Chronobiology of transient global amnesia

Introduction The etiology of transient global amnesia (TGA) is still a matter of debate. Based, among others, on the observation of a close temporal relation between certain events and subsequent TGA episodes, recent proposals discuss the relevance of stress-associated processes impacting on hippocampal functioning. Circadian, infra- and ultradian rhythmicity has been found to play a relevant role in the multifactorial pathomechanisms of various disorders but has not been thoroughly studied in TGA. Methods Data of patients with a final diagnosis of TGA were collected in Mannheim, Germany (06/1999–01/2018, n = 404), and in the Kansai district, Japan (04/2006–03/2018, n = 261). Chronological patterns of TGA occurrence were determined. Results Significant circadian rhythmicity of TGA occurrence with bimodal peaks (mid-morning, late afternoon) was found for the entire population (p = 0.002) and for either sub-cohort (Mannheim: p = 0.003, Kansai: p = 0.007). This finding was confirmed for either sex (women: p = 0.004, men: p = 0.004) and different age groups (< 65 years: p = 0.0009, ≥ 65 years: p = 0.003). There was no variation according to day of the week, month or season, but the proportion of patients with a weekday episode was significantly higher in the Mannheim cohort (p = 0.002). Discussion We identified a robust circadian rhythm in TGA occurrence which remarkably applied to either of the two study sites located on different continents and which was independent of sex and age. In light of abundant evidence of circadian rhythmicity of both, components of the human stress response system and memory, chronobiological analyses may provide an opportunity to further uncover the mechanisms underlying TGA.

Consequences of Chronic Stress on the PINE Network

Stress is a risk factor for the development and progression of a variety of disorders. At the same time stress is essential to initiate adaptation to the current situation and to promote survival of the fittest. Thus, responses to stress evolved to be fast and efficient. This is implemented by a tight networking of the psycho-immune-neuro-energy (PINE) system. Within the PINE network, glucocorticoids are the universal messengers that regulate overall physiology jointly with cytokines, neurotransmitters and energy status. While the secretion of glucocorticoids in response to stress is itself a rather unspecific reaction to any kind of stressor, complexity of the outcome is encoded by lifetime, recent and present events. Together, these individual experiences modulate the diurnal and ultradian rhythmicity of glucocorticoid levels. Given the time- and dose-dependency of glucocorticoid signaling, this rhythmicity allows for flexibility in the coping with stress. In a chronic stress setting, the interaction of PINE network components is altered. While stress-resilient individuals retain adaptive capacity, vulnerable individuals lose flexibility in their responsiveness. Gene × environment interactions could explain individual differences. To better elucidate the molecular underpinnings of risk and resiliency, models that allow studying the consequences of chronic stress on the PINE network are required.

Negative Energy Balance Enhances Ultradian Rhythmicity in Spring-Programmed Voles

Voles are small herbivorous rodents that can display both circadian activity rhythms (~24-h periodicity) and ultradian activity rhythms (~1- to 6-h periodicity). Ultradian rhythms are observed on an individual level, but also in synchronized populations. Ultradian rhythm period has been suggested to be influenced by energy balance, but the underlying mechanisms of ultradian rhythmicity are poorly understood. We manipulated energy balance by implementing the “work-for-food” paradigm, in which small rodents are exposed to increasing levels of food scarcity at different ambient temperatures in the laboratory. Photoperiodical spring-programmed voles on high workload changed their nocturnal circadian activity and body temperature rhythm to ultradian patterns, indicating that a negative energy balance induces ultradian rhythmicity. This interpretation was confirmed by the observation that ultradian patterns arose earlier at low temperatures. Interestingly, a positive relationship between ultradian period length and workload was observed in tundra voles. Spectral analysis revealed that the power of ultradian rhythmicity increased at high workload, whereas the circadian component of running wheel activity decreased. This study shows that the balance between circadian and ultradian rhythmicity is determined by energy balance, confirming flexible circadian and ultradian rhythms in females and males of 2 different vole species: the common vole ( Microtus arvalis) and the tundra vole ( Microtus oeconomus).

Environmental conditions alter behavioural organization and rhythmicity of a large Arctic ruminant across the annual cycle

The existence and persistence of rhythmicity in animal activity during phases of environmental change is of interest in ecology, evolution and chronobiology. A wide diversity of biological rhythms in response to exogenous conditions and internal stimuli have been uncovered, especially for polar vertebrates. However, empirical data supporting circadian organization in behaviour of large ruminating herbivores remains inconclusive. Using year-round tracking data of the largest Arctic ruminant, the muskox ( Ovibos moschatus ), we modelled rhythmicity as a function of behaviour and environmental conditions. Behavioural states were classified based on patterns in hourly movements, and incorporated within a periodicity analyses framework. Although circadian rhythmicity in muskox behaviour was detected throughout the year, ultradian rhythmicity was most prevalent, especially when muskoxen were foraging and resting in mid-winter (continuous darkness). However, when combining circadian and ultradian rhythmicity together, the probability of behavioural rhythmicity declined with increasing photoperiod until largely disrupted in mid-summer (continuous light). Individuals that remained behaviourally rhythmic during mid-summer foraged in areas with lower plant productivity (NDVI) than individuals with arrhythmic behaviour. Based on our study, we conclude that muskoxen may use an interval timer to schedule their behavioural cycles when forage resources are low, but that the importance and duration of this timer are reduced once environmental conditions allow energetic reserves to be replenished ad libitum. We argue that alimentary function and metabolic requirements are critical determinants of biological rhythmicity in muskoxen, which probably applies to ruminating herbivores in general.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Ultradian Rhythmicity in Sleep-Wakefulness Is Related to Color in Nestling Barn Owls

The possession of a rhythm is usually described as an important adaptation to regular changing environmental conditions such as the light-dark cycle. However, recent studies have suggested plasticity in the expression of a rhythm depending on life history and environmental factors. Barn owl ( Tyto alba) nestlings show variations in behavior and physiology in relation to the size of black feather spots, a trait associated with many behavioral and physiological phenotypes including the circadian expression of corticosterone and the regulation of body mass. This raises the possibility that individual spottiness could be associated with rhythmicity in sleep-wakefulness. Owlets showed ultradian rhythms in sleep-wakefulness, with a period length of 4.5 to 4.9 h. The period length of wakefulness and non-REM sleep was shorter in heavily compared to lightly spotted female nestlings, whereas in males, the opposite result was found. Furthermore, male and female nestlings displaying small black spots showed strong rhythmicity levels in wakefulness and REM sleep. This might be an advantage in a stable environment with predictable periodic changes in light, temperature, or social interactions. Heavily spotted nestlings displayed weak rhythms in wakefulness and REM sleep, which might enable them to be more flexible in reactions to unexpected events such as predation or might be a mechanism to save energy. These findings are consistent with previous findings showing that large-spotted nestlings switch more frequently between wakefulness and sleep, resulting in higher levels of vigilance compared to small-spotted conspecifics. Thus, nestlings with larger black feather spots might differently handle the trade-off between wakefulness and sleep, attention, and social interactions compared to nestlings with smaller black spots.