Characterization of pulsations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging.

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics.

Characterization of oscillations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging.

Development of innovative non-invasive neuroimaging methods and biomarkers are critical for studying brain disease. In this work, we have developed a methodology to characterize the frequency responses and spatial localization of oscillations and movements of cerebrospinal fluid (CSF) flow in the human brain. Using 7 Tesla human MRI and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture CSF oscillations and movements. Physiological data was simultaneously collected and correlated with the 7T MR data. The primary components of CSF oscillations were identified using spectral analysis (with frequency bands identified around 0.3Hz, 1.2Hz and 2.4Hz) and were mapped spatially and temporally onto the MR image domain and temporally onto the physiological domain. The developed methodology shows a good consistency and repeatability (standard deviation of 0.052 and 0.078 for 0.3Hz and 1.2Hz bands respectively) in-vivo for potential brain dynamics and CSF flow and clearance studies.

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.

Cardiometabolic function in retired night shift workers and retired day workers.

Night shift work is associated with poor cardiometabolic outcomes, even post-retirement. However, the characteristics of cardiometabolic function in retired night shift workers (RNSW) compared to retired day workers (RDW) are not well-understood. Rigorous characterization of cardiometabolic dysfunction in RNSW and RDW will inform targeted risk stratification for RNSW. This observational study evaluated whether RNSW (n = 71) had poorer cardiometabolic function than RDW (n = 83). We conducted a multimodal assessment of cardiometabolic function including metabolic syndrome prevalence, brachial artery flow-mediated dilation, and carotid intima-media thickness. Main analyses tested overall group differences. Sex-stratified follow-up analyses tested group differences separately in men and women. RNSW had 2.6-times higher odds of metabolic syndrome prevalence than RDW in unadjusted analyses (95% CI [1.1,6.3]); this association was not significant when adjusting for age, race and education. RNSW and RDW (Mage = 68.4; 55% female) did not differ in percent flow-mediated dilation or carotid intima-media thickness. In sex-stratified analyses, women RNSW had 3.3-times higher odds of having high body mass index than women RDW (95% CI [1.2,10.4]). Men RNSW had 3.9-times higher odds of having high triglycerides than men RDW (95% CI [1.1,14.2]). No other group differences were observed. We found mixed evidence that night shift work exposure was associated with cardiometabolic dysfunction in retirement, possibly in a sex-specific manner.

Smart Phone/Ecological Momentary Assessment of Sleep and Daytime Symptoms Among Older Adults With Insomnia.

OBJECTIVES: To employ smart phone/ecological momentary assessment (EMA) methods to evaluate the impact of insomnia on daytime symptoms among older adults. DESIGN: Prospective cohort study SETTING: Academic medical center PARTICIPANTS: Twenty-nine older adults with insomnia (M age = 67.5 ± 6.6 years, 69% women) and 34 healthy sleepers (M age = 70.4 ± 5.6 years, 65% women). MEASUREMENTS: Participants wore an actigraph, completed daily sleep diaries, and completed the Daytime Insomnia Symptoms Scale (DISS) via smart phone 4x/day for 2 weeks (i.e., 56 survey administrations across 14 days). RESULTS: Relative to healthy sleepers, older adults with insomnia demonstrated more severe insomnia symptoms in all DISS domains (alert cognition, positive mood, negative mood, and fatigue/sleepiness). A series of mixed model analyses were performed using the Benjamini-Hochberg procedure for correcting false discovery rate (BH-FDR) and an adjusted p-value <0.05. Among older adults with insomnia, all five prior-night sleep diary variables (sleep onset latency, wake after sleep onset, sleep efficiency, total sleep time, and sleep quality) were significantly associated with next-day insomnia symptoms (i.e., all four DISS domains). The median, first and third quintiles of the effect sizes (R2) of the association analyses were 0.031 (95% confidence interval (CI: [0.011,0.432]), 0.042(CI: [0.014,0.270]), 0.091 (CI:[0.014,0.324]). CONCLUSION: Results support the utility of smart phone/EMA assessment among older adults with insomnia. Clinical trials incorporating smart phone/EMA methods, including EMA as an outcome measure, are warranted.

Effects of continuous positive airway pressure treatment on sleep architecture in adults with obstructive sleep apnea and type 2 diabetes.

Obstructive sleep apnea (OSA) severely impacts sleep and has long-term health consequences. Treating sleep apnea with continuous positive airway pressure (CPAP) not only relieves obstructed breathing, but also improves sleep. CPAP improves sleep by reducing apnea-induced awakenings. CPAP may also improve sleep by enhancing features of sleep architecture assessed with electroencephalography (EEG) that maximize sleep depth and neuronal homeostasis, such as the slow oscillation and spindle EEG activity, and by reducing neurophysiological arousal during sleep (i.e., beta EEG activity). We examined cross-sectional differences in quantitative EEG characteristics of sleep, assessed with power spectral analysis, in 29 adults with type 2 diabetes treated with CPAP and 24 adults undergoing SHAM CPAP treatment (total n = 53). We then examined changes in spectral characteristics of sleep as the SHAM group crossed over to active CPAP treatment (n = 19). Polysomnography (PSG) from the CPAP titration night was used for the current analyses. Analyses focused on EEG frequencies associated with sleep maintenance and arousal. These included the slow oscillation (0.5-1 Hz), sigma activity (12-16 Hz, spindle activity), and beta activity (16-20 Hz) in F3, F4, C3, and C4 EEG channels. Whole night non-rapid eye movement (NREM) sleep and the first period of NREM spectral activity were examined. Age and sex were included as covariates. There were no group differences between CPAP and SHAM in spectral characteristics of sleep architecture. However, SHAM cross-over to active CPAP was associated with an increase in relative 12-16 Hz sigma activity across the whole night and a decrease in average beta activity across the whole night. Relative slow oscillation power within the first NREM period decreased with CPAP, particularly for frontal channels. Sigma and beta activity effects did not differ by channel. These findings suggest that CPAP may preferentially enhance spindle activity and mitigate neurophysiological arousal. These findings inform the neurophysiological mechanisms of improved sleep with CPAP and the utility of quantitative EEG measures of sleep as a treatment probe of improvements in neurological and physical health with CPAP.

Physical Exertion Partially Mitigates Task-Switching Deficits From Sleep Loss: Implications for Firefighters.

OBJECTIVE: The aim of the study is to investigate effects of physical exertion on cognitive deficits from sleep loss under conditions that mimic a firefighting scenario. METHODS: Twenty-four male participants completed a crossover study design with 3 conditions: total sleep deprivation, sleep disruption (three 60-minute awakenings), and rested control. Participants then completed 50 minutes of a physical exertion task involving treadmill exercise in a heated room while wearing firefighter protective clothing. Vigilant attention and task-switching performance were assessed pre- and post-sleep manipulation and pre- and post-physical exertion. Vigilant attention was also assessed mid-physical exertion. RESULTS: Total sleep deprivation and sleep disruption increased attentional lapses and task-switching RT. Total sleep deprivation additionally reduced task-switching accuracy. Performance after physical exertion improved only for task-switching RT after total sleep deprivation. CONCLUSIONS: Physical exertion selectively mitigated task-switching RT deficits from the most severe sleep loss condition, total sleep deprivation.

Homeostatic response to sleep deprivation and circadian rhythmicity are intact in older adults with insomnia.

STUDY OBJECTIVES: We examined whether homeostatic sleep drive and circadian rhythmicity differ in older adults with insomnia (OAI) compared to older good sleepers (GS). METHODS: OAI (n = 37) and GS (n = 30) participated in a 60-h in-lab study with sleep deprivation and constant routine paradigms. Homeostatic sleep drive was assessed by examining the effect of sleep deprivation on delta EEG power and theta EEG power, and repeated sleep latency tests. Circadian rhythm was assessed with salivary melatonin (phase and amplitude), core body temperature (phase, amplitude, and mesor), and sleep latency during a constant routine paradigm. Mixed models were used to assess interactions of group (OAS vs GS) with homeostatic sleep and circadian effects. RESULTS: Compared to GS, OAI showed a greater linear increase in waking theta power during sleep deprivation, but the two groups did not show differential responses to sleep deprivation in delta EEG, or in repeated sleep latency tests. The two groups did not differ in circadian phase or amplitude of melatonin or core body temperature rhythms. OAI had a significantly elevated core body temperature mesor compared to GS. CONCLUSIONS: Homeostatic response to sleep deprivation was intact in OAI compared to GS; theta EEG power suggested a greater homeostatic response in OAI. Circadian rhythm amplitude and phase were similar in OAI compared to GS. Elevated body temperature mesor in OAI may indicate elevated physiological arousal. These findings suggest that effective treatments for insomnia in older adults may leverage intact sleep and circadian regulatory mechanisms, rather than repair defective sleep and circadian regulation.

Exercise interventions preserve hippocampal volume: A meta-analysis.

Hippocampal volume is a marker of brain health and is reduced with aging and neurological disease. Exercise may be effective at increasing and preserving hippocampal volume, potentially serving as a treatment for conditions associated with hippocampal atrophy (e.g., dementia). This meta-analysis aimed to identify whether exercise training has a positive effect on hippocampal volume and how population characteristics and exercise parameters moderate this effect. Studies met the following criteria: (a) controlled trials; (b) interventions of physical exercise; (c) included at least one time-point of hippocampal volume data before the intervention and one after; (d) assessed hippocampal volume using either manual or automated segmentation algorithms. Animal studies, voxel-based morphometry analyses, and multi-modal interventions (e.g., cognitive training or meditation) were excluded. The primary analysis in n = 23 interventions from 22 published studies revealed a significant positive effect of exercise on total hippocampal volume. The overall effect was significant in older samples (65 years of age or older) and in interventions that lasted over 24 weeks and had less than 150 min per week of exercise. These findings suggest that moderate amounts of exercise for interventions greater than 6 months have a positive effect on hippocampal volume including in older populations vulnerable to hippocampal atrophy.

Slow-oscillation activity is reduced and high frequency activity is elevated in older adults with insomnia.

STUDY OBJECTIVES: High-frequency electroencephalographic activity (> 16 Hz activity) is often elevated during nonrapid eye movement sleep among individuals with insomnia, in line with the hyperarousal theory of insomnia. Evidence regarding sleep depth marked by slow-wave activity (< 4 Hz) is more mixed. Distinguishing subcomponents of slow-wave activity (slow-oscillation [< 1 Hz] or delta activity [1-4 Hz)]) may be critical in understanding these discrepancies, given that these oscillations have different neural generators and are functionally distinct. Here we tested the effects of insomnia diagnosis and insomnia treatment on nonrapid eye movement electroencephalography in older adults, distinguishing slow-oscillation and delta power. METHODS: In 93 older adults with insomnia and 71 good sleeper control participants (mean ages 68 years), effects of insomnia and cognitive behavioral therapy for insomnia (insomnia group only) on electroencephalographic spectral power were analyzed. Main effects and interactions with nonrapid eye movement period were assessed for the following frequency bands: slow-oscillation (0.5-1 Hz), delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), sigma (12-16 Hz), and beta (16-32 Hz). RESULTS: Slow-oscillation absolute and relative power were lower in the insomnia group compared with controls. There were no group differences in delta power. Insomnia was also associated with elevated 4-32 Hz absolute and relative power. After cognitive behavioral therapy for insomnia, absolute sigma and beta activity decreased. CONCLUSIONS: Deficits in slow-wave activity in insomnia are specific to the slow-oscillation. Elevated high frequency activity is reduced for sigma and beta power following cognitive behavioral therapy for insomnia . These findings inform the pathophysiology of insomnia, including the mechanisms underlying cognitive behavioral therapy for insomnia in older adults.

Does objectively-assessed sleep moderate the association between history of major depressive disorder and task-switching?

BACKGROUND: Executive function and psychomotor speed are consistently impaired in patients with major depressive disorder (MDD). Persistent cognitive impairments after depression remission are thought to reflect "scarring" from the neurotoxic effects of hypothalamic-pituitary-adrenal axis activity during a depressive episode. As sleep also deteriorates with depression and restores daytime executive functions, we examined whether adequate sleep could be protective against task-switching and psychomotor impairments associated with a history of MDD. METHODS: This cross-sectional study tested task-switching associations with MDD history, sleep, and their interaction to determine whether sleep continuity and sleep duration moderate the relationship between MDD history and task-switching performance. RESULTS: After adjusting for age, sex, education, current depressive symptoms, and use of anti-depressants, a history of MDD, particularly recurrent MDD, was associated with slower response speed and disproportionately lower accuracy on repetition trials compared to switch trials, reflecting impaired adoption of a task-set. Regardless of MDD history, higher wake after sleep onset and shorter total sleep time were associated with slower response times, but neither sleep measure moderated the association between depression history and task-switching performance. LIMITATIONS: This cross-sectional study cannot assess the causal direction of associations. One night of sleep in the laboratory was used to assess sleep and a single task-switching paradigm was used to assess executive function. CONCLUSIONS: These results suggest that longer, more continuous sleep is associated with greater psychomotor speed across healthy controls and those with a history of MDD, but MDD-task-switching associations are not mitigated by longer or more continuous sleep.

Infection with Herpes Simplex virus type 1 (HSV-1) and sleep: The dog that did not bark.

Persistent infection with Herpes Simplex viruses (HSV) and other brain infections is consistently associated with cognitive impairment. These infections can also affect sleep. Thus, sleep abnormalities could explain the cognitive dysfunction. We investigated the association between sleep variables and persistent HSV-1, HSV-2, cytomegalovirus (CMV) and Toxoplasma gondii (Tox) infections. Sleep data were collected from older adults with or without insomnia (N = 311, total); a subset completed polysomnographic and actigraphy studies (N = 145). No significant associations were found between the infections and insomnia or the remaining sleep variables following corrections for multiple comparisons. Sleep dysfunction is unlikely to explain the infection-related cognitive dysfunction.

Sleep moderates the relationship between amyloid beta and memory recall.

Amyloid-ß (Aß) accumulation is a hallmark of Alzheimer's disease, although Aß alone may be insufficient to cause impairments. Modifiable health factors, including sleep, may mitigate functional symptoms of neurodegeneration. We assessed whether sleep moderated the relationship between Aß and cognitive performance in 41 older adults, mean age 83 years. Sleep measures included actigraphy-assessed wake after sleep onset and total sleep time. Cognitive performance was assessed with memory recall, cognitive flexibility, and verbal fluency. Memory recall was assessed with the Rey-Osterrieth Complex Figure task, cognitive flexibility with the Trail Making test, and verbal fluency with FAS word generation. Aß was assessed with a global measure of Pittsburgh Compound B. Wake after sleep onset moderated the relationship between Aß and memory, with a stronger positive association for Aß and forgetting in those with poorer sleep. These results suggest a possible protective role of sleep in preclinical Alzheimer's disease.

Slow-Wave Activity Enhancement to Improve Cognition.

Slow-wave activity (SWA), and its coupling with other sleep features, reorganizes cortical circuitry, supporting cognition. This raises the question: can cognition be improved through SWA enhancement? SWA enhancement techniques range from behavioral interventions (such as exercise), which have high feasibility but low specificity, to laboratory-based techniques (such as transcranial stimulation), which have high specificity but are less feasible for widespread use. In this review we describe the pathways through which SWA is enhanced. Pathways encompass enhanced neural activity, increased energy metabolism, and endocrine signaling during wakefulness; also direct enhancement during sleep. We evaluate the robustness and practicality of SWA-enhancement techniques, discuss approaches for determining a causal role of SWA on cognition, and present questions to clarify the mechanisms of SWA-dependent cognitive improvements.

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.

Task switching in older adults with and without insomnia.

BACKGROUND: Task-switching deficits are common in older adults and in those with insomnia. Such deficits may be driven by difficulties with sleep continuity and dampened homeostatic sleep drive. OBJECTIVE: To identify the aspects of task switching affected by insomnia and its treatment, and to determine whether such effects are associated with sleep continuity and homeostatic sleep drive. METHODS: Polysomnographic sleep and task switching were tested in healthy older adults aged 60-93 years with insomnia (n = 48) and normal sleeping controls (n = 51). Assessments were repeated in the insomnia group after eight weeks of cognitive behavioral treatment for insomnia. Sleep measures included wake after sleep onset (WASO) and quantitative indices of homeostatic sleep drive (delta power during nonrapid eye movement [NREM] sleep and the ratio of delta power during the first and second NREM periods). A cued task-switching paradigm instructed participants to perform one of two tasks with varying preparatory cue-target intervals, manipulating task alternation, task repetition, and task preparation. RESULTS: The effect of preparatory cues on accuracy was diminished in the insomnia group compared with that in controls. Across the two groups, a stronger effect of preparatory cues was associated with a higher delta sleep ratio. Following insomnia treatment, task-repetition accuracy significantly improved. This improvement was associated with improvements in WASO. There were no group or treatment effects on response time or task alternation accuracy. CONCLUSIONS: Effects of insomnia diagnosis and treatment apply to conditions that depend on the maintenance of a task set, rather than a domain general effect across task switching. Such effects are associated with homeostatic sleep drive and sleep continuity.

Sleep-Wake Differences in Relative Regional Cerebral Metabolic Rate for Glucose among Patients with Insomnia Compared with Good Sleepers.

STUDY OBJECTIVES: The neurobiological mechanisms of insomnia may involve altered patterns of activation across sleep-wake states in brain regions associated with cognition, self-referential processes, affect, and sleep-wake promotion. The objective of this study was to compare relative regional cerebral metabolic rate for glucose (rCMRglc) in these brain regions across wake and nonrapid eye movement (NREM) sleep states in patients with primary insomnia (PI) and good sleeper controls (GS). METHODS: Participants included 44 PI and 40 GS matched for age (mean = 37 y old, range 21-60), sex, and race. We conducted [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans in PI and GS during both morning wakefulness and NREM sleep at night. Repeated measures analysis of variance was used to test for group (PI vs. GS) by state (wake vs. NREM sleep) interactions in relative rCMRglc. RESULTS: Significant group-by-state interactions in relative rCMRglc were found in the precuneus/posterior cingulate cortex, left middle frontal gyrus, left inferior/superior parietal lobules, left lingual/fusiform/occipital gyri, and right lingual gyrus. All clusters were significant at Pcorrected < 0.05. CONCLUSIONS: Insomnia was characterized by regional alterations in relative glucose metabolism across NREM sleep and wakefulness. Significant group-by-state interactions in relative rCMRglc suggest that insomnia is associated with impaired disengagement of brain regions involved in cognition (left frontoparietal), self-referential processes (precuneus/posterior cingulate), and affect (left middle frontal, fusiform/lingual gyri) during NREM sleep, or alternatively, to impaired engagement of these regions during wakefulness.