The Interactive Role of Sleep and Circadian Rhythms in Episodic Memory in Older Adults.

Adequate sleep is essential for healthy physical, emotional, and cognitive functioning, including memory. However, sleep ability worsens with increasing age. Older adults on average have shorter sleep durations and more disrupted sleep compared with younger adults. Age-related sleep changes are thought to contribute to age-related deficits in episodic memory. Nonetheless, the nature of the relationship between sleep and episodic memory deficits in older adults is still unclear. Further complicating this relationship are age-related changes in circadian rhythms such as the shift in chronotype toward morningness and decreased circadian stability, which may influence memory abilities as well. Most sleep and cognitive aging studies do not account for circadian factors, making it unclear whether age-related and sleep-related episodic memory deficits are partly driven by interactions with circadian rhythms. This review will focus on age-related changes in sleep and circadian rhythms and evidence that these factors interact to affect episodic memory, specifically encoding and retrieval. Open questions, methodological considerations, and clinical implications for diagnosis and monitoring of age-related memory impairments are discussed.

Extending sleep to improve glycemia: The Family Routines Enhancing Adolescent Diabetes by Optimizing Management (FREADOM) randomized clinical trial protocol.

Sleep deficiencies amongst individuals with type 1 diabetes mellitus (T1DM) have been linked with dysregulated glycemic control and greater morbidities. Sleep extension (EXT) has been identified as a viable intervention target to improve adolescent outcomes. The intervention aims to emphasize collaborative work with families to engage in behaviors that increase the likelihood of the youth increasing their sleep duration consistently. This study will randomize up to 175 youth with T1DM and at least one caregiver to either an EXT intervention or a family routines support (FRS) consultation. It is hypothesized that the EXT condition will lead to improvements in sleep, which in turn, will contribute to improved glycemic control. The primary endpoint is improved glycemic control assessed via a continuous glucose monitor (CGM) to ascertain average glucose levels across a week, glycemic variability, and percent time in the target range at one month and HbA1c at three months. Analyses will control for co-morbid conditions, including sleep-disordered breathing and obesity. This study will provide the needed data to support addressing sleep as part of the standards of care in youth with T1DM.

How and Why the Choice of Success Criteria Can Impact Therapy Service Delivery: A Worked Example From a Psychological Therapy Service for Anxiety and Depression.

Background: Well-defined measures of therapeutic benefit are essential for evaluating therapies and services. However, there is no single gold standard for defining 'successful' outcomes. We therefore examined the potential impact of adopting different success criteria. Method: We analysed data for 7,064 patients undergoing psychological therapy in a single UK IAPT (Increasing Access to Psychological Therapy) Service, each patient being assessed for depression (PHQ-9) and anxiety (GAD-7) both at the start and end of treatment. Predictors of successful outcomes based on these measures were analysed separately for three different success criteria: based either on assessing clinically significant change, or reliable change, in depression and anxiety. Results: The choice of criteria had little bearing on which variables predicted successful outcomes. However, the direction of the relationship between initial PHQ-9 or GAD-7 score and outcome success reverses when the criteria used to judge success are changed: successful outcomes are less probable under clinically significant change criteria for patients entering the service with more severe depression and/or anxiety but are more probable for such patients under reliable change criteria. Conclusion: Relevant for clinicians, researchers, and policymakers, the choice of success criteria adopted can substantially change the incentives for patient selection into a therapy service. Our analysis highlights how the methods used to evaluate treatment outcomes could impact the priorities and organisation of therapeutic services, which could then impact on who is offered treatment. We recommend further investigations of success criteria in other conditions or treatments to determine the reproducibility of the effects we found.

Outdoor recreational activity experiences improve psychological wellbeing of military veterans with post-traumatic stress disorder: Positive findings from a pilot study and a randomised controlled trial.

TRIAL REGISTRATION: The authors confirm that all ongoing and related trials for this intervention are registered. The studies reported in this manuscript are registered as clinical trials at ISRCTN: Pilot ID- ISRCTN15325073 RCT ID- ISRCTN59395217.

Differences in sleep architecture according to body mass index in children with type 1 diabetes.

Slow wave sleep (SWS), or deep sleep, is thought to be the most restorative stage of sleep and may be of a particular interest in the pathophysiology of obesity. The aim of this study was to investigate differences in sleep architecture based on body mass index (BMI) among a pediatric population with type 1 diabetes mellitus (T1DM). We hypothesized that children with T1DM who are obese would have less SWS than those who are not obese. Of 105 children with T1DM (mean age 13.54 years, 49.5% females) in this study, 19% were obese, 22% were overweight, and 59% had a normal BMI (81% non-obese). The overall SWS% among the participants was 13.2%. In contrast to our hypothesis, there was no significant difference in SWS% between obese and non-obese participants. However, the percent of time spent in rapid eye movement (REM) sleep among obese participants was significantly lower than those who were not obese (P = .022), which remained after adjusting the result for multiple covariates. While we found no significant association between the SWS time and BMI, obese adolescents with T1DM spent less time in REM sleep than those who were not obese. This study adds to the growing body of evidence supporting the importance of addressing sleep in clinical care of youth with T1DM.

Computational and neural signatures of pre and post-sensory expectation bias in inferior temporal cortex.

As we gather noisy sensory information from the environment, prior knowledge about the likely cause(s) of sensory input can be leveraged to facilitate perceptual judgments. Here, we investigated the computational and neural manifestation of cued expectations in human subjects as they performed a probabilistic face/house discrimination task in which face and house stimuli were preceded by informative or neutral cues. Drift-diffusion modeling of behavioral data showed that cued expectations biased both the baseline (pre-sensory) and drift-rate (post-sensory) of evidence accumulation. By employing a catch-trial functional MRI design we were able to isolate neural signatures of expectation during pre- and post-sensory stages of decision processing in face- and house-selective areas of inferior temporal cortex (ITC). Cue-evoked timecourses were modulated by cues in a manner consistent with a pre-sensory prediction signal that scaled with probability. Sensory-evoked timecourses resembled a prediction-error signal, greater in magnitude for surprising than expected stimuli. Individual differences in baseline and drift-rate biases showed a clear mapping onto pre- and post-sensory fMRI activity in ITC. These findings highlight the specificity of perceptual expectations and provide new insight into the convergence of top-down and bottom-up signals in ITC and their distinct interactions prior to and during sensory processing.

A 26-week, randomized trial of insulin detemir versus NPH insulin in children and adolescents with type 2 diabetes (iDEAt2).

There are limited studies evaluating the safety and efficacy of treatments in young people with type 2 diabetes (T2D). This study compared the efficacy and safety of insulin detemir versus neutral protamine Hagedorn (NPH) insulin, both in combination with metformin and lifestyle intervention, in children and adolescents with T2D. This randomized, open-label, phase 3 trial recruited patients (n = 42) aged 10-17 years diagnosed with T2D already receiving metformin ± other oral antidiabetic drugs ± basal insulin. Patients were randomized (1:1) to receive either insulin detemir or NPH insulin, both with the maximum tolerated dose of metformin, and lifestyle intervention, over 26 weeks. Enrollment terminated prematurely after 17 months due to a very slow recruitment rate (12% of the target met). After 26 weeks, the observed mean HbA1c value had decreased by 0.61% points in the insulin detemir group vs. 0.84% points in the NPH insulin group. The rate of symptomatic blood glucose-confirmed hypoglycemic episodes was 0.4 episodes/patient-year of exposure (PYE) for insulin detemir vs. 1.1 episodes/PYE for NPH insulin. CONCLUSION: No safety issues were revealed with either basal insulin. Due to the low number of patients recruited, no efficacy conclusions could be drawn. ClinicalTrials.gov identifier: NCT02131272. What is known: • There is a growing worldwide epidemic of type 2 diabetes in children and adolescents. • There is a lack of research and limited treatment options currently available in this population. What is new: • No safety issues with insulin detemir or neutral protamine Hagedorn insulin in children and adolescents with type 2 diabetes were observed. • Improving clinical trial recruitment, along with providing early, efficacious, and safe treatment options, in this population is critical.

Effect of cardiometabolic risk factors on the relationship between adiposity and bone mass in girls.

BACKGROUND/OBJECTIVE: Childhood obesity has been separately associated with cardiometabolic risk factors (CMRs) and increased risk of fracture. However, both augmented and compromised bone mass have been reported among overweight/obese children. Metabolic dysfunction, often co-existing with obesity, may explain the discrepancy in previous studies. The aim of this study was to examine whether the relationship between adiposity and dual-energy X-ray absorptiometry (DXA) derived bone mass differed in young girls with and without CMR(s). SUBJECTS/METHODS: Whole-body bone and body composition measures by DXA and measures of CMR (fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic and diastolic blood pressure, waist circumference (WC)) were obtained from 307, 9- to 12-year-old girls. Girls with 1 or ≥ 2 CMR(s) were considered to be at risk (vs. no CMR). Multiple linear regression was used to test the relationship of total fat mass with total body bone mineral content (BMC) after controlling for height, lean mass, CMR risk, and other potential confounders. RESULTS: There was a significant interaction between CMR risk and total body fat mass. When girls were stratified by CMR group, all groups had a significant positive relationship between fat mass and BMC (p < 0.05), however, girls with ≥ 2 CMRs had a lower BMC for a given level of body fat. Total body fat was not significantly related to bone mineral density (p > 0.05). CONCLUSION: Fat mass has a positive relationship with BMC even after controlling for lean mass. However, the positive relationship of fat mass with BMC may be attenuated if multiple CMRs are present.

Relative contributions of lean and fat mass to bone strength in young Hispanic and non-Hispanic girls.

BACKGROUND: With the high prevalence of childhood obesity, especially among Hispanic children, understanding how body weight and its components of lean and fat mass affect bone development is important, given that the amount of bone mineral accrued during childhood can determine osteoporosis risk later in life. The aim of this study was to assess the independent contributions of lean and fat mass on volumetric bone mineral density (vBMD), geometry, and strength in both weight-bearing and non-weight-bearing bones of Hispanic and non-Hispanic girls. METHODS: Bone vBMD, geometry, and strength were assessed at the 20% distal femur, the 4% and 66% distal tibia, and the 66% distal radius of the non-dominant limb of 326, 9- to 12-year-old girls using peripheral quantitative computed tomography (pQCT). Total body lean and fat mass were measured by dual-energy x-ray absorptiometry (DXA). Multiple linear regression was used to assess the independent relationships of fat and lean mass with pQCT bone measures while adjusting for relevant confounders. Potential interactions between ethnicity and both fat and lean mass were also tested. RESULTS: Lean mass was a significant positive contributor to all bone outcomes (p < 0.05) with the exception of vBMD at diaphyseal sites. Fat mass was a significant contributor to bone strength at weight bearing sites, but did not significantly contribute to bone strength at the non-weight bearing radius and was negatively associated with radius cortical content and thickness. Bone measures did not significantly differ between Hispanic and non-Hispanic girls, although there was a significant interaction between ethnicity and fat mass with total bone area at the femur (p = 0.02) and 66% tibia (p = 0.005) as well as bone strength at the femur (p = 0.03). CONCLUSION: Lean mass is the main determinant of bone strength for appendicular skeletal sites. Fat mass contributes to bone strength in the weight-bearing skeleton but does not add to bone strength in non-weight-bearing locations and may potentially be detrimental. Bone vBMD, geometry, and strength did not differ between Hispanic and non-Hispanic girls; fat mass may be a stronger contributor to bone strength in weight-bearing bones of Hispanic girls compared to non-Hispanic.

Physical Activity and Cognition: A Mediating Role of Efficient Sleep.

OBJECTIVE: Physical activity benefits executive control, but the mechanism through which this benefit occurs is unclear. Sleep is a candidate mechanism given that it improves with exercise and has restorative effects on the prefrontal cortex. The present cross-sectional study examined the mediating role of sleep in the relationship between physical activity and executive control in young and older adults. PARTICIPANTS: Young (n = 59) and older (n = 53) community-dwelling adults ages 21-30 and 55-80. METHODS: Participants wore an accelerometer for one week to assess sleep efficiency, total sleep time, and physical activity, operationalized as metabolic equivalent of task (METs) during time spent awake. Cognition was assessed in the laboratory across multiple measures of executive control, memory recall, and processing speed. Mediation analyses tested the role of sleep efficiency in the cross-sectional relationship between METs and cognitive performance accounting for age, sex, and education. RESULTS: METs were significantly associated with performance before, but not after accounting for covariates. METs were associated with sleep efficiency but not total sleep time. Sleep efficiency, but not total sleep time, mediated the relationship between METs and working memory, switching, verbal ability and fluency, and recall. Age group did not moderate the mediating role of sleep efficiency in the relationship between METs and performance. CONCLUSION: Sleep efficiency is one pathway by which physical activity may be associated with executive control across young and older adults.

Cortical Networks Involved in Memory for Temporal Order.

We examined the neurobiological basis of temporal resetting, an aspect of temporal order memory, using a version of the delayed-match-to-multiple-sample task. While in an fMRI scanner, participants evaluated whether an item was novel or whether it had appeared before or after a reset event that signified the start of a new block of trials. Participants responded "old" to items that were repeated within the current block and "new" to both novel items and items that had last appeared before the reset event (pseudonew items). Medial-temporal, prefrontal, and occipital regions responded to absolute novelty of the stimulus-they differentiated between novel items and previously seen items, but not between old and pseudonew items. Activation for pseudonew items in the frontopolar and parietal regions, in contrast, was intermediate between old and new items. The posterior cingulate cortex extending to precuneus was the only region that showed complete temporal resetting, and its activation reflected whether an item was new or old according to the task instructions regardless of its familiarity. There was also a significant Condition (old/pseudonew) × Familiarity (second/third presentations) interaction effect on behavioral and neural measures. For pseudonew items, greater familiarity decreased response accuracy, increased RTs, increased ACC activation, and increased functional connectivity between ACC and the left frontal pole. The reverse was observed for old items. On the basis of these results, we propose a theoretical framework in which temporal resetting relies on an episodic retrieval network that is modulated by cognitive control and conflict resolution.

Detecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells.

Genetic changes in human pluripotent stem cells (hPSCs) gained during culture can confound experimental results and potentially jeopardize the outcome of clinical therapies. Particularly common changes in hPSCs are trisomies of chromosomes 1, 12, 17, and 20. Thus, hPSCs should be regularly screened for such aberrations. Although a number of methods are used to assess hPSC genotypes, there has been no systematic evaluation of the sensitivity of the commonly used techniques in detecting low-level mosaicism in hPSC cultures. We have performed mixing experiments to mimic the naturally occurring mosaicism and have assessed the sensitivity of chromosome banding, qPCR, fluorescence in situ hybridization, and digital droplet PCR in detecting variants. Our analysis highlights the limits of mosaicism detection by the commonly employed methods, a pivotal requirement for interpreting the genetic status of hPSCs and for setting standards for safe applications of hPSCs in regenerative medicine.

Neural signatures of experience-based improvements in deterministic decision-making.

Feedback about our choices is a crucial part of how we gather information and learn from our environment. It provides key information about decision experiences that can be used to optimize future choices. However, our understanding of the processes through which feedback translates into improved decision-making is lacking. Using neuroimaging (fMRI) and cognitive models of decision-making and learning, we examined the influence of feedback on multiple aspects of decision processes across learning. Subjects learned correct choices to a set of 50 word pairs across eight repetitions of a concurrent discrimination task. Behavioral measures were then analyzed with both a drift-diffusion model and a reinforcement learning model. Parameter values from each were then used as fMRI regressors to identify regions whose activity fluctuates with specific cognitive processes described by the models. The patterns of intersecting neural effects across models support two main inferences about the influence of feedback on decision-making. First, frontal, anterior insular, fusiform, and caudate nucleus regions behave like performance monitors, reflecting errors in performance predictions that signal the need for changes in control over decision-making. Second, temporoparietal, supplementary motor, and putamen regions behave like mnemonic storage sites, reflecting differences in learned item values that inform optimal decision choices. As information about optimal choices is accrued, these neural systems dynamically adjust, likely shifting the burden of decision processing from controlled performance monitoring to bottom-up, stimulus-driven choice selection. Collectively, the results provide a detailed perspective on the fundamental ability to use past experiences to improve future decisions.

Content-specific evidence accumulation in inferior temporal cortex during perceptual decision-making.

During a perceptual decision, neuronal activity can change as a function of time-integrated evidence. Such neurons may serve as decision variables, signaling a choice when activity reaches a boundary. Because the signals occur on a millisecond timescale, translating to human decision-making using functional neuroimaging has been challenging. Previous neuroimaging work in humans has identified patterns of neural activity consistent with an accumulation account. However, the degree to which the accumulating neuroimaging signals reflect specific sources of perceptual evidence is unknown. Using an extended face/house discrimination task in conjunction with cognitive modeling, we tested whether accumulation signals, as measured using functional magnetic resonance imaging (fMRI), are stimulus-specific. Accumulation signals were defined as a change in the slope of the rising edge of activation corresponding with response time (RT), with higher slopes associated with faster RTs. Consistent with an accumulation account, fMRI activity in face- and house-selective regions in the inferior temporal cortex increased at a rate proportional to decision time in favor of the preferred stimulus. This finding indicates that stimulus-specific regions perform an evidence integrative function during goal-directed behavior and that different sources of evidence accumulate separately. We also assessed the decision-related function of other regions throughout the brain and found that several regions were consistent with classifications from prior work, suggesting a degree of domain generality in decision processing. Taken together, these results provide support for an integration-to-boundary decision mechanism and highlight possible roles of both domain-specific and domain-general regions in decision evidence evaluation.

The strength of gradually accruing probabilistic evidence modulates brain activity during a categorical decision.

The evolution of neural activity during a perceptual decision is well characterized by the evidence parameter in sequential sampling models. However, it is not known whether accumulating signals in human neuroimaging are related to the integration of evidence. Our aim was to determine whether activity accumulates in a nonperceptual task by identifying brain regions tracking the strength of probabilistic evidence. fMRI was used to measure whole-brain activity as choices were informed by integrating a series of learned prior probabilities. Participants first learned the predictive relationship between a set of shape stimuli and one of two choices. During scanned testing, they made binary choices informed by the sum of the predictive strengths of individual shapes. Sequences of shapes adhered to three distinct rates of evidence (RoEs): rapid, gradual, and switch. We predicted that activity in regions informing the decision would modulate as a function of RoE prior to the choice. Activity in some regions, including premotor areas, changed as a function of RoE and response hand, indicating a role in forming an intention to respond. Regions in occipital, temporal, and parietal lobes modulated as a function of RoE only, suggesting a preresponse stage of evidence processing. In all of these regions, activity was greatest on rapid trials and least on switch trials, which is consistent with an accumulation-to-boundary account. In contrast, activity in a set of frontal and parietal regions was greatest on switch and least on rapid trials, which is consistent with an effort or time-on-task account.

Role of sleep continuity and total sleep time in executive function across the adult lifespan.

The importance of sleep for cognition in young adults is well established, but the role of habitual sleep behavior in cognition across the adult life span remains unknown. We examined the relationship between sleep continuity and total sleep time as assessed with a sleep-detection device, and cognitive performance using a battery of tasks in young (n = 59, mean age = 23.05) and older (n = 53, mean age = 62.68) adults. Across age groups, higher sleep continuity was associated with better cognitive performance. In the younger group, higher sleep continuity was associated with better working memory and inhibitory control. In the older group, higher sleep continuity was associated with better inhibitory control, memory recall, and verbal fluency. Very short and very long total sleep time was associated with poorer working memory and verbal fluency, specifically in the younger group. Total sleep time was not associated with cognitive performance in any domains for the older group. These findings reveal that sleep continuity is important for executive function in both young and older adults, but total sleep time may be more important for cognition in young adults.

Prior probability and feature predictability interactively bias perceptual decisions.

Anticipating a forthcoming sensory experience facilitates perception for expected stimuli but also hinders perception for less likely alternatives. Recent neuroimaging studies suggest that expectation biases arise from feature-level predictions that enhance early sensory representations and facilitate evidence accumulation for contextually probable stimuli while suppressing alternatives. Reasonably then, the extent to which prior knowledge biases subsequent sensory processing should depend on the precision of expectations at the feature level as well as the degree to which expected features match those of an observed stimulus. In the present study we investigated how these two sources of uncertainty modulated pre- and post-stimulus bias mechanisms in the drift-diffusion model during a probabilistic face/house discrimination task. We tested several plausible models of choice bias, concluding that predictive cues led to a bias in both the starting-point and rate of evidence accumulation favoring the more probable stimulus category. We further tested the hypotheses that prior bias in the starting-point was conditional on the feature-level uncertainty of category expectations and that dynamic bias in the drift-rate was modulated by the match between expected and observed stimulus features. Starting-point estimates suggested that subjects formed a constant prior bias in favor of the face category, which exhibits less feature-level variability, that was strengthened or weakened by trial-wise predictive cues. Furthermore, we found that the gain on face/house evidence was increased for stimuli with less ambiguous features and that this relationship was enhanced by valid category expectations. These findings offer new evidence that bridges psychological models of decision-making with recent predictive coding theories of perception.