A Method for Predicting Ultradian Body Temperature Rhythms in Small Animals.

It has been found that the intraday dynamics of body temperature in small mammal and bird species on the adjacent day are similar. Therefore, by focusing on the body temperature dynamics of the previous day, it is possible to predict with a high degree of accuracy the periods of increase and decrease in body temperature for the current day. This phenomenon was observed when animals were kept under natural illumination and under artificial illumination when the phase of the intrinsic circadian rhythm shifted by 1-2 h every day. When analyzing this phenomenon in birds, it has been shown that the best match for body temperature dynamics occurs when comparing adjacent days based on sidereal days (a period of 23 h and 56 min). Over time, after several days, the daily patterns of body temperature fluctuation take on a completely different form and frequency. These facts suggest a connection between ultradian rhythms and the rotation of the Earth around its axis, and consequently, the position of animals on the surface of the planet relative to space objects.

Association between Ultradian Rhythms of Body Temperature in Small Mammals and Earth's Crust Stress.

Association was assessed between the data harvested by a long-baseline laser interference deformograph and the dynamics of body temperature (BT) in hamsters deprived of natural daily light-darkness changes. The power spectral data revealed the positive correlation between simultaneous time series of hamster BT and the Earth's crust deformation (ECD). The superposed epoch analysis established an association between abrupt upstrokes of hamster BT and ECD increments. Thus, the direct relationships between BT dynamics (reflecting predominance of sympathetic part of autonomic nervous system) and ECD (according to long-baseline laser interference deformography) were established. The study observed synchronization of the free-running circadian rhythm of hamster BT with the tidal stress in Earth's lithosphere. Further studies are needed to find the physical factor underlying the revealed relationships.

Multiple ultradian rhythms of metabolism, body temperature and activity in Djungarian hamsters.

Djungarian hamsters (Phodopus sungorus) living at constant 15 °C Ta in short photoperiod (8:16 h L:D) showed pronounced ultradian rhythms (URs) of metabolic rate (MR), body temperature (Tb) and locomotor activity. The ultradian patterns differed between individuals and varied over time. The period length of URs for MR, Tb and activity was similar although not identical. Wavelet analysis showed that three different URs are existing in parallel, URs of small amplitude and short duration (URsmall), URs of medium amplitude and medium duration (URmedium) and URs of large amplitude (URlarge), superimposed on each other. URlarge were accompanied by an increase in locomotor activity, whereas URsmall and URmedium were of metabolic origin with lacking or delayed responses of activity. An energetic challenge to cold which raised total energy requirements by about 50% did not accelerate the period length of URs, but extended the amplitude of URsmall and URmedium. URlarge corresponds with the URs of activity, feeding and drinking, sleep and arousal as described in previous studies, which are related to midbrain dopaminergic signalling and hypothalamic ultradian signalling. The cause and control of URmedium and URsmall is unknown. Their periods are similar to periods of central and peripheral endocrine ultradian signalling, suggesting a link with URs of metabolism.

Silencing of ultradian rhythms and metabolic depression during spontaneous daily torpor in Djungarian hamsters.

Ultradian rhythms of metabolism, body temperature and activity are attenuated or disappear completely during torpor in Djungarian hamsters, for all three ultradian periodicities (URsmall, URmedium and URlarge). URsmall and URmedium disappear during entrance into torpor, whereas URlarge disappear later or continue with a low amplitude. This suggests a tight functional link between torpor and the expression of ultradian rhythms, i.e. torpor is achieved by suppression of metabolic rate as well as silencing of ultradian rhythms. Spontaneous torpor is often initiated after an ultradian burst of activity and metabolic rate, beginning with a period of motionless rest and accompanied by a decrease of metabolic rate and body temperature. To extend previous findings on the potential role of the adrenergic system on torpor induction we analysed the influence of the ß3-adrenergic agonist Mirabegron on torpor in Djungarian hamsters, as compared to the influence of the ß-adrenergic antagonist Propranolol. Hamsters were implanted with 10 day release pellets of Mirabegron (0.06 mg day-1) or Propranolol (0.3 mg day-1). Mirabegron transiently supressed and accelerated ultradian rhythms but had no effect on torpor behaviour. Propranolol did not affect torpor behaviour nor the expression of ultradian rhythms with the dosage applied during this study.

Circadian and ultradian rhythms: Clinical implications.

The hypothalamic-pituitary-adrenal axis is an extremely dynamic system with a combination of both circadian and ultradian oscillations. This state of 'continuous dynamic equilibration' provides a platform that is able to anticipate events, is sensitive in its response to stressors, remains robust during perturbations of both the internal and external environments and shows plasticity to adapt to a changed environment. In this review, we describe these oscillations of glucocorticoid (GC) hormones and why they are so important for GC-dependent gene activation in the brain and liver, and their consequent effects on the regulation of synaptic and memory function as well as appetite control and metabolic regulation. Abnormalities of mood, appetite and metabolic regulation are well-known consequences of GC therapy, and we suggest that the pattern of GC treatment and hormone replacement should be a much higher priority for endocrinologists and the pharmaceutical industry. One of the major impediments to our research on the importance of these cortisol rhythms in our patients has been our inability to measure repeated levels of hormones across the day in patients in their home or work surroundings. We describe how new wearable methodologies now allow the measurement of 24-h cortisol profiles - including during sleep - and will enable us to define physiological normality and allow us both to develop better diagnostic tests and inform, at an individual patient level, how to improve replacement therapy.

A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.

Beyond day and night: The importance of ultradian rhythms in mouse physiology.

Our circadian world shapes much of metabolic physiology. In mice ∼40% of the light and ∼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.

Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms.

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.

The significance of ultradian oscillations in development.

Genes regulating developmental processes have been identified, but the mechanisms underlying their expression with the correct timing are still under investigation. Several genes show oscillatory expression that regulates the timing of developmental processes, such as somitogenesis and neurogenesis. These oscillations are also important for other developmental processes, such as cell proliferation and differentiation. In this review, we discuss the significance of oscillatory gene expression in developmental time and other forms of regulation.

Dietary restriction modulates ultradian rhythms and autocorrelation properties in mice behavior.

Animal behavior emerges from integration of many processes with different spatial and temporal scales. Dynamical behavioral patterns, including daily and ultradian rhythms and the dynamical microstructure of behavior (i.e., autocorrelations properties), can be differentially affected by external cues. Identifying these patterns is important for understanding how organisms adapt to their environment, yet unbiased methods to quantify dynamical changes over multiple temporal scales are lacking. Herein, we combine a wavelet approach with Detrended Fluctuation Analysis to identify behavioral patterns and evaluate changes over 42-days in mice subjected to different dietary restriction paradigms. We show that feeding restriction alters dynamical patterns: not only are daily rhythms modulated but also the presence, phase and/or strength of ~12h-rhythms, as well as the nature of autocorrelation properties of feed-intake and wheel running behaviors. These results highlight the underlying complexity of behavioral architecture and offer insights into the multi-scale impact of feeding habits on physiology.

Seasonal Influence on Salivary Myeloperoxidase Diurnal Variations in Young Healthy Subjects: A Preliminary Study.

BACKGROUND: The interaction between oxidative status markers and biological rhythms is considered particularly important in the pathogenesis of many diseases and more effective therapies. We aimed to determine if the salivary secretion of myeloperoxidase exhibits diurnal variations, and if the potential daily variability differs seasonally. METHODS: The study was performed in Poznan, Poland (52,25°N, 16,58°E) in 10 healthy male volunteers (age median 23.5 years). Whole mixed unstimulated saliva was collected in summer (August) and winter (December) during 36 h at 2-h intervals starting at 6 a.m. on Saturday and ending at 6 p.m. on Sunday, in the domestic setting. The samples were analysed for myeloperoxidase (MPO) and cortisol by immunoassays. The presence of the circadian rhythm of cortisol secretion in saliva confirmed the rhythmicity of the volunteers. RESULTS: For salivary MPO, significantly higher concentrations compared to midnight and noon were observed for 4 a.m. in both summer and winter. Using the cosinor analysis, the variations in salivary MPO levels showed a moderate fit for the 12-h period rhythm (acrophases: in summer 05:37/17:37, in winter 06:16/18:16), without significant differences in the rhythm parameters in summer and winter. However, higher self-reported Global Seasonal Score (which may predispose to seasonal affective disorder) was associated with significantly stronger relative amplitude (RS = 0.811) in winter season only. CONCLUSIONS: In conclusion, our findings suggest the possible ultradian rhythm for MPO in saliva, with two peaks during the day, regardless of the season.

Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Personalized Non-contact Sleep Stage Estimation with Weighted Probability Estimation by Ultradian Rhythm.

This paper focused on ultradian rhythms (a sleep cycle of approximately 60 to 120 minute) for personalizing sleep stage estimation, and proposed a personalized sleep stage estimation method that weights the results estimated by machine learning with the predicted ultradian rhythms. The ultradian rhythms are predicted by the body movement density which is correlated with ultradian rhythm. To investigate the effectiveness of the proposed method, this paper conducts human subjects experiment for eight subjects.Clinical relevance- The proposed method is compared with the results estimated by conventional ML, and the result of the proposed method is competitive with their conventional counterparts. This indicates that the ultradian rhythm has the potential for developing personalized sleep stage estimation.

Temporal dynamics and composition of ocular surface microbiota in C57BL/6J mice: uncovering a 12h ultradian rhythm.

Purpose: This study aimed to investigate the presence of rhythmic fluctuations in the composition, abundance, and functions of commensal core bacteria on the ocular surface of C57BL/6J mice. Methods: Male C57BL/6J mice, aged 12 weeks, were subjected to a 12-hour light/12-hour dark cycle. Ocular surface tissue samples were collected at four time points (ZT) over a 24-hour period at six-hour intervals. The core ocular surface microbiota's oscillation cycles and frequencies were assessed using 16S rRNA gene sequencing targeting the V3-V4 region, along with the JTK_CYCLE algorithm. Functional predictions of these bacteria were conducted using PICRUSt2. Results: Deep sequencing of the ocular surface microbiota highlighted the high abundance of commensal bacteria, with Proteobacteria, Actinobacteriota, and Firmicutes collectively constituting over 90% of the total sample abundance. Among the 22 core bacterial genera, 11 exhibited robust 12-hour rhythms, including Halomonas, Pelagibacterium, Pseudomonas, Nesterenkonia, norank_f_Hyphomonadaceae, Stenotrophomonas, Anoxybacillus, Acinetobacter, Zoogloea, Brevibacillus, and Ralstonia. Further taxonomic analysis indicated significant intra-cluster similarities and inter-cluster differences at the order, family, and genus levels during ZT0/12 and ZT6/18. Community interaction networks and functional prediction analyses revealed synchronized 12-hour rhythmic oscillations in neural, immune, metabolic, and other pathways associated with symbiotic bacteria. Conclusion: This study demonstrates the presence of ultradian rhythmic oscillations in commensal bacteria on the ocular surface of normal C57BL/6J mice, with a 12-hour cycle. These findings suggest a crucial role for ultradian rhythms in maintaining ocular surface homeostasis in the host.

Ultradian rhythms: Life's dance to the music of time.

A recent and updated translation of a book, earlier published in Russian in 2021, contains a fascinating account of the development of a central theme in our understanding of the kinetics of cellular growth and development (Brodsky 2022). The book deals with the twin concepts of ultradian (i.e. about one hour period) signals and cellto-cell communication. The author, Vsevolod Ya. Brodsky, has performed a major service by discussing in a comprehensive manner studies on high-frequency oscillations in intercellular communication. The book will be especially valuable to readers who are not familiar with the extensive Russian literature on the subject, much of which has been ignored elsewhere. The present Commentary uses it as a take-off point in order to highlight issues that are common to the area of biological rhythms generally and ultradian oscillations in particular. In view of the importance of the book, we critique it towards the latter part of the Commentary in the style of a book review.

Effect of Heliogeophysical and Atmospheric Factors on the Degree of Synchronization of Ultradian Rhythms of Body Temperature in Mice.

In a long-term (8 months) study, we examined the degree of synchronization of ultradian body temperature oscillations of two isolated groups of mice kept under constant dim illumination. In most cases, the periods of increased activity accompanied by rapid elevation of body temperature coincided in these groups of mice, but in some days, no significant synchronization between the examined parameters was observed. Analysis of the effects of environmental factors on the degree of synchronization of ultradian rhythms in mice revealed association of this parameter with the dynamics of atmospheric pressure (AtmP) and to a lesser extent with the vertical component of interplanetary magnetic field Bz. The loss in synchronicity of ultradian rhythms of mouse activity occurred after a rapid drop of AtmP or during pronounced negative Bz. Therefore, these factors can be viewed as desynchronizers of the biological ultradian rhythms.

Analysis of Association of Ultradian Body Temperature Rhythms in Animals with Intensity of Fluctuations of Radioactive Decay of Natural 40K Isotope.

The study monitored the long-term body temperature (BT) oscillations of C57BL/6 mice and outbred starlings (Sturnus vulgaris) to compare them with fluctuation in decay rate of radioactive natural 40K isotope. The spectrum analysis revealed simultaneous changes of the predominant periods in BT spectra of the animals and those in fluctuation in 40K decay rate. A positive correlation was established between BT dynamics and fluctuation in decay rate. The superposed epoch analysis revealed predominant coincidence of the moments of BT and fluctuation in 40K decay rate. The novel data indicate association between BT ultradian rhythms with quasirhythmic variations of fluctuation in 40K decay rate.

DEC-7/SUSD2, a sushi domain-containing protein, regulates an ultradian behavior mediated by intestinal epithelial Ca2+ oscillations in Caenorhabditis elegans.

In Caenorhabditis elegans, rhythmic posterior body wall muscle contractions mediate the highly regular defecation cycle. These contractions are regulated by inositol-1,4,5-trisphosphate (InsP3) receptor-dependent Ca2+ oscillations in intestinal epithelial cells. Here, we find that mutations in dec-7, which encodes the nematode ortholog of the human Sushi domain-containing 2 protein (SUSD2), lead to an increase in InsP3 receptor-dependent rhythmic posterior body wall muscle contractions. DEC-7 is highly expressed in the intestinal epithelia and localizes to the cell-cell junction. The increase in rhythmic activity caused by the loss of dec-7 is dependent on the innexin gap junction protein INX-16. Moreover, DEC-7 is required for the clustering of INX-16 to the cell-cell junction of the intestinal epithelia. We hypothesize that DEC-7/SUSD2 regulates INX-16 activity to mediate the rhythmic frequency of the defecation motor program. Thus, our data indicate a critical role of a phylogenetically conserved cell-cell junction protein in mediating an ultradian rhythm in the intestinal epithelia of C. elegans.NEW & NOTEWORTHY The conserved complement group protein DEC-7/SUSD2 acts at the apical cell-cell junction of C. elegans intestinal epithelia to mediate gap junction protein organization and function to facilitate a Ca2+ wave-regulated ultradian behavior.

Physiological Rhythms and Biological Variation of Biomolecules: The Road to Personalized Laboratory Medicine.

The concentration of biomolecules in living systems shows numerous systematic and random variations. Systematic variations can be classified based on the frequency of variations as ultradian (<24 h), circadian (approximately 24 h), and infradian (>24 h), which are partly predictable. Random biological variations are known as between-subject biological variations that are the variations among the set points of an analyte from different individuals and within-subject biological variation, which is the variation of the analyte around individuals' set points. The random biological variation cannot be predicted but can be estimated using appropriate measurement and statistical procedures. Physiological rhythms and random biological variation of the analytes could be considered the essential elements of predictive, preventive, and particularly personalized laboratory medicine. This systematic review aims to summarize research that have been done about the types of physiological rhythms, biological variations, and their effects on laboratory tests. We have searched the PubMed and Web of Science databases for biological variation and physiological rhythm articles in English without time restrictions with the terms "Biological variation, Within-subject biological variation, Between-subject biological variation, Physiological rhythms, Ultradian rhythms, Circadian rhythm, Infradian rhythms". It was concluded that, for effective management of predicting, preventing, and personalizing medicine, which is based on the safe and valid interpretation of patients' laboratory test results, both physiological rhythms and biological variation of the measurands should be considered simultaneously.

A dynamically coherent pattern of rhythms that matches between distant species across the evolutionary scale.

We address the temporal organization of circadian and ultradian rhythms, crucial for understanding biological timekeeping in behavior, physiology, metabolism, and alignment with geophysical time. Using a newly developed five-steps wavelet-based approach to analyze high-resolution time series of metabolism in yeast cultures and spontaneous movement, metabolism, and feeding behavior in mice, rats, and quails, we describe a dynamically coherent pattern of rhythms spanning over a broad range of temporal scales (hours to minutes). The dynamic pattern found shares key features among the four, evolutionary distant, species analyzed. Specifically, a branching appearance given by splitting periods from 24 h into 12 h, 8 h and below in mammalian and avian species, or from 14 h down to 0.07 h in yeast. Scale-free fluctuations with long-range correlations prevail below ~ 4 h. Synthetic time series modeling support a scenario of coexisting behavioral rhythms, with circadian and ultradian rhythms at the center of the emergent pattern observed.