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54-63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring's ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring's ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the context of maternal HPA regulation. © 2014 Dinces, Romeo, McEwen and Tang.Link_to_subscribed_fulltex

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter- individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y ( NPY) is anxiolytic(1,2) and its release is induced by stress(3). NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories(4-6). Here we show that haplotype- driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype- driven NPY expression predicted higher emotion- induced activation of the amygdala, as well as diminished resiliency as assessed by pain/ stress- induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism ( SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter- individual variation in resiliency to stress, a risk factor for many diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62768/1/nature06858.pd

Multisite reliability of MR-based functional connectivity

Recent years have witnessed an increasing number of multisite MRI functional connectivity (fcMRI) studies. While multisite studies are an efficient way to speed up data collection and increase sample sizes, especially for rare clinical populations, any effects of site or MRI scanner could ultimately limit power and weaken results. Little data exists on the stability of functional connectivity measurements across sites and sessions. In this study, we assess the influence of site and session on resting state functional connectivity measurements in a healthy cohort of traveling subjects (8 subjects scanned twice at each of 8 sites) scanned as part of the North American Prodrome Longitudinal Study (NAPLS). Reliability was investigated in three types of connectivity analyses: (1) seed-based connectivity with posterior cingulate cortex (PCC), right motor cortex (RMC), and left thalamus (LT) as seeds; (2) the intrinsic connectivity distribution (ICD), a voxel-wise connectivity measure; and (3) matrix connectivity, a whole-brain, atlas-based approach assessing connectivity between nodes. Contributions to variability in connectivity due to subject, site, and day-of-scan were quantified and used to assess between-session (test-retest) reliability in accordance with Generalizability Theory. Overall, no major site, scanner manufacturer, or day-of-scan effects were found for the univariate connectivity analyses; instead, subject effects dominated relative to the other measured factors. However, summaries of voxel-wise connectivity were found to be sensitive to site and scanner manufacturer effects. For all connectivity measures, although subject variance was three times the site variance, the residual represented 60–80% of the variance, indicating that connectivity differed greatly from scan to scan independent of any of the measured factors (i.e., subject, site, and day-of-scan). Thus, for a single 5 min scan, reliability across connectivity measures was poor (ICC=0.07–0.17), but increases with increasing scan duration (ICC=0.21–0.36 at 25 min). The limited effects of site and scanner manufacturer support the use of multisite studies, such as NAPLS, as a viable means of collecting data on rare populations and increasing power in univariate functional connectivity studies. However, the results indicate that aggregation of fcMRI data across longer scan durations is necessary to increase the reliability of connectivity estimates at the single-subject level

Protocol for the proactive or reactive telephone smoking cessation support (PORTSSS) trial

Background: Telephone quit lines are accessible to many smokers and are used to engage motivated smokers to make quit attempts. Smoking cessation counselling provided via telephone can either be reactive (i.e. primarily involving the provision of evidence-based information), or proactive (i.e. primarily involving repeated, sequenced calls from and interaction with trained cessation counsellors). Some studies have found proactive telephone counselling more effective and this trial will investigate whether or not proactive telephone support for smoking cessation, delivered through the National Health Service (NHS) Smoking Helpline is more effective or cost-effective than reactive support. It will also investigate whether or not providing nicotine replacement therapy (NRT), in addition to telephone counselling, has an adjunctive impact on smoking cessation rates and whether or not this is cost effective. Methods: This will be a parallel group, factorial design RCT, conducted through the English national NHS Smoking Helpline which is run from headquarters in Glasgow. Participants will be smokers who call the helpline from any location in England and who wish to stop smoking. If 644 participants are recruited to four equally-sized trial groups (total sample size = 2576), the trial will have 90% power for detecting a treatment effect (Odds Ratio) of 1.5 for each of the two interventions: i) proactive versus reactive support and ii) the offer of NRT versus no offer. The primary outcome measure for the study is self-reported, prolonged abstinence from smoking for at least six months following an agreed quit date. A concurrent health economic evaluation will investigate the cost effectiveness of the two interventions when delivered via a telephone helpline. Discussion: The PORTSSS trial will provide high quality evidence to determine the most appropriate kind of counselling which should be provided via the NHS Smoking Helpline and also whether or not an additional offer of cost-free NRT is effective and cost effective for smoking cessation. Trial Registration: (clinicaltrials.gov): NCT0077594

Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial

Background: The use of nicotine replacement therapy before quitting smoking is called nicotine preloading. Standard smoking cessation protocols suggest commencing nicotine replacement therapy only on the first day of quitting smoking (quit day) aiming to reduce withdrawal symptoms and craving. However, other, more successful smoking cessation pharmacotherapies are used prior to the quit day as well as after. Nicotine preloading could improve quit rates by reducing satisfaction from smoking prior to quitting and breaking the association between smoking and reward. A systematic literature review suggests that evidence for the effectiveness of preloading is inconclusive and further trials are needed. Methods/Design: This is a study protocol for a multicenter, non-blinded, randomized controlled trial based in the United Kingdom, enrolling 1786 smokers who want to quit, funded by the National Institute for Health Research, Health Technology Assessment program, and sponsored by the University of Oxford. Participants will primarily be recruited through general practices and smoking cessation clinics, and randomized (1:1) either to use 21 mg nicotine patches, or not, for four weeks before quitting, whilst smoking as normal. All participants will be referred to receive standard smoking cessation service support. Follow-ups will take place at one week, four weeks, six months and 12 months after quit day. The primary outcome will be prolonged, biochemically verified six-month abstinence. Additional outcomes will include point prevalence abstinence and abstinence of four-week and 12-month duration, side effects, costs of treatment, and markers of potential mediators and moderators of the preloading effect. Discussion: This large trial will add substantially to evidence on the effectiveness of nicotine preloading, but also on its cost effectiveness and potential mediators, which have not been investigated in detail previously. A range of recruitment strategies have been considered to try and compensate for any challenges encountered in recruiting the large sample, and the multicentre design means that knowledge can be shared between recruitment teams. The pragmatic study design means that results will give a realistic estimate of the success of the intervention if it were to be rolled out as part of standard smoking cessation service practice. Trial registration: Current Controlled Trials ISRCTN33031001. Registered 27 April 2012

Phenological mismatch in Arctic-breeding shorebirds: Impact of snowmelt and unpredictable weather conditions on food availability and chick growth

The ecological consequences of climate change have been recognized in numerous species, with perhaps phenology being the most well-documented change. Phenological changes may have negative consequences when organisms within different trophic levels respond to environmental changes at different rates, potentially leading to phenological mismatches between predators and their prey. This may be especially apparent in the Arctic, which has been affected more by climate change than other regions, resulting in earlier, warmer, and longer summers. During a 7-year study near Utqiaġvik (formerly Barrow), Alaska, we estimated phenological mismatch in relation to food availability and chick growth in a community of Arctic-breeding shorebirds experiencing advancement of environmental conditions (i.e., snowmelt). Our results indicate that Arctic-breeding shorebirds have experienced increased phenological mismatch with earlier snowmelt conditions. However, the degree of phenological mismatch was not a good predictor of food availability, as weather conditions after snowmelt made invertebrate availability highly unpredictable. As a result, the food available to shorebird chicks that were 2–10 days old was highly variable among years (ranging from 6.2 to 28.8 mg trap−1 day−1 among years in eight species), and was often inadequate for average growth (only 20%–54% of Dunlin and Pectoral Sandpiper broods on average had adequate food across a 4-year period). Although weather conditions vary among years, shorebirds that nested earlier in relation to snowmelt generally had more food available during brood rearing, and thus, greater chick growth rates. Despite the strong selective pressure to nest early, advancement of nesting is likely limited by the amount of plasticity in the start and progression of migration. Therefore, long-term climatic changes resulting in earlier snowmelt have the potential to greatly affect shorebird populations, especially if shorebirds are unable to advance nest initiation sufficiently to keep pace with seasonal advancement of their invertebrate prey

The NANOGrav 12.5 yr Data Set: A Computationally Efficient Eccentric Binary Search Pipeline and Constraints on an Eccentric Supermassive Binary Candidate in 3C 66B

The radio galaxy 3C 66B has been hypothesized to host a supermassive black hole binary (SMBHB) at its center based on electromagnetic observations. Its apparent 1.05 yr period and low redshift (∼0.02) make it an interesting testbed to search for low-frequency gravitational waves (GWs) using pulsar timing array (PTA) experiments. This source has been subjected to multiple searches for continuous GWs from a circular SMBHB, resulting in progressively more stringent constraints on its GW amplitude and chirp mass. In this paper, we develop a pipeline for performing Bayesian targeted searches for eccentric SMBHBs in PTA data sets, and test its efficacy by applying it to simulated data sets with varying injected signal strengths. We also search for a realistic eccentric SMBHB source in 3C 66B using the NANOGrav 12.5 yr data set employing PTA signal models containing Earth term-only as well as Earth+pulsar term contributions using this pipeline. Due to limitations in our PTA signal model, we get meaningful results only when the initial eccentricity e 0 < 0.5 and the symmetric mass ratio η > 0.1. We find no evidence for an eccentric SMBHB signal in our data, and therefore place 95% upper limits on the PTA signal amplitude of 88.1 ± 3.7 ns for the Earth term-only and 81.74 ± 0.86 ns for the Earth+pulsar term searches for e 0 < 0.5 and η > 0.1. Similar 95% upper limits on the chirp mass are (1.98 ± 0.05) × 109 and (1.81 ± 0.01) × 109 M ☉. These upper limits, while less stringent than those calculated from a circular binary search in the NANOGrav 12.5 yr data set, are consistent with the SMBHB model of 3C 66B developed from electromagnetic observations