Postoperative cognitive dysfunction: spotlight on light, circadian rhythms, and sleep.

Postoperative cognitive dysfunction (POCD) is a neurological disorder characterized by the emergence of cognitive impairment after surgery. A growing body of literature suggests that the onset of POCD is closely tied to circadian rhythm disruption (CRD). Circadian rhythms are patterns of behavioral and physiological change that repeat themselves at approximately, but not exactly, every 24 h. They are entrained to the 24 h day by the daily light-dark cycle. Postoperative CRD affects cognitive function likely by disrupting sleep architecture, which in turn provokes a host of pathological processes including neuroinflammation, blood-brain barrier disturbances, and glymphatic pathway dysfunction. Therefore, to address the pathogenesis of POCD it is first necessary to correct the dysregulated circadian rhythms that often occur in surgical patients. This narrative review summarizes the evidence for CRD as a key contributor to POCD and concludes with a brief discussion of how circadian-effective hospital lighting can be employed to re-entrain stable and robust circadian rhythms in surgical patients.

Corrigendum: Postoperative cognitive dysfunction: spotlight on light, circadian rhythms, and sleep.

[This corrects the article DOI: 10.3389/fnins.2024.1390216.].

Alignment Between 24-h Light-Dark and Activity-Rest Rhythms Is Associated With Diabetes and Glucose Metabolism in a Nationally Representative Sample of American Adults.

OBJECTIVE: The alignment between environmental stimuli (e.g., dark, light) and behavior cycles (e.g., rest, activity) is an essential feature of the circadian timing system, a key contributor to metabolic health. However, no previous studies have investigated light-activity alignment in relation to glycemic control in human populations. RESEARCH DESIGN AND METHODS: The analysis included ∼7,000 adults (aged 20-80 years) from the National Health and Nutrition Examination Survey (NHANES) (2011-2014) with actigraphy-measured, multiday, 24-h activity and light data. We used phasor analysis to derive phasor magnitude and phasor angle, which measures coupling strength and phase difference between the activity-rest and light-dark cycles, respectively. We used multinomial logistic regression and multiple linear regression to study phasor magnitude and phasor angle in relation to diabetes (primary outcome) and multiple secondary biomarkers of glycemic control. RESULTS: Lower alignment strength (i.e., a shorter phasor magnitude) and more delayed activity relative to the light cycle (i.e., a larger phasor angle) were both associated with diabetes. Specifically, compared with individuals in the quintiles indicating the most proper alignment (Q5 for phasor magnitude and Q1 for phasor angle), those in the quintiles with the most impaired alignment had a >70% increase in the odds of diabetes for phasor magnitude (odds ratio 1.76 [95% CI 1.39, 2.24]) and for phasor angle (1.73 [1.34, 2.25]). Similar associations were observed for biomarkers for glucose metabolism. The results were generally consistent across diverse sociodemographic and obesity groups. CONCLUSIONS: The alignment pattern between 24-h activity-rest and light-dark cycles may be a critical factor in metabolic health.

Evaluation of a Novel Ambient Light Survey Question in the Cancer Prevention Study-3.

Nighttime light exposure may increase cancer risk by disrupting the circadian system. However, there is no well-established survey method for measuring ambient light. In the Cancer Prevention Study-3, 732 men and women answered a light survey based on seven environments. The light environment in the past year was assessed twice, one year apart, and four one-week diaries were collected between the annual surveys. A total of 170 participants wore a meter to measure photopic illuminance and circadian stimulus (CS). Illuminance and CS values were estimated for lighting environments from measured values and evaluated with a cross validation approach. The kappas for self-reported light environment comparing the two annual surveys were 0.61 on workdays and 0.49 on non-workdays. Kappas comparing the annual survey to weekly diaries were 0.71 and 0.57 for work and non-workdays, respectively. Agreement was highest for reporting of darkness (95.3%), non-residential light (86.5%), and household light (75.6%) on workdays. Measured illuminance and CS identified three peaks of light (darkness, indoor lighting, and outdoor daytime light). Estimated illuminance and CS were correlated with the measured values overall (r = 0.77 and r = 0.67, respectively) but were less correlated within each light environment (r = 0.23-0.43). The survey has good validity to assess ambient light for studies of human health.

Cardiovascular disease and lifestyle choices: Spotlight on circadian rhythms and sleep.

The advent of electric lighting in the built environment has radically transformed the human experience of light and darkness, which is often insufficient to stimulate and synchronize the circadian system to the day-night cycle. The lack of circadian system entrainment leads to poor sleep and could be an important biophysical mechanism underlying increased incidence of certain types of diseases, including cardiovascular (CV) disease (CVD). This contribution proposes to carve out a niche for including daily exposures to light and darkness among lifestyle factors for reducing the risk and progression of CVD. The fundamental workings of the human circadian system and its primary outputs are described. The discussion then progresses to light's effects on the circadian system and its outputs, and how threats to circadian health pose risks for CV health. The contribution concludes with simple recommendations for incorporating regular, robust daily exposures in lifestyle adjustments to combat CVD risks and progression.

Associations of 24-Hour Light Exposure and Activity Patterns and Risk of Cognitive Impairment and Decline in Older Men: The MrOS Sleep Study.

BACKGROUND: Older men with the worse alignment of activity and light may have lower levels of cognition and increased rates of cognitive decline. METHODS: This cohort consisted of 1 036 older men (81.1 ± 4.6 years) from the MrOS Sleep Study (2009-2012). Light and activity levels were gathered by wrist actigraphy. Phasor analysis was used to quantify the alignment of light-dark and rest-activity patterns (magnitude) and their temporal relationship (angle). Global cognitive function (Modified Mini-Mental State examination [3MS]) and executive function (Trails B test) were measured, then repeated 4.2 ± 0.8 years later. Linear regression models examined the associations of phasor magnitude and angle with cognition and cognitive decline. Models were adjusted for age, clinic, race, education, and season. RESULTS: Smaller phasor magnitude (worse aligned light and activity patterns) was associated with lower initial level and increased decline in executive function. Compared to those with higher phasor magnitude, those with lower magnitude took an average of 11.1 seconds longer to complete the Trails B test (quartile 1 vs quartile 4, p = .02). After follow-up, Trails B completion time increased an average of 5.5 seconds per standard deviation decrease in phasor magnitude (95% confidence interval [CI] 0.7-10.4, p = .03). There were no associations with phasor angle, and none with magnitude and global cognition (3MS). CONCLUSION: Among older men, worse alignment of light and activity patterns was associated with worse initial performance and increased decline in executive function, but not related to global cognition. Interventions that improve the alignment of light and activity may slow cognitive decline in older adults.

Tailored lighting intervention (TLI) for improving sleep-wake cycles in older adults living with dementia.

Introduction: Sleep disturbance is a hallmark of Alzheimer's disease and related dementias, and caregiver stress caused by patients' nighttime wandering, injuries, and agitation are frequently at the root of decisions to move them to assisted living facilities, where typically dim institutional lighting can further exacerbate their sleep problems. This study explored the effects of a circadian-effective lighting intervention on actigraphic sleep measures and subjective assessments of sleep disturbance, depression, and sleep-disturbed behaviors. Methods: Fourteen older adult (≥60 years) participants (11 females, mean age = 84.1 [SD 8.9]), all diagnosed with moderate to severe dementia and sleep disturbance, were recruited from 3 assisted living and memory care facilities. Following a crossover, placebo-controlled design, 3 different lighting modes were used to deliver high levels of circadian stimulus to the participants' eyes for two 8-week intervention periods in a counter balanced order with a 4-week washout between the study's 2 conditions (dim light control vs. active intervention). Actigraphy and questionnaire data were collected over 7-day assessment periods that preceded (baseline weeks 1 and 9) and concluded (post-intervention week 9 and 22) the intervention periods. Actigraphic outcomes included sleep duration, sleep time, sleep efficiency, sleep start time, and sleep end time. Subjective assessments included the Cornell Scale for Depression in Dementia (CSDD), Pittsburgh Sleep Quality Index (PSQI), and Sleep Disorders Inventory (SDI) instruments. Results: Under the active condition, sleep duration significantly (p = 0.018) increased and sleep start time significantly (p = 0.012) advanced after the intervention compared to baseline. Also under the active condition, PSQI (p = 0.012), CSDD (p = 0.007), Sleep Disorders Inventory frequency (p = 0.015), and SDI severity (p = 0.015) scores were significantly lower after the intervention compared to baseline. Discussion: This study demonstrates that a circadian-effective lighting intervention delivering bright days and dark nights improves measures of sleep and mood in dementia patients living in controlled environments.

The circadian stimulus-oscillator model: Improvements to Kronauer's model of the human circadian pacemaker.

Modeling how patterns of light and dark affect circadian phase is important clinically and organizationally (e.g., the military) because circadian disruption can compromise health and performance. Limit-cycle oscillator models in various forms have been used to characterize phase changes to a limited set of light interventions. We approached the analysis of the van der Pol oscillator-based model proposed by Kronauer and colleagues in 1999 and 2000 (Kronauer99) using a well-established framework from experimental psychology whereby the stimulus (S) acts on the organism (O) to produce a response (R). Within that framework, using four independent data sets utilizing calibrated personal light measurements, we conducted a serial analysis of the factors in the Kronauer99 model that could affect prediction accuracy characterized by changes in dim-light melatonin onset. Prediction uncertainty was slightly greater than 1 h for the new data sets using the original Kronauer99 model. The revised model described here reduced prediction uncertainty for these same data sets by roughly half.

Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer.

In the United States, African American (AA) men have a 2.4 times higher mortality rate due to prostate cancer than White men. The multifactorial causes of the racial disparities in prostate cancer involve various social determinants of health, socioeconomic status, and access to healthcare. However, emerging evidence also suggests that circadian rhythm disruption (CRD) contributes to prostate cancer, and AA men may be more susceptible to developing CRDs. Circadian rhythms play a significant role in metabolism, hormone secretion, and sleep/wake cycles. Disruption in these circadian rhythms can be caused by airplane travel/jetlag, night shift work, exposure to light, and neighborhood noise levels, which can contribute to sleep disorders and chronic conditions such as obesity, diabetes, cardiovascular disease, and depression. The drivers of the racial disparities in CRD include night shift work, racial discrimination, elevated stress, and residing in poor neighborhoods characterized by high noise pollution. Given the increased vulnerability of AA men to CRDs, and the role that CRDs play in prostate cancer, elucidating the clock-related prostate cancer pathways and their behavior and environmental covariates may be critical to better understanding and reducing the racial disparities in prostate cancer.

Corrigendum: Modeling Circadian Phototransduction: Quantitative Predictions of Psychophysical Data.

[This corrects the article DOI: 10.3389/fnins.2021.615322.].

Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers.

The circadian system is an innate clock mechanism that governs biological processes on a near 24-hour cycle. Circadian rhythm disruption (i.e., misalignment of circadian rhythms), which results from the lack of synchrony between the master circadian clock located in the suprachiasmatic nuclei (SCN) and the environment (i.e., exposure to day light) or the master clock and the peripheral clocks, has been associated with increased risk of and unfavorable cancer outcomes. Growing evidence supports the link between circadian disruption and increased prevalence and mortality of genitourinary cancers (GU) including prostate, bladder, and renal cancer. The circadian system also plays an essential role on the timely implementation of chronopharmacological treatments, such as melatonin and chronotherapy, to reduce tumor progression, improve therapeutic response and reduce negative therapy side effects. The potential benefits of the manipulating circadian rhythms in the clinical setting of GU cancer detection and treatment remain to be exploited. In this review, we discuss the current evidence on the influence of circadian rhythms on (disease) cancer development and hope to elucidate the unmet clinical need of defining the extensive involvement of the circadian system in predicting risk for GU cancer development and alleviating the burden of implementing anti-cancer therapies.

Circadian rhythm disruption with high-fat diet impairs glycemic control and bone quality.

Biological functions, including glycemic control and bone metabolism, are highly influenced by the body's internal clock. Circadian rhythms are biological rhythms that run with a period close to 24 hours and receive input from environmental stimuli, such as the light/dark cycle. We investigated the effects of circadian rhythm disruption (CRD), through alteration of the light/dark schedule, on glycemic control and bone quality of mice. Ten-week-old male mice (C57/BL6, n = 48) were given a low-fat diet (LFD) or a high-fat diet (HFD) and kept on a dayshift or altered schedule (RSS3) for 22 weeks. Mice were divided into four experimental groups (n = 12/group): Dayshift/LFD, Dayshift/HFD, RSS3/LFD, and RSS3/HFD. CRD in growing mice fed a HFD resulted in a diabetic state, with a 36.2% increase in fasting glucose levels compared to the Dayshift/LFD group. Micro-CT scans of femora revealed a reduction in inner and outer surface expansion for mice on a HFD and altered light schedule. Cancellous bone demonstrated deterioration of bone quality as trabecular number and thickness decreased while trabecular separation increased. While HFD increased cortical bone mineral density, its combination with CRD reduced this phenomenon. The growth of mineral crystals, determined by small angle X-ray scattering, showed HFD led to smaller crystals. Considering modifications of the organic matrix, regardless of diet, CRD exacerbated the accumulation of fluorescent advanced glycation end-products (fAGEs) in collagen. Strength testing of tibiae showed that CRD mitigated the higher strength in the HFD group and increased brittleness indicated by lower post-yield deflection and work-to-fracture. Consistent with accumulation of fAGEs, various measures of toughness were lowered with CRD, but combination of CRD with HFD protected against this decrease. Differences between strength and toughness results represent different contributions of structural and material properties of bone to energy dissipation. Collectively, these results demonstrate that combination of CRD with HFD impairs glycemic control and have complex effects on bone quality.

Spatial sensitivity of human circadian response: Melatonin suppression from on-axis and off-axis light exposures.

A better understanding of the spatial sensitivity of the human circadian system to photic stimulation can provide practical solutions for optimized circadian light exposures. Two psychophysical experiments, involving 25 adult participants in Experiment 1 (mean age = 34.0 years [SD 15.5]; 13 females) and 15 adult participants in Experiment 2 (mean age = 43.0 years [SD 12.6]; 12 females), were designed to investigate whether varying only the spatial distribution of luminous stimuli in the environment while maintaining a constant spectrally weighted irradiance at the eye could influence nocturnal melatonin suppression. Two spatial distributions were employed, one where the luminous stimulus was presented On-axis (along the line of sight) and one where two luminous stimuli were both presented Off-axis (laterally displaced at center by 14°). Two narrowband LED light sources, blue (λmax  = 451 nm) for first experiment and green (λmax  = 522 nm) for second experiment, were used in both the On-axis and the Off-axis spatial distributions. The blue luminous stimulus targeting the fovea and parafovea (On-axis) was about three times more effective for suppressing melatonin than the photometrically and spectrally matched stimulus targeting the more peripheral retina (Off-axis). The green luminous stimulus targeting the fovea and parafovea (On-axis) was about two times more effective for suppressing melatonin than the photometrically and spectrally matched stimulus targeting the more peripheral retina (Off-axis).

Relative light sensitivities of four retinal hemi-fields for suppressing the synthesis of melatonin at night.

The magnitude of the stimulus to the biological clock will depend upon the distribution of circadian phototransduction circuits across the retinae and the spatial distribution of luminous stimuli in the environment. The present study compared nocturnal melatonin suppression for light exposures to the superior, inferior, nasal, and temporal retina in one eye independent of shading from the brow and the nose. The stimulus was a 40° diameter luminous disc, half of which was blue light (LED, λpeak = 470 nm) and the other amber light (LED, λpeak = 590 nm). Experimentally, the orientation of the bipartite disc was rotated to each of the four cardinal points of the visual field. A full, 40° blue disc was also employed by replacing the amber half-disc with another blue half-disc. The blue full- and half-discs always produced 100 photopic lx at the cornea. As hypothesized, nocturnal melatonin suppression was statistically greatest when the blue half-disc was delivered to the nasal hemi-field (35%); the other three hemi-fields were equally affected by the blue half-disc (≈20%). Melatonin suppression for the full-disc was 24%, which was not statistically different than the average suppression for the four hemi-fields of 27%.

Intermittent Light Exposures in Humans: A Case for Dual Entrainment in the Treatment of Alzheimer's Disease.

Circadian sleep disorders are common among American adults and can become especially acute among older adults, especially those living with Alzheimer's disease (AD) and mild cognitive impairment (MCI), leading to the exacerbation of symptoms and contributing to the development and advancement of the diseases. This review explores the connections between circadian sleep disorders, cognition, and neurodegenerative disease, offering insights on rapidly developing therapeutic interventions employing intermittent light stimuli for improving sleep and cognition in persons with AD and MCI. Light therapy has the potential to affect sleep and cognition via at least two pathways: (1) a regular and robust light-dark pattern reaching the retina that promotes circadian phase shifting, which can promote entrainment and (2) 40 Hz flickering light that promotes gamma-wave entrainment. While this is a new area of research, preliminary evidence shows the potential of dual circadian and gamma-wave entrainment as an important therapy not only for those with AD, but for others with cognitive impairment.

Modeling Circadian Phototransduction: Quantitative Predictions of Psychophysical Data.

A revised computational model of circadian phototransduction is presented. The first step was to characterize the spectral sensitivity of the retinal circuit using suppression of the synthesis of melatonin by the pineal gland at night as the outcome measure. From the spectral sensitivity, circadian light was defined. Circadian light, thereby rectifies any spectral power distribution into a single, instantaneous photometric quantity. The second step was to characterize the circuit's response characteristic to different amounts of circadian light from threshold to saturation. By doing so a more complete instantaneous photometric quantity representing the circadian stimulus was defined in terms of both the spectral sensitivity and the response magnitude characteristic of the circadian phototransduction circuit. To validate the model of the circadian phototransduction circuit, it was necessary to augment the model to account for different durations of the circadian stimulus and distribution of the circadian stimulus across the retina. Two simple modifications to the model accounted for the duration and distribution of continuous light exposure during the early biological night. A companion paper (https://www.frontiersin.org/articles/10.3389/fnins.2020.615305/full) provides a neurophysiological foundation for the model parameters.

Light-Dark Patterns Mirroring Shift Work Accelerate Atherosclerosis and Promote Vulnerable Lesion Phenotypes.

Background Despite compelling epidemiological evidence that circadian disruption inherent to long-term shift work enhances atherosclerosis progression and vascular events, the underlying mechanisms remain poorly understood. A challenge to the use of mouse models for mechanistic and interventional studies involving light-dark patterns is that the spectral and absolute sensitivities of the murine and human circadian systems are very different, and light stimuli in nocturnal mice should be scaled to represent the sensitivities of the human circadian system. Methods and Results We used calibrated devices to deliver to low-density lipoprotein receptor knockout mice light-dark patterns representative of that experienced by humans working day shifts or rotating shift schedules. Mice under day shifts were maintained under regular 12 hours of light and 12 hours of dark cycles. Mice under rotating shift schedules were subjected for 11 weeks to reversed light-dark patterns 4 days in a row per week, followed by 3 days of regular light-dark patterns. In both protocols the light phases consisted of monochromatic green light at an irradiance of 4 µW/cm2. We found that the shift work paradigm disrupts the foam cell's molecular clock and increases endoplasmic reticulum stress and apoptosis. Lesions of mice under rotating shift schedules were larger and contained less prostabilizing fibrillar collagen and significantly increased areas of necrosis. Conclusions Low-density lipoprotein receptor knockout mice under light-dark patterns analogous to that experienced by rotating shift workers develop larger and more vulnerable plaques and may represent a valuable model for further mechanistic and/or interventional studies against the deleterious vascular effects of rotating shift work.

Lighting and Alzheimer's Disease and Related Dementias: Spotlight on Sleep and Depression.

Alzheimer's disease and related dementias is the collective term for a progressive neurodegenerative disease for which there is presently no cure. This paper focuses on two symptoms of the disease, sleep disturbances and depression, and discusses how light can be used as a non-pharmacological intervention to mitigate their negative effects. Bright days and dark nights are needed for health and well-being, but the present components of the built environment, especially those places where older adults spend most of their days, are too dimly illuminated during the day and too bright at night. To be effective light needs to be correctly specified, implemented, and measured. Yet without the appropriate specification and measurement of the stimulus, researchers will not be able to successfully demonstrate positive results in the field, nor will lighting designers and specifiers have the confidence to implement lighting solutions for promoting better sleep and mood in this population.

Long-Term, All-Day Exposure to Circadian-Effective Light Improves Sleep, Mood, and Behavior in Persons with Dementia.

BACKGROUND: Persons with Alzheimer's disease and related dementias (ADRD) frequently experience sleep-wake (circadian) cycle disturbances that lead them to remain awake at night, causing stress and fatigue for families and caregivers. Light therapy shows promise as a nonpharmacological treatment for regulating sleep in this population. OBJECTIVE: We investigated the long-term impact of a circadian-effective lighting intervention on sleep, mood, and behavior problems in persons with ADRD. METHODS: This 25-week clinical trial administered an all-day lighting intervention to 47 patients with ADRD in 9 senior-care facilities, employing wrist-worn actigraphy measures and standardized measures of sleep quality, mood, and behavior. RESULTS: The intervention significantly improved Pittsburgh Sleep Quality Index scores, from an estimated mean±SEM of 11.89±0.53 at baseline to 5.36±0.63 at the end of the intervention. Additional improvements were noted for sleep efficiency data from actigraph measurements. The intervention significantly reduced Cornell Scale for Depression in Dementia scores (mean±SEM of 11.36±0.74 at baseline and 4.18±0.88 at the end of the intervention) and Cohen-Mansfield Agitation Inventory scores (mean±SEM of 47.10±1.98 at baseline and 35.33±2.23 at the end of the intervention). CONCLUSION: A regular circadian-effective daytime lighting intervention can improve sleep at night and reduce depression and agitation in patients with dementia living in controlled environments. More importantly, the positive effects of the tailored lighting intervention on these outcomes appear to be cumulative over time.