Subcostal versus right lateral ultrasound measurements of inferior vena cava: Measurements obtained from these two views are not equivalent in non-ICU patients.

Objective: The objective of this study is to assess concordance between the subcostal and right lateral view for ultrasonographic inferior vena cava measurements including the end-inspiratory diameter, end-expiratory diameter and respiratory variation represented by the caval index in spontaneously breathing healthy adults. Methods: We recruited a convenience sample of 33 healthy adults. A phased array ultrasound probe was used to obtain inferior vena cava measurements from a subcostal view in the sagittal plane and from a right lateral view in the coronal plane with B-mode ultrasound. End-inspiratory diameter, end-expiratory diameter and caval index were obtained for each view. A two-tailed t-test was performed to compare the caval indices obtained by the two views. Bland-Altman analysis was used to obtain the limits of agreement for the inferior vena cava diameter and caval index across the two views. Results: Subcostal and right lateral caval indices across all participants were significantly different according to a paired t-test (p < 0.0001). The Bland-Altman analysis showed wide limits of agreement in end-inspiratory diameter (-0.97 and 0.50 cm) and in end-expiratory diameter (-0.94 and 0.90 cm). The right lateral view underestimated the inferior vena cava caval index relative to the subcostal view. Conclusions: The subcostal and right lateral views are not equivalent in obtaining inferior vena cava measurements in spontaneously breathing healthy adults. Current cut-off values for measurement-based applications of inferior vena cava ultrasound, including fluid responsiveness using caval indices, may not be accurate when values are obtained from the right lateral view in the coronal plane of the inferior vena cava in patients.

Lesion-induced sprouting promotes neurophysiological integration of septal and entorhinal inputs to granule cells in the dentate gyrus of rats.

Axonal sprouting of dentate gyrus (DG) afferents after entorhinal cortex (EC) lesion is a model preparation to assess lesion-induced functional reorganization in a denervated target structure. Following a unilateral EC lesion, the surviving contralateral entorhinal projection, termed the crossed temporodentate pathway (CTD), and the heterotypic septal input to the DG, the septodentate pathway (SD), undergo extensive axonal sprouting. We explored whether EC lesion alters the capacity of the SD pathway to influence CTD-evoked granule cell excitability in the DG. We recorded extracellular field excitatory postsynaptic potentials (fEPSPs) after CTD stimulation alone and paired SD-CTD stimulation. Male rats were given unilateral EC lesions or sham operations; evoked fEPSPs in the DG were recorded at 4-, 15-, and 90-days post-entorhinal lesion to assess functional reorganization of the CTD and SD pathways. We found significantly increased fEPSP amplitudes in cases with unilateral lesions compared to sham-operates at 15- and 90-days post lesion. Within each time point, paired SD-CTD stimulation resulted in significantly depressed fEPSP amplitudes compared to amplitudes evoked after CTD stimulation alone and this effect was solely seen in cases with EC lesion. In cases where granule cell discharge was observed, SD stimulation increased discharge amplitude elicited by the CTD stimulation at 90-days postlesion. These findings demonstrate that synaptic remodeling following unilateral cortical lesion results in a synergistic interaction between two established hippocampal afferents that is not seen in uninjured brains. This work may be important for models of neurodegenerative disease and neural injury that target these structures and associated hippocampal circuitry.

Racial disparities in sleep-related cardiac function in young, healthy adults: implications for cardiovascular-related health.

STUDY OBJECTIVES: Considerable evidence shows that individuals from marginalized racial/ethnic groups in the United States experience greater rates of sleep disturbance and cardiovascular complications. Because sleep is a modifiable factor that is critically involved in cardiovascular health, improved understanding of the association between sleep and cardiovascular health during early adulthood can prevent cardiovascular disparities. This study examined racial/ethnic differences in cardiovascular function during sleep using heart rate and heart-rate-variability analyses. METHODS: Participants in this laboratory-based sleep study included healthy, "good sleepers" who were in early adulthood and resided in the United States at the time of participation (14 non-Hispanic Black [NHB; age = 30.9 (6.6), 57% female], 12 Asian [Asian, age = 26.0 (5.2), 42% female], and 24 non-Hispanic white [NHW; age = 24.6 (5.8), 79% female]). RESULTS: After adjusting for demographic factors and an apnea-hypopnea index, we found significantly higher heart rate within NREM Stage 2 (N2) (b = -22.6, p = .04) and REM sleep (b = -25.8, p =.048) and lower heart rate variability during N2 sleep (b = -22.6, p = .04) among NHB individuals compared with NHW individuals. Furthermore, NHB and Asian participants demonstrated significantly lower percent of time in slow wave sleep (SWS) compared with NHW participants (NHB: b = -22.6, p =.04; Asian: b = -22.6, p = .04). Individuals' percent of time in SWS significantly mediated differences in heart rate during N2 (indirect = 0.94, 95% CI [0.03, 2.68]) and REM sleep (indirect = 1.02, 95% CI [0.04, 3.04]). CONCLUSIONS: Our results showed disparities in sleep-related cardiovascular function in early adulthood that are mediated by SWS. These data suggest targeting sleep health in early adulthood might help reduce cardiovascular disease burden on individuals from marginalized groups.

Experimental sleep disruption attenuates morphine analgesia: findings from a randomized trial and implications for the opioid abuse epidemic.

Preclinical studies demonstrate that sleep disruption diminishes morphine analgesia and modulates reward processing. We sought to translate these preclinical findings to humans by examining whether sleep disruption alters morphine's analgesic and hedonic properties. We randomized 100 healthy adults to receive morphine versus placebo after two nights of undisturbed sleep (US) and two nights of forced awakening (FA) sleep disruption. Sleep conditions were counterbalanced, separated by a two-week washout. The morning after both sleep conditions, we tested cold pressor pain tolerance before and 40-min after double-blind injection of .08 mg/kg morphine or placebo. The primary outcome was the analgesia index, calculated as the change in cold pressor hand withdrawal latency (HWL) before and after drug injection. Secondary outcomes were ratings of feeling "high," drug "liking," and negative drug effects. We found a significant sleep condition by drug interaction on the analgesia index (95% CI - 0.57, - 0.001). After US, subjects receiving morphine demonstrated significantly longer HWL compared to placebo (95% CI 0.23, 0.65), but not after FA (95% CI - 0.05, 0.38). Morphine analgesia was diminished threefold under FA, relative to US. After FA, females (95% CI - 0.88, - 0.05), but not males (95% CI - 0.23, 0.72), reported decreased subjective "high" effects compared to US. After FA, females (95% CI 0.05, 0.27), but not males (95% CI - 0.10, 0.11), administered morphine reported increased negative drug effects compared to US. These data demonstrate that sleep disruption attenuates morphine analgesia in humans and suggest that sleep disturbed males may be at greatest risk for problematic opioid use.

Experimental sleep disruption and reward learning: moderating role of positive affect responses.

STUDY OBJECTIVES: Sleep disturbances increase vulnerability for depression, but the mechanisms underlying this relationship are not well known. We investigated the effects of experimental sleep disruption on response bias (RB), a measure of reward learning previously linked to depression, and the moderating role of positive affect responses. METHODS: Participants (N = 42) were healthy adults enrolled in a within-subject crossover sleep disruption experiment that incorporated one night of uninterrupted sleep (US) and one night of forced awakenings (FA) in random order. On the day following each experimental sleep night, participants completed a probabilistic reward task to assess RB, and the Positive and Negative Affect Schedule-X. Participants were subgrouped according to positive affect responses: Preserved Positive Affect (i.e. positive affect scores maintained or increased; n = 15) or Reduced Positive Affect (i.e. positive affect scores decreased; n = 27) following FA. RESULTS: Contrary to our hypotheses, across participants, RB did not significantly differ between the US and FA sleep conditions (p = .67). However, the effect of sleep condition on RB was moderated by positive affect response (p = .01); those with preserved positive affect showed heightened RB following FA, whereas those with reduced positive affect showed diminished RB following FA. Changes in negative affect between US and FA did not moderate RB. CONCLUSION: The inability to preserve positive affect through periods of sleep disruption may be a marker of diminished reward learning capability. Understanding how sleep disruption impacts positive affect responses and reward learning identifies a pathway by which sleep disturbances may confer risk for depression.

Sex differences in measures of central sensitization and pain sensitivity to experimental sleep disruption: implications for sex differences in chronic pain.

Study Objectives: Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Methods: Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. Results: FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Conclusions: Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

Sleep, Pain Catastrophizing, and Central Sensitization in Knee Osteoarthritis Patients With and Without Insomnia.

OBJECTIVE: Osteoarthritis (OA), a chronic degenerative joint disorder, is characterized by joint pain. Emerging research demonstrates that a significant number of patients evidence central sensitization (CS), a hyperexcitability in nociceptive pathways, which is known to amplify and maintain clinical pain. The clinical correlates of CS in OA, however, are poorly understood. Insomnia is prevalent in older adults with OA, and recent experiments suggest associations between poor sleep and measures of CS. Catastrophizing, a potent predictor of pain outcomes, has also been associated with CS, but few studies have investigated possible interactions between catastrophizing, sleep, and CS. METHODS: We conducted a case-control study of 4 well-characterized groups of adults with insomnia and/or knee OA. A total of 208 participants completed multimodal sleep assessments (questionnaire, diary, actigraphy, and polysomnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between CS, catastrophizing, and insomnia. Descriptive characterization of each measure is presented, with specific focus on sleep efficiency and CS. RESULTS: The knee OA-insomnia group demonstrated the greatest degree of CS compared to controls. In the overall sample, we found that catastrophizing moderated the relationship between sleep efficiency and CS. Specifically those with low sleep efficiency and high catastrophizing scores reported increased levels of CS. In addition, CS was significantly associated with increased clinical pain. CONCLUSION: These findings highlight the importance of assessing sleep efficiency, CS, and catastrophizing in chronic pain patients and have important clinical implications for treatment planning.

Cognitive-behavioral therapy for insomnia in knee osteoarthritis: a randomized, double-blind, active placebo-controlled clinical trial.

OBJECTIVE: Insomnia is prevalent among patients with knee osteoarthritis (OA). Research indicates that sleep disruption may amplify clinical pain by altering central pain modulation, suggesting that treatment of insomnia may improve pain. The aims of this study were to evaluate the efficacy of cognitive-behavioral therapy for insomnia (CBT-I) in patients with knee OA, to determine whether improvements in sleep predict reduced pain, and to determine whether alterations in pain modulation mediate improvements in clinical pain. METHODS: We conducted a randomized, double-blind, active placebo-controlled clinical trial of CBT-I in 100 patients with knee OA and insomnia (mean ± SD age 59.4 ± 9.5 years). Patients were randomized (1:1) to receive either 8 sessions of CBT-I or behavioral desensitization (placebo). We conducted in-home polysomnography (PSG), diary assessment, and sensory tests of pain modulation at baseline, posttreatment, 3 months, and 6 months. RESULTS: Intent-to-treat analyses demonstrated substantial improvement in sleep in both groups of patients. Patients in the CBT-I group had significantly greater reductions in wake after sleep onset (WASO), as measured by patient diary and PSG. Patients in both groups reported significant and comparable reductions in pain over 6 months, with one-third reporting a 30% reduction in pain severity. Baseline-to-posttreatment reductions in WASO as measured by diary and PSG predicted subsequent decreases in clinical pain. This effect was significantly greater for CBT-I compared with behavioral desensitization. No significant changes in laboratory measures of pain modulation were observed. CONCLUSION: Compared with active placebo, CBT-I was efficacious in reducing sleep maintenance insomnia. CBT-I decreased clinical pain, but not pain modulation, suggesting that it has the potential to augment pain management in knee OA. Future work is needed to identify the mechanisms by which improved sleep reduces clinical pain.

Immunohistochemical characterization of axonal sprouting in mice.

PURPOSE: Transgenic manipulation of mouse physiology facilitates the preclinical study of genetic risk factors, neural plasticity, and reactive processes accompanying Alzheimer's disease. Alternatively, entorhinal cortex lesions (ECLs) model pathophysiological denervation and axonal sprouting in rat. Given reports of anatomical differences between the mouse and rat hippocampus, application of the ECL paradigm to transgenic mice first requires comprehensive characterization of axonal sprouting in the wild-type. METHODS: Adult male C57BL/6 mice sustained unilateral transections of the perforant pathway. Subjects were sacrificed at 1, 4, 10, 18, and 28 days postlesion, and hippocampal sections were stained for AChE, the postsynaptic terminal marker drebrin, and the presynaptic terminal proteins SNAP-25, GAP-43, synapsin, and synaptophysin. To examine synaptic turnover and reinnervation, ipsilateral-to-contralateral staining densities were determined within the dentate molecular layer, and shrinkage-corrected ratios were compared to 28 day-yoked sham cases. RESULTS: At 28 days postlesion, ipsilateral terminal marker densities exhibited significant depression. In contrast, qualitative analyses at earlier time points suggested altered AChE staining patterns and increased SNAP-25 and synapsin immunoreactivity in the inner molecular layer (IML) of the dentate gyrus. CONCLUSIONS: C57BL/6 mice exhibit synaptic reorganization following perforant path transections. The IML may provide a key target for evaluation and intervention in ECL mouse models.