Internal Rhythms

A free running rhythm refers to the genetically determined internal rhythm that a healthy individual displays when isolated from all external time cues.

From: Progress in Neurobiology, 2009

Circadian System

Ana Beatriz Rezende Paula, ... Mauro César Isoldi, in Advances in Protein Chemistry and Structural Biology, 2023

3 Light as a modulator of cardiac protein expression

Much is known about the synchronization of internal rhythms with the light/dark cycle and the effect of different wavelengths, intensities, and timing of light on human physiology and behavior. A lot of research involving the environmental light track has been carried out under controlled laboratory conditions. Since the circadian clock evolved under natural conditions long before artificial light existed, research has been conducted today on the effects and impacts of daylight on the physiology of living things, despite the unpredictable and less controllable variations of environmental light (Danilenko, Wirz-Justice, Kräuchi, Weber, & Terman, 2000; Webler, Spitschan, Foster, Andersen, & Peirson, 2019).

Light is a crucial environmental cue for vision and for the entrainment of the central clock in the suprachiasmatic nucleus, mediated by melanopsin which is found localized in the intrinsically photosensitive ganglion cells of the retina (Aranda & Schmidt, 2021). Several physiological processes are modulated by light, such as sleep, alertness, pupil size and synchronization of circadian rhythms (Beier, Zhang, Yurgel, & Hattar, 2021).

Alterations in circadian rhythms arising from jet lag or shift work, can lead to damage of central oscillators (Witte et al., 1998) and impairment in the drag of internal clocks with the LD cycle, due to internal desynchronization between the central clock and peripheral oscillators (Molcan, Vesela, & Zeman, 2016). Such damage caused by these events and/or conditions is associated with the development of various disorders, such as cardiovascular disease (Khan, Duan, Yao, & Hou, 2018). Furthermore, recent studies have pointed to the impacts of artificial light on circadian rhythms. Normotensive and hypertensive rats exposed to artificial light for five weeks showed changes in protein expression in the left ventricle of the heart, in addition to reduced expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2), endothelin 1 (ET-1), and the angiotensin II type 1 receptor (Ag-II), important regulators of cardiac contraction (Sutovska, Miklovic, & Molcan, 2021). Heart rate and contractility of the heart are modulated via the autonomic nervous system, through the SERCA2 protein. This protein is involved in the regulation of cytoplasmic calcium by pumping calcium from the cytosol to the sarcoplasmic reticulum (Bovo, Huke, Blatter, & Zima, 2017). Its regulation occurs by phospholamban phosphorylation through stimulation of protein kinases A and C which is triggered by catecholamines, angiotensin 2 and ET-1, thus modulating cardiac activity (Okumura et al., 2014). In contrast, the return of calcium to the cytosol occurs through the ryanodine receptor 2 (Bovo et al., 2017). In short, artificial light would be activates the SCN, in the dark phase, and suppressing the activity of the autonomic nervous system and adrenal glands, leading to reduced calcium loading of the heart (Kalsbeek et al., 2012; Molcan et al., 2019).

Many cardiovascular parameters oscillate during the 24-hours period, such as metabolism, heart rate, cardiac output, and the synthesis and release of hormones (Durgan et al., 2005). Some cardiovascular events, such as acute myocardial infarction, ventricular tachyarrhythmias, and ruptured aortic aneurysms, are also influenced by circadian machinery, peaking in the morning (Cohen, Rohtla, Lavery, Muller, & Mittleman, 1997; Eksik et al., 2007; Manfredini et al., 2004). Rotter et al. (2014) sought to test whether calcineurin and the cardioprotective protein regulator calcineurin 1 (RCAN1), contribute to the circadian rhythm by protecting against cardiac damage from ischemia and reperfusion. WT mice, nocautes for Rcan1 (Rcan1-KO) and overexpressed for Rcan1 (Rcan1-Tg) were subjected to myocardial ischemia in a light-on condition between 10 am and 10 pm (AM) or between midnight and noon (PM). Surgeries occurred within the first two hours (AM) or the last two hours (PM) of the light phase. A ligature was performed on the left descending coronary (LAD) resulting in an ischemia, encompassing 60% of the left ventricle (LV). After 45 minutes of ischemia, the ligature was removed and reperfusion was confirmed. Western blotting reported that protein levels of the RCAN1.4 isoform were higher in ZT1 compared to ZT11. However, protein levels of RCAN1.1 and the catalytic subunit of calcineurin did not differ between ZTs. After 3 hours of infarction and reperfusion, the protein levels of RCAN1.4 increased regardless of the light exposure period (AM and PM). That is, the calcineurin/Rcan1.4 feedback loop is activated in response to I/R, regardless of the time of day when the challenge occurs. Even 24 hours after infarction, protein levels of RCAN1.4 remained elevated. Importantly, calceurin is a protein involved in synaptic signaling, neuron survival, cytokine production, and angiogenesis processes that contribute to myocardial survival after an episode of infarction.

Worthy of note, it is important to point out that circadian variations occur at both the physiological and molecular levels of the heart (Martino et al., 2004). At the transcriptional level, the mRNA profile exhibits rhythms throughout the LD cycle. These oscillations are essential for coordinating biological and biochemical processes in cardiac physiology. However, proteins are fundamentally important in the underlying processes. However, gene and protein expression levels do not always correlate, due to post-translational mechanisms (Nickel & Rabouille, 2009). It is estimated that about 7.8% of the soluble cardiac proteome varies over 24-hour cycles. Of these 90 spots (7.8%), 38 exhibit higher abundance in the light period (sleep time of mice), and 52 predominate in the dark period (wake time of mice). Among the various proteins present in the heart, noteworthy the trifunctional enzyme-β subunit, mitochondrial (HADHB), δ-1-pyrrolinie-5-carboxylate dehydrogenase, mitochondrial (P5CDh), aconitate hydratase, mitochondrial (ACO2), protein kinase CAMP-activated catalytic subunit α (PRKACA), ATP synthase-α, mitochondrial (ATP5A1), stress-induced phosphoprotein-1 (STIP1), peroxiredoxin-1 (PRDX1), insulin-like growth factor II (IGF2), inner membrane protein, mitochondrial (IMMT), and heat shock protein family D member 1 (HSPD1) (Podobed et al., 2014). Podobed et al. (2014), seeking to understand the relationship between the circadian clock and protein expression, evaluated the cardiac proteome in a CCM mouse model. They observed alterations in temporal expression profiles, with the most prominent proteins in the hearts of CCM animals being pyruvate dehydrogenase E1a, mitochondrial (PDHE1a), aspartate aminotransferase, mitochondrial (GOT2) and dihydrolipoamide S-succinyltransferase (DLST), while proteins of lower expression were P dehydrogenase, mitochondrial (ALDH2), lactate dehydrogenase B (LDHB), enoyl CoA hydratase, mitochondrial (ECHS1) and hydroxybutyrate dehydrogenase, mitochondrial (BDH1). Regulation of PDHE1a and LDHB occurrs at the translational level contributing to the observed rhythms in glucose and lactate metabolism and is supported by previous observations that rhythmic cardiac glucose and lactate metabolism are disrupted in CCM mice (Durgan, Pat, et al., 2011). Furthermore, the post-translational modification of the PDH protein in CCM hearts is potentially phosphorylation. PDH, when phosphorylated, is inactivated. Decreased PDH activity, in addition to decreased LDHB, ECHS1, and BDH1, may limit the acetyl-CoA production in CCM hearts. In other words, part of the cardiac proteome is regulated by the circadian clock, both modulating total protein levels and post-translational modifications (Podobed et al., 2014).

Studies have pointed to the effects of an altered LD cycle on cardiovascular physiology (Martino et al., 2007) and in the expression of cardiac molecules (Martino & Sole, 2009). Seeking to understand the effects of altered LD cycling on cardiovascular health and the cardiac proteome, WT animals were subjected to an established LD disruption protocol (10:10 L/D). Altered protein profiles of ALDH4A1, STIP1, IGF2, PER2 proteins and implications for cardiac function were identified. These findings highlight for the effects of circadian disruption, such as shift work, on cardiovascular health (Podobed et al., 2014).

In summary, these findings highlight for the effects of LD cycle manipulation on cardiac proteomics, which differs, quantitatively, within the 24 hours cycle (LD cycle). Variations in protein expression in the heart as well as cardiac function are dependent on the circadian clock mechanism of cardiomyocytes (Fig. 2). Therefore, further studies are needed for a better understanding of cardiovascular physiology and its disorders.

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Sleep and Wakefulness

Suzanne Stevens, Wayne A. Hening, in Textbook of Clinical Neurology (Third Edition), 2007

Circadian Rhythm Disorders

This group of disorders involves a disruption of the inherent circadian pattern of wakefulness and sleep.36 Jet lag arises from transmeridian flights of long duration, usually through at least three time zones, and reflects the adaptation necessary to reset the internal rhythm to the day‐night cycle of the destination. Jet lag is enhanced by the sleep deprivation that usually occurs before a prolonged trip, loss of sleep, and altered conditions during flight. Depending on the distance traveled, recovery may take 7 days or more, especially for eastward travel.

Circadian rhythm disorders may also present as sleep‐onset insomnia.62 Patients with irregular sleep hours, such as shift workers or international travelers, are continuously fighting their inherent circadian rhythms. In particular, travel in an eastward direction may provoke an inability to sleep at the desired times in the new time zone. Adolescents are often phase delayed, becoming so‐called “night owls,” preferring a later bedtime and awakening time. In some individuals, this pattern may carry over into adulthood, causing significant problems with maintaining an acceptable job schedule. These patients may be incorrectly diagnosed with sleep‐onset insomnia rather than phase‐delayed sleep. In phase‐advanced sleep, the major sleep period occurs early so that bedtime and final awakening occur before the desired times, which is a frequent complaint of the elderly.

In contrast, shift workers are required to change their major sleep period without the reinforcement of external light‐dark cycles and in the absence of social patterns that conform to their new sleep schedule. Following a single change in shift, 2 weeks may be needed for readjustment. However, often shift workers are required to change their schedules every 2 to 4 weeks and frequently are progressively changed from night to afternoon to morning shifts. Thus, they may have a chronic desynchronization with their circadian clock.

Finally, there are so‐called “natural night owls” and “morning larks” who are most comfortable with their major sleep period either later or earlier than can accommodate socially acceptable daytime activities, such as work or school.

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Circadian System

André Furtado, ... Telma Quintela, in Advances in Protein Chemistry and Structural Biology, 2023

Abstract

Molecular clocks are responsible for defining 24-h cycles of behaviour and physiology that are called circadian rhythms. Several structures and tissues are responsible for generating these circadian rhythms and are named circadian clocks. The suprachiasmatic nucleus of the hypothalamus is believed to be the master circadian clock receiving light input via the optic nerve and aligning internal rhythms with environmental cues. Studies using both in vivo and in vitro methodologies have reported the relationship between the molecular clock and sex hormones. The circadian system is directly responsible for controlling the synthesis of sex hormones and this synthesis varies according to the time of day and phase of the estrous cycle. Sex hormones also directly interact with the circadian system to regulate circadian gene expression, adjust biological processes, and even adjust their own synthesis. Several diseases have been linked with alterations in either the sex hormone background or the molecular clock. So, in this chapter we aim to summarize the current understanding of the relationship between the circadian system and sex hormones and their combined role in the onset of several related diseases.

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Mammalian Hormone-Behavior Systems

Matthew P. Butler, ... Rae Silver, in Hormones, Brain and Behavior (Third Edition), 2017

Amplitude: The strength or magnitude of an oscillation.

Arrhythmia: When a system that is normally rhythmic loses rhythmicity. For example, lesions of the SCN lead to arrhythmia in mice.

Circadian time (CT): Unit of time based on an organism's free-running period. Typically CT0 is the onset of activity in diurnal organisms and CT12 is the onset of activity for nocturnal organisms.

Circadian: A cycle or oscillation with a period close to 24h, from circa = about and diem = day. This term is generally used to describe processes that are endogenously driven and that will persist in the absence of any external cues, such as light.

Clock gene: A gene involved in the basic genetic negative feedback loops underlying circadian rhythms.

Desynchronization: When a rhythm becomes uncoupled from a synchronizing cue or when two or more internal rhythms are no longer coupled.

Diurnal: Used to describe rhythmic phenomena that are not endogenous but rather driven by the external light–dark cycle. Also used to refer to day-active animals.

Endogenous rhythm: Self-sustained rhythm that persists in constant conditions, such as constant darkness.

Entrainment: Synchronization of the circadian system to external cues. The light–dark cycle is the dominant entraining signal for most organisms, but other cues, such as food, can also entrain organisms.

Free-running: The state of an oscillator running at its own endogenous period, without external perturbations, such as entrainment to a light–dark cycle. The free-running period of an animal is usually measured in constant darkness.

Nocturnal: Night active.

Pacemaker: Anything that can generate robust, endogenous rhythms and can synchronize other rhythmic entities to its own rhythm. The SCN is the master pacemaker, responsible for synchronizing all of the body's rhythms to its own.

Period: The duration of a cycle or oscillation, typically close to 24 h for circadian processes.

Phase: The time at which a cyclic event occurs as measured against a reference time frame, such as time of day. A phase advance causes the event to occur earlier in the day, while a phase delay causes it to occur later.

Subjective day/night: Under free-running conditions subjective day is the period from CT0 to CT12, when diurnal organisms would typically be active. Subjective night is the period from CT12 to CT0 when nocturnal organisms would typically be active.

Zeitgeber: Any cue or signal that can synchronize or entrain a rhythm. For example light is a very powerful zeitgeber capable of entraining the body clock to environmental light/dark cycles. Zeitgeber time (ZT) is a unit of time measured from the onset of a zeitgeber. For example, ZT0 is the moment when the cue appears and ZT12 is 12 hours after the cue is presented.

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Metabolic Aspects of Aging

Yih-Woei Fridell, Felipe Sierra, in Progress in Molecular Biology and Translational Science, 2018

6 Circadian regulation and CR

Much advance has been made in the last 2 decades in elucidating the mechanisms whereby CR exerts its positive effects on longevity and healthspan. While the precise molecular mechanisms are yet to be determined, three cellular pathways including the mTOR pathway, the insulin/IGF-1 system, and the sirtuin-regulated pathway have been shown to be conserved in mediating CR effects in model organisms.47,48 More recently, emerging research has revealed a new and exciting connection between CR mediators and circadian rhythm.

The central and peripheral circadian clock systems coordinate an internal rhythm to maintain many aspects of physiology and behavior. Metabolic homeostasis and circadian clocks are interdependent and feeding is one of the stimuli capable of entraining peripheral clocks.49 For example, time-restricted feeding of nocturnal mice during daytime shifted the phase of several peripheral clocks significantly within 1 week of feeding, including the liver clock, which exhibited a rapid phase shift within 2 days of altered feeding schedule.50,51 To investigate a role of circadian regulation in CR-mediated longevity and health benefits, Katewa et al. demonstrated that in Drosophila mutations of the core circadian molecules timeless or period attenuated DR-mediated lifespan extension.52 In addition, consistent with a link between circadian regulation and metabolism, mutations in timeless or period abolish the changes in fat turnover upon DR, whereas overexpression of timeless in peripheral tissues improves fat metabolism and extends lifespan of flies fed on control diet. As overexpression of timeless enhances the amplitude of its rhythmicity, these results suggest an intriguing notion that optimal circadian regulation may mimic DR in modulating metabolic control in promoting longevity.52

The mammalian circadian clock network consists of transcriptional feedback loops including transcription factors CLOCK and BMAL1, which form a complex and regulate the transcription of other clock genes, Periods (Per1 and Per2) and Cryptochromes (Cry1 and Cry2), whose activities, in turn, inhibit CLOCK:BMAL1 transcriptional activity forming a negative feedback mechanism. The expression of Bmal1 can also be controlled by molecules constituting an “accessory loop.”53 Consistent with fly studies,52 interactions between clock genes and CR effects in rodents have been demonstrated. First, CR significantly affects the rhythmicity of expression of circadian clock genes at both transcription and translation levels, resulting in modulated expression of several clock-controlled transcriptional factors and putative longevity genes.54 Second, CR-dependent effects on some clock gene expression were absent in the liver of mice deficient for Bmal1 suggesting both BMAL1-dependent and BMAL1-independent mechanisms in orchestration of the circadian clock network.55 Third, the importance of BMAL1-dependent clock function in CR was illustrated in Bmal1-deficient mice, which failed to respond to CR-mediated lifespan extension.55 While CR significantly reduces circulating IGF-1 and insulin levels in wild-type mice, such responses were substantially diminished in Bmal1/ mice, suggesting BMAL1-dependent circadian clock function as an essential mediator of CR.

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Circadian Rhythms in Older Adults

Gregory J. Tranah, ... Sonia Ancoli-Israel, in Principles and Practice of Sleep Medicine (Sixth Edition), 2017

Pathophysiologic Mechanisms

In interpreting the foregoing results, two possibilities should be considered. First, activity rhythms may directly influence morbidity and mortality in older adults independent of other features of aging. In support of this association, emerging animal and human data show the existence of both central and peripheral (e.g., in the liver, pancreas, and other organs) circadian rhythms, with evidence that misalignment of internal rhythms may be a predisposing factor for impaired glucose tolerance and alterations in immunologic and inflammatory processes. Previous studies suggested that some but not all peripheral circadian oscillators exhibit age-related changes in rhythmicity61 and that some of these tissues retained the capacity to oscillate but were not being appropriately driven in vivo (e.g., by physical activity or feeding).62 The presence of arrhythmic peripheral tissues may be due to weakened behavioral and physiologic rhythms that provide less effective signals to the peripheral oscillators.54 The change in phase relationships of behavioral and physiologicl rhythms, therefore, may not be due to age-related changes in the entrained phase of the SCN itself but rather may arise from age-related alterations in other rhythmic components of the circadian system.39 Evidence of an age-related phase advance is clear from studies involving body temperature, sleep-wake cycle, melatonin, and cortisol,37 in which a phase difference of approximately 1 hour typically is found between young and old individuals. Age-related phase advances also are found in the circadian rhythms of blood pressure, levels of iron and magnesium, and numbers of neutrophils and lymphocytes.38 Acrophase deviations from the mean may represent an altered phase relationship between the circadian activity rhythm and the light-dark cycle.

For example, the circadian timing system most likely affects memory, cognitive function, and behavior through a variety of neuroanatomic and neurophysiologic mechanisms.63 The circadian contribution to cognition also may arise from the synchronized activities of an integrated network of clocks in the brain under the direction of the SCN pacemaker.64 It is also possible that circadian activity rhythms are biomarkers of advanced physiologic aging that provide additional risk over and beyond that of traditional covariates, but which may have no direct causal association with dementia or MCI. Sleep and rhythm disturbances are common in many neurodegenerative diseases including Alzheimer disease,65-67 dementia,68 and Lewy body disease.69 The major sleep complaints associated with neurodegenerative diseases include insomnia, hypersomnia, parasomnia, excessive nocturnal motor activity, sleep apnea, and sleep-wake rhythm disturbances.70 Sleep is disturbed early in the neurodegenerative process, and sleep disturbances are observed in the presence of MCI.71,72 Furthermore, it has been suggested that sleep disturbance increases with severity of the neurodegeneration.73 Although neurodegenerative diseases are believed to be proteinopathies resulting from excessive protein misfolding and intracellular protein aggregation, the role of sleep and rhythm disturbances in the neurodegenerative process has been largely unexplored. The accumulation of amyloid-beta in the brain extracellular space is a critical factor in the pathogenesis of Alzheimer disease, and both the sleep-wake cycle and orexin have been shown to play a role in regulating amyloid-beta dynamics.74 Orexins and their receptors are involved in a number of central75 and peripheral76 functions and play an important role in maintaining wakefulness by preventing unwanted transitions into sleep, as seen in narcolepsy.77

A second possible mechanism to consider in interpreting the evidence to date is that circadian activity rhythms are biomarkers of advanced physiologic aging that provide additional risk over and beyond that of traditional covariates, but which may have no direct causal association with mortality. In this instance, available data may provide evidence that circadian activity rhythms are markers for a greater risk for disease or death not measured by conventional markers. Although the biologic mechanisms underlying the associations between disrupted activity rhythms and increased risk of cardiovascular events are unknown, the results of the study by Paudel and associates38 suggest that the associations are independent of age, race, instrumental activities of daily living impairments, smoking status, cognitive function, use of antidepressants, walking for exercise, and history of CVD, stroke, or peripheral vascular disease. Although it generally is perceived that circadian rhythm disruptions precede CVD-related events, it is plausible that comorbid CVD and/or other conditions such as diabetes worsen circadian rhythm disruptions through their debilitating impact on sleep-wake activity. It also is possible that circadian rhythms and conditions such as diabetes share common causative factors.

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Neuroplasticity

Simone Rossi, ... Matteo Feurra, in Handbook of Clinical Neurology, 2022

Brain Oscillations in Brain Disorders and Their Modulation

The association of different patterns of brain oscillations with a certain behavior does not answer the central question whether they are really necessary for task completion or instead they reflect simple epiphenomena of the task. The same concept applies to the relationship of brain oscillations with clinical manifestations of neurologic or psychiatric disorders. However, in these cases, there is mounting literature supporting a link between loco-regional dysfunctions and specific patterns of rhythmic activities, as well as their (dys)-synchrony within specific networks (Uhlhaas and Singer, 2010; Uhlhaas and Singer, 2012). For example, it is now clear that exaggerated activity of the beta band in cortical (motor and premotor cortices, supplementary motor area) and subcortical (subthalamic nuclei and cerebellum) circuits sustains bradykinesia in Parkinsonian patients, and that electric stimulation of the subthalamic nucleus restores such an activity to more physiologic levels, while increasing gamma activity and reducing motor symptoms (Muthuraman et al., 2020).

Alteration of neural dynamics in the gamma range in schizophrenic patients performing different cognitive tasks is consistent with the notion that gamma activity is constitutive for physiologic cortical functions (Fries, 2009). Indeed, abnormalities in the gamma range may be associated with impairment of several cognitive function, such as those in autism spectrum disorders and Alzheimer's Disease (AD) (Uhlhaas and Singer, 2010). In 2013, the Food and Drug Administration approved the ratio between beta activity (usually reduced) and theta activity (usually increased) in frontal regions as the first EEG biomarker to support the clinical diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD).

Thus, neural oscillations and their degree of synchronization seem to represent suitable markers of large-scale coordinated dynamics of distributed brain functions, both in the healthy and diseased brains. From a translational perspective, the possibility of modulating these oscillatory activities with noninvasive brain stimulation methods has helped to clarify these issues, opening new opportunities both for research and possibly for clinical applications.

Transcranial magnetic stimulation (TMS)

Research on TMS for the investigation of induced brain oscillatory activity has basically leveraged on two different approaches that combine the simultaneous use of TMS and EEG. The first approach is based on the application of a short train of rTMS, with pulses delivered at a given frequency on a brain region, so that the local endogenous rhythm can be “entrain” at that specific frequency. The second one is based on online TMS-EEG co-registration methods and considers the delivery of focal single pulses inducing a sort of resonance of the “natural frequency” of the stimulated region that depends on the engaged cortico-thalamic modules (Rosanova et al., 2009).

Other studies using offline EEG recordings following prolonged rTMS intervention to determine changes in spontaneous oscillations, either in healthy subjects or in patients with neuropsychiatric diseases, will not be discussed in the current survey.

Bursts of rTMS

The first study in this sense used short rTMS bursts of stimulation applied at the individual alpha activity plus 1 Hz on frontal and parietal sites (Klimesch et al., 2003). The concept behind was that, if the initial level of alpha activity in a reference interval preceding a cognitive task predicts successful task performance, then “entraining” it with rTMS would likely improve that task. Indeed, this was the case. After rTMS, performance in a mental rotation task improved and alpha activity entrained in the reference interval increased, followed by a greater event-related alpha desynchronization that was causal for performance. In the following years, many studies (reviewed in fig. 2 of Thut and Miniussi, 2009) addressed the question whether repeated bursts of rTMS modified the ongoing oscillatory activity. They showed that rTMS over the motor cortex or early visual areas mostly affected activity in the alpha and beta bands, whereas stimulation of the dorsolateral prefrontal cortex (DLPFC) interfered with slower EEG bands. Interestingly, after-effects were widespread to brain regions other than the stimulation target, suggesting possible network interactions. There have also been attempts to synchronize two distant brain regions, such as the motor and visual cortices, by simultaneous stimulation in alpha frequency range. The simultaneous EEG recordings showed increased interregional coherence in this band, but behavioral consequences were not addressed (Plewnia et al., 2008).

Thut et al. (2011) demonstrated that short bursts of rhythmic rTMS may cause local entrainment of natural brain oscillations, emulating the oscillations that accompany a cognitive task. They used rTMS with alpha range frequency based on MEG-derived oscillations of the stimulated parietal cortex during a visual attention task. The endogenous alpha activity was effectively entrained with progressive synchronization (i.e., alpha-phase locking) of the parietal oscillator during the rTMS burst. These phenomena did not occur in several control conditions. Unfortunately, the effects on perception or attention were not directly assessed, although the strict relationships between alpha activity and performance was thoroughly discussed (Thut et al., 2011).

Outside the visual domain, the rTMS-induced entrainment approach has provided important information regarding the causal role of brain oscillations in working and episodic memory tasks (Hanslmayr et al., 2019). rTMS at theta frequency applied over the left intraparietal sulcus increased working memory performance. This occurred in parallel with an increase of theta oscillations not only during the stimulation but also after the rTMS burst (Albouy et al., 2017), accompanied by increased parieto-frontal connectivity in the theta range.

Finally, Hanslmayr et al. (2014) elegantly showed the causal role of beta desynchronization in frontal areas for successful completion of a verbal episodic memory task. They applied a burst of ~ 18.5 Hz rTMS to the left inferior prefrontal cortex during encoding, a stimulation that impaired the memory trace formation and entrained the beta activity for 1.5 s after the stimulation. This occurred only when the individual beta frequency stimulation matched the stimulated frequency, thus suggesting that rTMS drove a functionally relevant internal rhythm (Hanslmayr et al., 2014).

Evoked oscillations by single-pulses TMS-EEG

Another approach is based on the delivery of single-pulse TMS over a specific brain area to induce topographically organized resonant oscillations (Rosanova et al., 2009). The electric activity of the resting brain is organized into complex thalamo-cortical and cortico-cortical interactions that oscillate in a loco-regional manner (Steriade et al., 1990). In healthy awake subjects, an external perturbation, as the one induced by a TMS pulse, gives rise to dominant alpha oscillations when applied over visual areas (such as area 19), to dominant beta oscillations when applied on a parietal region (such as area 7) and to faster beta-gamma oscillations when applied on a frontal area (such as area 6). These patterns occur after an early stereotyped response around 20 ms and persist a sufficient time for detecting them in the EEG analysis (Rosanova et al., 2009). The induced oscillations could emerge following the reset of the spontaneous rhythm (i.e., the natural frequency) of the stimulated area (Paus et al., 2001; Fuggetta et al., 2005). Such a phase-resetting of ongoing oscillations has been repeatedly described after TMS delivered on the motor cortex (Brignani et al., 2008; Veniero et al., 2011).

Whichever the mechanisms involved, loco-regional perturbation-evoked brain oscillations may represent a powerful tool to investigate neurologic and psychiatric disorders from an unexplored perspective.

Clinical applications

The number of clinical applications of TMS-evoked oscillations in psychiatry and neurology is increasing; they include also the investigation of the mechanisms of action of drugs on the central nervous system. With this approach, it has been found that patients with schizophrenia, unlike normal subjects, failed to respond to TMS over area 6 with beta-gamma oscillations, while preserving the other oscillatory patterns in response to stimulation of parietal and occipital regions (Ferrarelli et al., 2008). Similar results were obtained in major depression and bipolar disorders that share with schizophrenia a common GABA-ergic dysfunction (Canali et al., 2015).

Major depression is also linked to the presence of cortical EEG asymmetries in frontal regions with hypoactivity of the left hemisphere and hyperactivity of the right (Davidson, 2004). In an interesting case report of a patient with major depressive disorder, Pellicciari et al. (2017) utilized a protocol with theta burst (TBS) of the DLPFC, with inhibitory continuous (cTBS) over the right hemisphere and excitatory intermittent (iTBS) on the left. After 10 days of this intervention, the Hamilton depression scale score decreased from 18 to 13 and the frontal oscillatory activity evoked by single TMS pulses of the DLPFCs was examined. In the left DLPFC the local amount of alpha and theta bands oscillations decreased, while faster frequencies such as beta and gamma bands increased. Conversely, in the right DLPFC, local alpha band oscillations increased significantly, while the other frequencies showed an increasing trend (Pellicciari et al., 2017). Therefore, TMS-evoked oscillations could represent a suitable neurophysiologic marker for explaining the clinical outcome in depression.

The same research team studied TMS-evoked oscillations also in Alzheimer's disease. After 2 weeks of excitatory rTMS of the left precuneus, a central node of the Default Mode Network, at 20 Hz they evaluated changes of cortical connectivity with TMS-EEG and the clinical outcome (Koch et al., 2018). In parallel with memory improvement, they found increased beta power in the left precuneus, a change that usually reflects memory enhancement (Feurra et al., 2016). Importantly, the increase was confined to the beta range, likely reflecting the long-lasting entrainment of the frequency used in the rTMS treatment (Koch et al., 2018) (see also Chapter 31).

TMS-EEG has been applied in a unique study to investigate the mechanisms of spontaneous motor recovery following a stroke. TMS was applied over the motor and posterior parietal cortices (PPC) of the affected and unaffected hemisphere were evaluated in patients within 20 days from the occurrence of a subcortical stroke and longitudinally for a period of 180 days (Pellicciari et al., 2018). At baseline, TMS-evoked oscillations in the alpha and beta ranges decreased when the motor cortex was stimulated in both hemispheres, while delta activity increased in the unaffected hemisphere. At all follow up testing points, only alpha-evoked oscillations were constantly higher in the affected hemisphere. These findings were spatially specific, as TMS-evoked oscillations of the PPC did not change. TMS-evoked alpha activity tested at 20- and 40-day follow-up predicted motor recovery (Pellicciari et al., 2018). This approach can open an innovative manner to assess the clinical evolution of sudden lesional events.

Finally, the administration of drugs may change the pattern of TMS-induced oscillations. For instance, GABA-A-ergic drugs such as diazepam, alprazolam and zolpidem increase synchronization in the lower alpha range, while GABA-B-ergic drugs such as baclofen decrease synchronization in the lower alpha range but increased it in the higher alpha band. Both classes of drugs increase desynchronization in the higher beta-band (Premoli et al., 2017).

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Volume 2

Yoshiki Tsuchiya, ... Kazuhiro Yagita, in Encyclopedia of Sleep and Circadian Rhythms, 2023

Introduction

Homeostasis is a fundamental concept for the maintenance of constant internal conditions in body physiology including body temperature, pH, osmolarity, blood pressure, hormones, and metabolites. It is critically important for living organisms to keep their internal environment within a range of physiological settings. Feedback regulations such as the hypothalamus-pituitary axis of endocrine systems represent the mechanism for keeping internal homeostasis. On the other hand, it is also necessary for organisms to adapt to internal and external changing environment. Especially, adaptation to diurnal environmental changes is of particular importance for most organisms living on the earth. In humans, diverse physiological phenomena including sleep–wake cycles, body temperature, hormone secretion, and metabolisms show clear circadian rhythms (Fig. 1) (Aschoff, 1984; Hastings et al., 2003; Bass and Takahashi, 2010). These observations exemplify the concept of circadian homeostasis, in which internal conditions are actively modulated to fit diurnal fluctuation of environment. Earlier studies have shown that the sleep–wake cycle free-runs with a longer period than 24 h in human subjects isolated in a deep cellar without any external time cues (Aschoff and Wever, 1962; Wever, 1979), indicating that circadian rhythms are endogenous rhythms produced by the intrinsic autonomous mechanism, which is called the circadian clock. The circadian clock makes an internal rhythm of about 24 h and temporally integrate physiological functions and behavior to exert their efficient coordination. Both the circadian clock and homeostatic regulations contribute to appropriate maintenance of body physiology. For instance, an adrenocortical hormone glucocorticoid (cortisol in humans) is known to show circadian variation with a peak phase in the early morning (Kadmiel and Cidlowski, 2013). Cortisol promotes gluconeogenesis and increases blood glucose levels. Circadian variation of blood cortisol could play a role in maintaining blood glucose homeostasis by increasing blood glucose levels in the early morning. In this way, diverse physiological processes are regulated by interplay between the circadian clock and homeostatic regulation.

Fig. 1. The circadian clock controls daily physiological rhythms. The master circadian pacemaker in the SCN controls whole-body physiology with both neural and humoral factors. Core body temperature, blood cortisol and melatonin levels as well as autonomic nerve activities show diurnal oscillations through the 24 h sleep/wake cycle, in which gray shadings indicate sleep.

Most organisms living on the earth, from cyanobacteria to humans, have circadian rhythms. Circadian rhythms are observed in a wide range of the hierarchical structure from sleep–wake rhythms and body temperature rhythms at the organismal level to diurnal fluctuations in cellular functions and gene expression patterns at the cellular level. The phases of rhythms widely distribute in a day among various physiological processes and are also different across species, between diurnal and nocturnal patterns of activity. For example, in humans, the core body temperature is high in the afternoon, decreases during night, and reaches a nadir in the early morning, while nocturnal rats are known to have the highest body temperature at night. The regulation of body temperature depends on heat production and heat dissipation and its rhythm is not a direct reflection of rest and activity because the rhythm is observed even in the absence of sleep (Aschoff et al., 1974; Kräuchi, 2002). Circadian rhythms are also observed in hormone secretion. As noted above, the blood cortisol level is highest in the early morning and lower from evening to night. The serum concentration of melatonin, which is secreted by the pineal gland, reaches the peak at night (Cardinali and Pévet, 1998). As for gene expression, circadian expression of a distinct set of tissue-specific genes is observed in diverse types of organs and tissues. These rhythms across multiple spatial and temporal hierarchies are not simply the result of a sequential cascade reactions but are coordinately synchronized and orchestrated by the circadian clock. Such a coordination of whole-body rhythms should play a crucial role in homeostatic regulation, and thus, the disruption of coordinated rhythms can be associated with multiple diseases including metabolic and cardiovascular diseases and cancers.

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URL: https://www.sciencedirect.com/science/article/pii/B9780128229637002929

Environmental stimulus perception and control of circadian clocks

Nicolas Cermakian, Paolo Sassone-Corsi, in Current Opinion in Neurobiology, 2002

Environmental cues can reset daily the phase of molecular internal rhythms, ensuring that the organism's behaviour remains tied to the rhythms in its environment. The main resetting cue for animals is light, provided by the day-night cycles [1–3]. Light signals are perceived by the retina and information is conveyed to the SCN through the retinohypothalamic tract (RHT) [4], and induces in retinorecipient neurons of the SCN a cascade of events including the activation of mitogen-activated protein kinases (MAPKs) [5] and cAMP-responsive element binding protein (CREB) [6•,7•], upregulation of several genes including clock genes [1,2] and specific chromatin modification [8] (Fig. 1a). Here, we focus on recent reports that deal with the reception of environmental cues by circadian clocks in animals, including photoreception by the retina and by different anatomical clock structures, as well as responses to other environmental signals.

Fig. 1. Light signalling in SCN neurons and zebrafish peripheral cells. (a) Light signalling in SCN neurons in response to signals from the retina. RHT neurons release glutamate in synapses of the ventrolateral SCN. Activation of the N-methyl-D-aspartate (NMDA) receptor initiates a cascade of events leading ultimately to induction of immediate-early genes (such as c-fos) and clock genes (such as Per1), specific chromatin remodelling (such as histone H3 phosphorylation [8]) and phase resetting of SCN-controlled rhythms. Per1 and c-fos gene induction is dependent upon the activation of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and the transcription factor CREB. A role for the cAMP-protein kinase A (PKA), nitric oxide (NO) and cyclic GMP (cGMP) pathways has also been suggested. (b) Signaling in zebrafish cells (Z3 line) in response to light. CRY perceives light and induces signal transduction pathways involving MAPK kinase (MEK), PKA and protein kinase C (PKC). This leads to the induction of clock genes (such as Per2) and subsequent phase resetting of the molecular rhythms of the cells. NO, nitric oxide; CRE, cAMP response element; LRE, light response element; H3, histone H3.

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Special Issue: Sleep, Circadian Rhythms and Alcohol

Brant P. Hasler, ... Duncan B. Clark, in Alcohol, 2015

Circadian rhythms primer

We live on a rotating planet, with light and dark periods that alternate over the 24-h day. Accordingly, most organisms have evolved to experience internal rhythms with approximately 24-h periods, known as circadian rhythms. Circadian rhythms exist in many physiological, behavioral, and psychological processes, including the sleep-wake cycle, and serve to organize these processes for optimal interaction with the environment. In humans and other mammals, these rhythms, which exist in tissues throughout the brain and body, are kept in time by a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN coordinates rhythms of various peptides and hormones, as well as temperature, which serve as internal messengers and synchronize rhythms in other brain areas and the periphery (Hastings, Reddy, & Maywood, 2003; Reppert & Weaver, 2002). The clock is primarily entrained – that is, synchronized to the environment – by light. Light is the most powerful entraining cue, or zeitgeber (“time giver” in German). Other cues, such as food, social interaction, activity, and drugs, also can entrain rhythms (Mistlberger & Skene, 2005).

Disruptions in regular exposure to light and, to a lesser degree, disruptions in other zeitgebers, can lead to internal desynchrony among various rhythms. Sustained desynchrony can have adverse effects on health and well-being. In shift work and jet lag, the sleep-wake cycle and exposure to the external light/dark cycle are misaligned from internal timing, requiring re-entrainment to the new schedule. In the case of night shift work, some individuals never entrain to the reversed schedule, and chronically exhibit circadian misalignment (Sack et al., 2007a). Jet lag is another example. After plane travel to other time zones, re-entrainment can require multiple days and proceeds at different rates in various internal processes. Circadian misalignment compromises function across physiological systems, and is likely responsible for the health ills ranging from gastrointestinal distress and affective disturbance associated with jet lag, to diabetes and cancer associated with long-term shift work (Davis & Mirick, 2006; Drake, Roehrs, Richardson, Walsh, & Roth, 2004; Monk & Buysse, 2013; Rogers & Reilly, 2002).

An important individual difference in circadian timing is termed chronotype. Early chronotypes have relatively advanced circadian timing, defined as being predisposed to earlier sleep-wake schedules. Late chronotypes have relatively delayed circadian timing, defined as being predisposed to later sleep-wake schedules (Roenneberg, Wirz-Justice, & Merrow, 2003). Definitive determination of chronotype requires the measurement of endogenous circadian phase via a physiological circadian marker such as melatonin or core body temperature. However, this is not always practical for larger studies or clinical settings. As a result, self-report measures of chronotype, also termed morningness-eveningness or diurnal preference, have achieved wide usage (e.g., Adan et al., 2012).

Early and late chronotypes (or morning- and evening-types) not only differ on sleep and circadian variables, but also exhibit marked differences in other areas of physical and mental health. As described in more detail below, late chronotypes (evening-types) tend to report more disturbed sleep and more irregular sleep timing, more depression, and increased rates of drug and alcohol use (Adan, 1994; Broms et al., 2011; Drennan, Klauber, Kripke, & Goyette, 1991; Gau et al., 2007; Hasler, Allen, Sbarra, Bootzin, & Bernert, 2010; Negriff, Dorn, Pabst, & Susman, 2011; Pieters, Van Der Vorst, Burk, Wiers, & Engels, 2010; Wittmann, Dinich, Merrow, & Roenneberg, 2006). These differences have been attributed to a phenomenon called social jet lag (Wittmann et al., 2006), which is operationalized as the difference between weekday and weekend sleep timing (typically the midpoint of sleep). Based on the social jet lag hypothesis, the later sleep-wake schedules preferred by evening-types are poorly matched with schedules imposed by school or work. As a result, evening-types suffer sleep onset insomnia and sleep loss on school or work days (typically weekdays). They have trouble falling asleep when attempting to sleep at a point in the circadian cycle incompatible with sleep onset, and their sleep bouts are curtailed by early rise times. In contrast, on free days (typically weekends) they tend toward later sleep-wake schedules and longer sleep durations, which result, in turn, in delays in their circadian timing. The “jet lag” occurs as the evening-types try to shift back to an earlier schedule at the conclusion of the weekend.

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URL: https://www.sciencedirect.com/science/article/pii/S0741832914201145