The circadian syndrome is a predictor for cognition impairment in middle-aged adults: Comparison with the metabolic syndrome.

AIMS: Circadian syndrome (CircS) is considered a better predictor for cardiovascular disease than the metabolic syndrome (MetS). We aim to examine the associations between CircS and MetS with cognition in Chinese adults. METHOD: We used the data of 8546 Chinese adults aged ≥40 years from the 2011 China Health and Retirement Longitudinal Study. MetS was defined using harmonised criteria. CircS included the components of MetS plus short sleep and depression. The cut-off for CircS was set as ≥4. Global cognitive function was assessed during the face-to-face interview. RESULTS: CircS and MetS had opposite associations with the global cognition score and self-reported poor memory. Compared with individuals without the CircS and MetS, the regression coefficients (95%CI) for global cognition score were -1.02 (-1.71 to -0.34) for CircS alone and 0.52 (0.09 to 0.96) for MetS alone in men; -1.36 (-2.00 to -0.72) for CircS alone and 0.60 (0.15 to 1.06) for MetS alone in women. Having CircS alone was 2.53 times more likely to report poor memory in men (95%CI 1.80-3.55) and 2.08 times more likely in women (95%CI 1.54-2.81). In contrast, having MetS alone was less likely to report poor memory (OR 0.64 (0.49-0.84) in men and 0.65 (0.52-0.81) in women). People with CircS and MetS combined were more likely to have self-reported poor memory. CONCLUSIONS: CircS is a strong and better predictor for cognition impairment than MetS in Chinese middle-aged adults. MetS without short sleep and depression is associated with better cognition.

Effects of photoperiod and food on glucose intolerance and subsequent ocular pathology in the fat sand rat.

Type 2 diabetes mellitus (T2DM) and its ocular complications, such as cataract and diabetic retinopathy (DR) have been linked to circadian rhythm-disturbances. Using a unique diurnal animal model, the sand rat (Psammomys obesus) we examined the effect of circadian disruption by short photoperiod acclimation on the development of T2DM and related ocular pathologies. We experimented with 48 male sand rats. Variables were day length (short photoperiod, SP, vs. neutral photoperiod NP) and diet (standard rodent diet vs. low-energy diet). Blood glucose, the presence of cataract and retinal pathology were monitored. Histological slides were examined for lens opacity, retinal cell count and thickness. Animals under SP and fed standard rodent diet (SPSR) for 20 weeks had higher baseline blood glucose levels and lower glucose tolerance compared with animals kept under NP regardless of diet, and under SP with low energy diet (SPLE). Animals under SPSR had less cells in the outer nuclear layer, a lower total number of cells in the retina, and a thickened retina. Higher blood glucose levels correlated with lower number of cells in all cellular layers of the retina and thicker retina. Animals under SPSR had higher occurrence of cataract, and a higher degree of cataract, which correlated with higher blood glucose levels. Sand rats kept under SPSR develop cataract and retinal abnormalities indicative of DR, whereas sand rats kept under NP regardless of diet, or under SPLE, do not. These ocular abnormalities significantly correlate with hyperglycemia.

Salivary cortisol concentration and perceived stress measure in response to acute natural stress: The role of morningness-eveningness preference.

Chronotype reflects the morningness-eveningness preference over a 24-h period. Significant data indicates meaningful differences between evening types (ET) and morning types (MT) in behavior, personality traits, health and well-being. The aim of this study was to investigate cortisol response and subjective perceived stress of MT and ET individuals in response to an acute natural stressor. Twenty six definite MT (mean age 23.4 ± 1.7) and twenty six definite ET (mean age 23.8 ± 1.3) college students were recruited for this study. Participants were instructed to evaluate their perceived subjective stress and to provide saliva samples for cortisol levels at four different time points: Morning of regular school day, morning immediately before a final exam, afternoon of a regular school day and afternoon immediately before a final exam. For general mood assessment, the participants were also asked to fill out the Positive and Negative Affect Schedule (PANAS) questionnaire. The most outstanding finding of this study was the blunting of cortisol increase in response to acute stress in the morning in the ET group: Salivary cortisol was higher before a final exam only in MT but not in ET. However, no differences between the groups were found in the subjective stress measure. In the PANAS scale, ET showed lower positive affect, and a trend towards a higher negative affect. Overall, our results suggest dysregulation of cortisol response in ET individuals, possibly due to their daily struggle to function in a morning-oriented society. These results further highlight the challenges faced by ET individuals and raise the question of possible interventions to assist them.

Real-time sensing of war's effects on wellbeing with smartphones and smartwatches.

BACKGROUND: Modern wars have a catastrophic effect on the wellbeing of civilians. However, the nature of this effect remains unclear, with most insights gleaned from subjective, retrospective studies. METHODS: We prospectively monitored 954 Israelis (>40 years) from two weeks before the May 2021 Israel-Gaza war until four weeks after the ceasefire using smartwatches and a dedicated mobile application with daily questionnaires on wellbeing. This war severely affected civilians on both sides, where over 4300 rockets and missiles were launched towards Israeli cities, and 1500 aerial, land, and sea strikes were launched towards 16,500 targets in the Gaza Strip. RESULTS: We identify considerable changes in all the examined wellbeing indicators during missile attacks and throughout the war, including spikes in heart rate levels, excessive screen-on time, and a reduction in sleep duration and quality. These changes, however, fade shortly after the war, with all affected measures returning to baseline in nearly all the participants. Greater changes are observed in individuals living closer to the battlefield, women, and younger individuals. CONCLUSIONS: The demonstrated ability to monitor objective and subjective wellbeing indicators during crises in real-time is pivotal for the early detection of and prompt assistance to populations in need.

This study investigated the impact of the May 2021 Israel-Gaza war on the wellbeing of Israeli civilians. To do so, 954 Israelis over the age of 40 were monitored for six weeks before and after the war using smartwatches and a mobile application that asked daily wellbeing questions. The researchers found that during the war, people experienced spikes in heart rate, decreased sleep quality and duration, and increased screen time. These changes were more significant in people living closer to the battlefield, women, and younger individuals. However, after the ceasefire, wellbeing indicators returned to baseline levels. The study shows that monitoring wellbeing in real-time during crises can help identify and assist populations in need.

Changes in menstrual cycle length and in sleep-wake behaviors during COVID-19 related lockdown in Israel.

COVID-19 related lockdowns changed our life. Studies report that young women are more susceptible to lockdown-induced adverse effects and stress. As stress and menstrual cycle are associated, we hypothesized that menstrual cycle length might change during lockdown. We examined menstrual cycle length, and sleep-wake behaviors during lockdown in Israel. Participants were 97 women in their fertile years who used Tempdrop fertility sensor™ to track cycles. Data were collected before, during and after lockdown in Israel. Our main finding is that lockdown was associated with changes in menstrual cycle length of most participants, with either increased of decreased length. Changes were reversed when lockdown was terminated. Sleep duration increased during lockdown but we found no relationship between sleep and menstrual cycle. We suggest these findings contribute to the understanding of the relationship between stress, sleep, and menstrual cycle. Further studies should explore the sources for differential effects in sub-groups of women.

The Circadian Syndrome Is a Significant and Stronger Predictor for Cardiovascular Disease than the Metabolic Syndrome-The NHANES Survey during 2005-2016.

The study aimed to compare the predictive value of the Circadian Syndrome (CircS) and Metabolic Syndrome (MetS) for cardiovascular disease (CVD). We used data of 12,156 adults aged ≥20 years who attended National Health and Nutrition Examination Survey (NHANES) 2005-2016. Mortality was obtained from the registry updated to 2019. The CircS was defined based on components of the MetS, in addition to short sleep and depression. Both the MetS and CircS were directly associated with self-reported history of CVD. The odds ratios for prevalent CVD associated with the CircS and MetS, respectively, were 2.92 (95% confidence interval (CI) 2.21-3.86) and 3.20 (2.38-4.30) in men, and 3.27 (2.34-4.59) and 3.04 (2.15-4.30) in women. The CircS had a better predictive power for prevalent CVD than that of MetS, as indicated by the higher positive predictive value (PPV); in men, the PPV for prevalent CVD with CircS was 23.1% and with MetS 20.9%, and in women these were 17.9% vs. 16.4%, respectively. However, the PPV of the CircS and MetS did not differ for the CVD mortality prediction. Women with CircS alone had a higher risk for both prevalent CVD and CVD mortality than those with MetS alone. In conclusion, the CircS is a significant and stronger predictor for CVD than the MetS in US adults.

Circadian rhythms-related disorders in diurnal fat sand rats under modern lifestyle conditions: A review.

Modern lifestyle reduces environmental rhythmicity and may lead to circadian desynchrony. We are exposed to poor day-time lighting indoors and excessive night-time artificial light. We use air-conditioning to reduce ambient temperature cycle, and food is regularly available at all times. These disruptions of daily rhythms may lead to type 2 diabetes mellitus (T2DM), obesity, cardiometabolic diseases (CMD), depression and anxiety, all of which impose major public health and economic burden on societies. Therefore, we need appropriate animal models to gain a better understanding of their etiologic mechanisms, prevention, and management.We argue that the fat sand rat (Psammomys obesus), a diurnal animal model, is most suitable for studying the effects of modern-life conditions. Numerous attributes make it an excellent model to study human health disorders including T2DM, CMD, depression and anxiety. Here we review a comprehensive series of studies we and others conducted, utilizing the fat sand rat to study the underlying interactions between biological rhythms and health. Understanding these interactions will help deciphering the biological basis of these diseases, which often occur concurrently. We found that when kept in the laboratory (compared with natural and semi-wild outdoors conditions where they are diurnal), fat sand rats show low amplitude, nocturnal or arrhythmic activity patterns, dampened daily glucose rhythm, glucose intolerance, obesity and decreased survival rates. Short photoperiod acclimation exacerbates these pathologies and further dampens behavioral and molecular daily rhythms, resulting in CMD, T2DM, obesity, adipocyte dysfunction, cataracts, depression and anxiety. Increasing environmental rhythmicity by morning bright light exposure or by access to running wheels strengthens daily rhythms, and results in higher peak-to-trough difference in activity, better rhythmicity in clock genes expression, lower blood glucose and insulin levels, improved glucose tolerance, lower body and heart weight, and lower anxiety and depression. In summary, we have demonstrated that fat sand rats living under the correspondent of "human modern lifestyle" conditions exhibit dampened behavioral and biological rhythms and develop circadian desynchrony, which leads to what we have named "The Circadian Syndrome". Environmental manipulations that increase rhythmicity result in improvement or prevention of these pathologies. Similar interventions in human subjects could have the same positive results and further research on this should be undertaken.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption.

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

Changes in sleep patterns of college students in Israel during COVID-19 lockdown, a sleep diaries study.

To prevent and reduce the spread of COVID-19, governments around the world apply social restrictions and lockdowns. Such lockdowns significantly alter daily routine and habits. A growing body of research indicates that lockdowns affect sleep and circadian rhythms. The current study further explores this effect using sleep logs for a relatively long duration including lockdown and post-lockdown periods in Israel. For two consecutive months, both during lockdown and during post-lockdown periods, from March 13th, 2020 to May 12th, 2020, Israeli students were asked to fill out daily sleep logs in which they report their sleep and wake times. The participants were also asked to fill out the Morningness-Eveningness Questionnaire (MEQ) in the beginning of the study. Data show increase in sleep duration and a delayed midsleep point during lockdown, compared to post-lockdown periods, both on workdays and on weekends. An interaction between chronotype and lockdown was also observed; morning types sleep more both during lockdown and during post-lockdown periods. Interestingly, the midsleep point of late chronotypes is later during both workdays and weekends even during lockdown when social constrains on sleep time are in part removed. Overall, the current results based on detailed and relatively long-term sleep logs analysis confirm previous work using limited measures, such as one-time questionnaires. A lockdown period affects sleep-wake behavior: during lockdown people sleep duration is increased and their sleep onset is delayed. Nevertheless, the circadian preference of individuals is conserved across conditions.

Sex differences in the response to circadian disruption in diurnal sand rats.

Most animal model studies on physiological functions and pathologies are conducted in males. However, diseases such as depression, type 2 diabetes (T2DM) and cardiovascular disease, all show different prevalence and characteristics in females and males. Moreover, most mammal studies are conducted in nocturnal mice and rats, while modelling diurnal humans. We therefore used male and female fat sand rats (Psammomys obesus), which are diurnal in the wild, as an animal model for T2DM, to explore the effects of mild circadian disruption on behavior, glucose tolerance, cholesterol and heart weight. We found significant differences between the sexes: on average, in response to short photoperiods (SP) acclimation, males showed higher levels of depression-like behavior, lower glucose tolerance, and increased plasma cholesterol levels compared with females, with no effect on heart/body weight ratio. Females, however did show an increase in heart/body weight ratio in response to SP acclimation. We also found that regardless of sex, arrhythmic animals showed higher blood glucose levels, cholesterol levels, heart/body weight ratio, and depressive-like behavior compared with rhythmic animals. Hence, we suggest that the expression of the Circadian Syndrome could be different between males and females. Additional work with females is required to clearly delineate the specific effects in both sexes, and promote sex-based health care, prevention measures and therapies.

Effects of photoperiod and diet on BDNF daily rhythms in diurnal sand rats.

Brain-derived neurotrophic factor (BDNF), its receptors and epigenetic modulators, are implicated in the pathophysiology of affective disorders, T2DM and the circadian system function. We used diurnal sand rats, which develop type 2 diabetes (T2DM), anxiety and depressive-like behavior under laboratory conditions. The development of these disorders is accelerated when animals are maintained under short photoperiod (5:19L:D, SP) compared to neutral photoperiod (12:12L:D, NP). We compared rhythms in plasma BDNF as well as BDNF and PER2 expression in the frontal cortex and suprachiasmatic nucleus (SCN) of sand rats acclimated to SP and NP. Acclimation to SP resulted in higher insulin levels, significantly higher glucose levels in the glucose tolerance test, and significantly higher anxiety- and depression-like behaviors compared with animals acclimated to NP. NP Animals exhibited a significant daily rhythm in plasma BDNF levels with higher levels during the night, and in BDNF expression levels in the frontal cortex and SCN. No significant BDNF rhythm was found in the plasma, frontal cortex or SCN of SP acclimated animals. We propose that in sand rats, BDNF may, at least in part, mediate the effects of circadian disruption on the development of anxiety and depressive-like behavior and T2DM.

Differential effects of COVID-19 lockdowns on well-being: interaction between age, gender and chronotype.

The unprecedented restrictions imposed due to the COVID-19 pandemic altered our daily habits and severely affected our well-being and physiology. The effect of these changes is yet to be fully understood. Here, we analysed highly detailed data on 169 participants for two to six months, before and during the second COVID-19 lockdown in Israel. We extracted 12 well-being indicators from sensory data of smartwatches and from self-reported questionnaires, filled daily using a designated mobile application. We found that, in general, lockdowns resulted in significant changes in mood, sleep duration, sport duration, social encounters, resting heart rate and number of steps. Examining subpopulations, we found that younger participants (aged 20-40 years) suffered from a greater decline in mood and number of steps than older participants (aged 60-80 years). Likewise, women suffered from a higher increase in stress and reduction in social encounters than men. Younger early chronotypes did not increase their sleep duration and exhibited the highest drop in mood. Our findings underscore that while lockdowns severely impacted our well-being and physiology in general, greater damage has been identified in certain subpopulations. Accordingly, special attention should be given to younger people, who are usually not in the focus of social support, and to women.

Beneficial effects of daytime high-intensity light exposure on daily rhythms, metabolic state and affect.

While the importance of the circadian system to health and well-being is extensively studied, the role of daylight exposure in these interactions is relatively poorly understood. Here we show, using a diurnal animal model naturally exposed to daylight, that daily morning exposure to 3000 lux, full spectrum electric light has beneficial health effects. Compared with controls, sand rats (Psammomys obesus) subjected to morning light treatment demonstrate daily rhythms with high peak to trough difference in activity, blood glucose levels and per2 gene expression in the suprachiasmatic nucleus, pre-frontal cortex, kidney and liver. The treated animals were also healthier, being normoglycemic, having higher glucose tolerance, lower body and heart weight and lower anxiety- and depression-like behavior. Our results suggest that exposure to high intensity light is important for the proper function of the circadian system and well-being, and are important in face of human's low exposure to daylight and extensive use of artificial light at night.

Proposing the sweet solution preference test as a screening assay for anti-manic effects of mood stabilizers.

BACKGROUND: There is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. NEW METHOD: In the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). RESULTS: Data demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. COMPARISON WITH EXISTING METHODS: The results support the utilization of the SSP as mice screening model for anti-manic effects of drugs with stronger predictive validity compared with other methods. CONCLUSIONS: The SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.

Proteinoid Nanocapsules as Drug Delivery System for Improving Antipsychotic Activity of Risperidone.

Risperidone (RSP) is an atypical antipsychotic drug widely used to treat schizophrenia and bipolar disorder. Nanoparticles (NPs) are being developed as in vivo targeted drug delivery systems, which cross the blood-brain barrier and improve pharmacokinetics and drug effectiveness. Here, biodegradable proteinoids were synthesized by thermal step-growth polymerization from the amino acids l-glutamic acid, l-phenylalanine and l-histidine and poly (l-lactic acid). Proteinoid NPs containing RSP were then formed by self-assembly, overcoming the insolubility of the drug in water, followed by PEGylation (poly ethylene glycol (PEG) conjugation to increase the stability of the NPs in the aqueous continuous phase. These NPs are biodegradable owing to their peptide and ester moieties. They were characterized in terms of diameter, size distribution, drug loading, and long-term storage. Behavioral studies on mice found enhanced antipsychotic activity compared to free RSP.

Similarities and dissimilarities in the effects of benzodiazepines and specific serotonin reuptake inhibitors (SSRIs) in the defensive marble burying test: A systematic review and meta-analysis.

One problem areas of animal models and tests for neuropsychiatric disorders is unclear reproducibility, including both internal and external validity. One way to examine external validity is with systematic reviews and meta-analyses, a standard practice in clinical research that is relatively neglected in preclinical research. Considering the need to evaluate the validity and reproducibility of frequently used animal models, this study presents a meta-analysis of the effects of prototypic benzodiazepines and specific serotonin reuptake inhibitors (SSRIs) in the mouse defensive marble burying test (MBT). These drug groups were selected because although they differ in their biological targets as well as in their clinical use, they are both commonly used for the treatment of anxiety disorders. A PubMed literature search was performed to identify studies that examined the effects of benzodiazepines (diazepam, alprazolam, chlordiazepoxide, clonazepam) or SSRIs (fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine) in the MBT in mice. For benzodiazepines, 73 experiments were included. Benzodiazepines effect size was 2.04 and Q statistics was 1959 with a significant correlation between dose and effect size (r = 0.31, p = 0.007). For SSRIs we identified 47 experiments. Effect size of SSRIs was 2.24 and Q statistics was 493.38. No correlation was found between dose and effect size (r = 0.23, p = 0.12). The current results support the external validity of the defensive marble burying test as a screening test for anxiolytic effects. However, these results indicate that significant attention should be given to the administration schedules of benzodiazepines and SSRIs.

Exploring test batteries for depression- and anxiety-like behaviours in female and male ICR and black Swiss mice.

Objective and rationale: Animal models are critical for the study of mental disorders and their treatments but are repeatedly criticized for problems with validity and reproducibility. One approach to enhance validity and reproducibility of models is to use test batteries rather than single tests. Yet, a question regarding batteries is whether one can expect a consistent individual behavioural phenotype in mice across tests that can be presumed to be part of the same construct. This study was designed to explore the relationship between the behaviours of mice across tests in some variations of test batteries for depression- and anxiety-like behaviours. Methods: Female and male healthy, intact, and untreated mice from the ICR and black Swiss strains were used in four separate experiments. With some variations, mice were exposed to a battery of behavioural tests representing affective- and anxiety-like behaviours. Data were analysed for differences between sexes and for correlations between behaviours within and across the tests in the battery. Results: No differences were found between the sexes. With very few exceptions, we found correlations within tests (when one test has more than one measure or is repeated) but not across different tests within the battery. Conclusions: The results cast some doubt on the utility of behavioural test batteries to represent different facets of emotional behaviour in healthy intact outbred mice, without any interventions or treatments. Additional studies are designed to explore whether stronger relationship between the tests will appear after manipulations or drug treatments.

Revisiting the validity of the mouse tail suspension test: Systematic review and meta-analysis of the effects of prototypic antidepressants.

Animal models in neuropsychiatric research need validation. One way to address external validity is systematic reviews and meta-analyses. The present study presents a meta-analysis of the effects of antidepressants in the mouse tail suspension test (TST). A PubMed search identified studies that examined imipramine and fluoxetine effects in the TST. Inclusion criteria were testing in the light phase; trial duration was six minutes; immobility time scored 6 or (last) 4 min; adult mice; acute intraperitoneal (IP) administration. Effect sizes (ES) were estimated using Cohen's d, heterogeneity of ES with Cochran's Q test, correlations between dose and ES with Pearson's correlation and differences between strains with Analysis of variance. Results show that antidepressants decrease immobility time in the TST and a correlation between drug dose and ES but no effects of strain. We suggest that the TST is a valid tool to quantitatively, consistently and reproducibly capture the immobility-reducing aspects of fluoxetine and imipramine and that the lack of strain effects is due to small number of experiments in many of the strains.