Circadian Rhythm Abnormalities
Total Page:16
File Type:pdf, Size:1020Kb
Review Article Address correspondence to Dr Phyllis C. Zee, Northwestern University, 710 North Lake Circadian Rhythm Shore Dr, Chicago, IL 60611, [email protected]. Relationship Disclosure: Abnormalities Dr Zee has received personal compensation for activities Phyllis C. Zee, MD, PhD; Hrayr Attarian, MD, FAASM, FCCP; with Jazz Pharmaceuticals; Merck & Co, Inc; Perdue Aleksandar Videnovic, MD, MSc Pharma; Philips Respironics; Sanofi-Aventis; Takeda Pharmaceutical Company Limited; UCB; and Zeo, Inc. ABSTRACT Dr Zee receives research Purpose: This article reviews the recent advances in understanding of the funda- support from Philips mental properties of circadian rhythms and discusses the clinical features, diagnosis, Respironics. Dr Attarian receives personal and treatment of circadian rhythm sleep disorders (CRSDs). compensation for activities Recent Findings: Recent evidence strongly points to the ubiquitous influence of with American Physicians circadian timing in nearly all physiologic functions. Thus, in addition to the prominent Institute. Dr Videnovic reports no disclosure. sleep and wake disturbances, circadian rhythm disorders are associated with cognitive Unlabeled Use of impairment, mood disturbances, and increased risk of cardiometabolic disorders. The Products/Investigational recent availability of biomarkers of circadian timing in clinical practice has improved Use Disclosure: Dr Zee discusses the unlabeled use of our ability to identify and treat these CRSDs. melatonin for the treatment of Summary: Circadian rhythms are endogenous rhythms with a periodicity of circadian disorders. Dr Attarian approximately 24 hours. These rhythms are synchronized to the physical environment discusses the unlabeled use of melatonin and light boxes to by social and work schedules by various photic and nonphotic stimuli. CRSDs result advance or delay circadian from a misalignment between the timing of the circadian rhythm and the external rhythms. Dr Videnovic environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its discusses the unlabeled use of melatonin, ramelteon, and afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, supplemental light exposure to nonY24-hour, and irregular sleep-wake rhythm disorders). The most common symp- advance circadian rhythms and toms of these disorders are difficulties with sleep onset and/or sleep maintenance and treat jet-lag disorder. excessive sleepiness that are associated with impaired social and occupational * 2013, American Academy of Neurology. functioning. Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian realignment with timed exposure to light, avoidance of bright light at inappropriate times, and adherence to scheduled sleep and wake times. In addition, pharmacologic agents are recommended for some of the CRSDs. For delayed sleep-phase, nonY24-hour, and shift work disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift work disorder, wake- enhancing agents such as caffeine, modafinil, and armodafinil are options for the management of excessive sleepiness. Continuum (Minneap Minn) 2013;19(1):132–147. OVERVIEW OF THE HUMAN hormone secretion, glucose homeosta- CIRCADIAN SYSTEM sis, and cell-cycle regulation. The timing Circadian rhythms are physiologic and of these physiologic rhythms may behavioral cycles with a recurring perio- become altered, leading to changes in dicity of approximately 24 hours, gen- the phase relationship of rhythms to erated by the endogenous biological each other, which can cause internal pacemaker, the suprachiasmatic nucleus desynchronization. This loss of coordi- (SCN), located in the anterior hypothal- nation of rhythms may have negative amus.1 These rhythms control a variety consequences on rest-activity cycles of biological processes, such as sleep- and other physiologic and behavioral wake cycle, body temperature, feeding, functions. 132 www.aan.com/continuum February 2013 Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 1 KEY POINTS Circadian Entrainment tinct neurochemical properties. While h + Circadian rhythms are Circadian rhythms are synchronized with -aminobutyric acid is the dominant physiologic and the earth’s rotation by daily adjustments neurotransmitter in the SCN, present in behavioral cycles with a in the timing of the SCN, following the nearly all SCN neurons, SCN neuropep- recurring periodicity of exposure to stimuli that signal the time tides are highly localized within either approximately 24 hours, of day. These stimuli are known as the core or shell nuclei. The SCN core generated by the zeitgebers (German for ‘‘time-givers’’), contains high density of vasoactive in- endogenous biological of which light is the most important and testinal polypeptide, gastrin-releasing pacemaker, the potent stimulus. The magnitude and peptide, and bombesin-containing neu- suprachiasmatic nucleus, located in the direction of the change in phase de- rons. Somatostatin and neurophysin are anterior hypothalamus. pends on when within the circadian dominant neurochemicals within the h system the light pulse is presented. A SCN shell. Circadian rhythms are plot of phase changes according to the The SCN receives photic information synchronized with the earth’s rotation by time of light stimulus presentation from the retina via direct (retinohypo- thalamic) and indirect (retinogeniculate) daily adjustments in provides a phase response curve. Expo- the timing of the pathways.3 The melanopsin-containing sure to light results in a phase response suprachiasmatic curvewithdelaysintheearlysubjective ganglion cells of the retina are the pri- nucleus, following the night (ie, evening) and advances in the mary photoreceptors for the circadian exposure to stimuli that late subjective night (ie, early morning). system. The SCN also receives nonphotic signal the time of day. In addition to light, feeding schedules, information from the raphe nuclei. Sev- These stimuli are activity, and the hormone melatonin eral less-characterized afferents con- known as ‘‘zeitgebers’’ canalsoaffectthecircadiantiming.1 verge in the SCN from basal forebrain, (German for The timing of melatonin secretion by pons, medulla, and posterior hypothal- ‘‘time-giver’’), of the pineal gland is regulated by the SCN, amus. The major efferents from the SCN which light is the most with the onset of secretion approxi- project to the subparaventricular zone important and potent stimulus. The magnitude mately 2 hours before natural sleep time and the paraventricular nucleus of the hypothalamus, dorsomedial hypothal- and direction of the and being highest during the middle of change in phase depends 1 amus, thalamus, preoptic and retrochias- the night. Melatonin onset measured on when within the in a dim light environment (DLMO) is a matic areas, stria terminalis, lateral circadian system the stable marker of circadian phase and is septum, and intergeniculate nucleus. light pulse is presented. used in research as well as clinical prac- The SCN also communicates via diffu- tice to determine the timing of the en- sion of humoral signals to the rest of dogenous circadian rhythm. the brain. These diffusible SCN outputs likely include transforming growth fac- Neuroanatomy and tor !, cardiotrophinlike cytokine, and Neurochemistry prokineticin 2. A major development The central circadian timing system has in chronobiology research has been three distinct components: (1) a circa- the discovery of circadian clocks in dian pacemaker, the SCN, (2) input non-SCN brain regions and almost all pathways for light and other stimuli that peripheral tissues.4 While the signals synchronize the pacemaker to the envi- mediating communication between the ronment, and (3) output rhythms that SCN and peripheral oscillators remain are regulated by the pacemaker. The under extensive investigation, it is clear SCN is the central pacemaker that links that the central clock (ie, SCN) and pe- the 24-hour changes in the external ripheral clocks may have distinct circa- environment with the 24-hour changes dian synchronizers. The SCN, however, in the internal environment (Figure 7-1).2 is most likely dominant in maintain- The SCN is composed from the ‘‘core’’ ing circadian rhythmicity of peripheral and ‘‘shell’’ subnuclei, which have dis- clocks. Continuum (Minneap Minn) 2013;19(1):132–147 www.aan.com/continuum 133 Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Circadian Rhythm Abnormalities FIGURE 7-1 Schematic illustration of the pathway responsible for entrainment of melatonin secretion by light. The circadian regulation of melatonin secretion is dependent on an indirect pathway that originates in photosensitive ganglion cells in the retina and reaches the suprachiasmatic nucleus, the circadian pacemaker, via the retinohypothalamic tract. The suprachiasmatic nucleus controls the sympathetic output to the pineal gland, which is responsible for melatonin secretion via an inhibitory projection to the paraventricular nucleus of the hypothalamus. This pathway is responsible for the peak of melatonin secretion during darkness. Reprinted with permission from Benarroch EE, Neurology.2 B 2008, American Academy of Neurology. www.neurology. org/content/71/8/594.extract. Genetic Regulation During the night, the PER-CRY repressor Circadian rhythms are determined complex is degraded, and the cycle