Respiration phase‐locks to fast stimulus presentations: Implications for the interpretation of posterior midline “deactivations”

The posterior midline region (PMR)—considered a core of the default mode network—is deactivated during successful performance in different cognitive tasks. The extent of PMR‐deactivations is correlated with task‐demands and associated with successful performance in various cognitive domains. In the domain of episodic memory, functional MRI (fMRI) studies found that PMR‐deactivations reliably predict learning (successful encoding). Yet it is unclear what explains this relation. One intriguing possibility is that PMR‐deactivations are partially mediated by respiratory artifacts. There is evidence that the fMRI signal in PMR is particularly prone to respiratory artifacts, because of its large surrounding blood vessels. As respiratory fluctuations have been shown to track changes in attention, it is critical for the general interpretation of fMRI results to clarify the relation between respiratory fluctuations, cognitive performance, and fMRI signal. Here, we investigated this issue by measuring respiration during word encoding, together with a breath‐holding condition during fMRI‐scanning. Stimulus‐locked respiratory analyses showed that respiratory fluctuations predicted successful encoding via a respiratory phase‐locking mechanism. At the same time, the fMRI analyses showed that PMR‐deactivations associated with learning were reduced during breath‐holding and correlated with individual differences in the respiratory phase‐locking effect during normal breathing. A left frontal region—used as a control region—did not show these effects. These findings indicate that respiration is a critical factor in explaining the link between PMR‐deactivation and successful cognitive performance. Further research is necessary to demonstrate whether our findings are restricted to episodic memory encoding, or also extend to other cognitive domains. Hum Brain Mapp 35:4932–4943, 2014. © 2014     

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact “lower is better,” with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed “less effective,” based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β₁-selective blocker and β₃- adrenoceptor agonist; β₃-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.     

Specialized Care of Women and Newborns Affected by Opioids With a CORE Team of Nurses

Staff on a mother–baby unit of a large suburban Level II facility identified the need to provide specialized nursing care to women affected by opioids. The manager of the unit recognized inconsistencies in care and frustration expressed by women and staff. She recruited a CORE (Champion for our Opiate patients using Respectful and Relevant Engagement and Education) group of staff nurses to care for these women. CORE nurses received specialized education and resources and served as the primary nurses for women admitted to the unit with a positive urine drug screening result or a history of drug use during pregnancy. Having a CORE team has brought a consistent approach when providing care to families affected by opioids.     

Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals

The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr_80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr_80–100 and SUVr_110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.     

Sex-Specific Mechanism of Social Hierarchy in Mice

The establishment of social hierarchies is a naturally occurring, evolutionarily conserved phenomenon with a well-established impact on fitness and health. Investigations of complex social group dynamics may offer novel opportunities for translational studies of autism spectrum disorder. Here we describe a robust behavioral paradigm using an automated version of the tube test. Isogenic groups of male and female mice establish linear social hierarchies that remain highly stable for at least 14 days, the longest interval tested. Remarkably, however, their social strategy is sex-specific: females primarily utilize intrinsic attributes, whereas males are strongly influenced by prior social experience. Using both genetic and pharmacological manipulations, we identify testosterone as a critical sex-specific factor for determining which social strategy is used. Males inheriting a null mutation of the sex-determining region Y (Sry) gene used a similar social cognitive strategy as females. In contrast, females with transgenic expression of Sry utilized a typically male social strategy. Analogously, castration of males and testosterone supplementation of females yielded similar outcomes, with a reversal of their social cognitive strategy. Together, our results demonstrate a sex-specific mechanism underlying social hierarchy, in which both males and females retain the functional capacity to adapt their social strategy. More generally, we expect the automated tube test to provide an important complementary approach for both fundamental and translational studies of social behavior.