In this review we will consider only parasomnias of childhood for which a genetic basis has been reported. Sleepwalking, confusional arousals and night terrors. Nocturnal enuresis is considered one of the most prevalent and persistent sleep problem in childhood and is defined as two or more incontinent episodes in a month in children between 5 and 6 years of age or one or more episodes after 6 years of age in the absence of physical disorders such as diabetes, seizures or urinary tract infection. Four gene loci have been identified 8q, 12q, 12q, 22q Although most of the sleep disorders do not have by now an identified molecular basis, modern techniques are being increasingly applied to determine the contribution of genes to sleep and its associated disorders.
The clinical importance of these discoveries may relate not only to improved diagnostic methods but also as target for drug development. Nunes ML. Sleep disorders. J Pediatr Rio J. Curr Opin Genet Dev. Sleep disturbances and teacher ratings of school achievement and temperament in children. Sleep Med. Tafti M. Quantitative genetics of sleep in inbred mice. Dialogues Clin Neurosci. Macromolecule biosynthesis: a key function of sleep. Physiol Genomics. BMC Med Genet. PER2 controls circadian periods through nuclear localization in the suprachiasmatic nucleus. Genes Cells. Guilleminaut C, Anagnos A.
Principles and practice of sleep medicine. Philadelphia: WB Saunders; Wurtman RJ. Narcolepsy and the hypocretins. Ganjavi H, Shapiro CM. J Neuropsychiatry Clin Neurosci. Nishino S. Clinical and neurobiological aspects of narcolepsy. Dauvilliers Y, Tafti M. Molecular genetics and treatment of narcolepsy. Ann Med. Taheri S. The genetics of sleep disorders. Minerva Med. Dauvilliers Y. Ann Neurol. Identification of differentially expressed genes in blood cells of narcoleptic patients. Genomewide association analysis of human narcolepsy and a new resistance gene.
Am J Hum Genet. Brain Res. Homer1a is a core brain molecular correlate of sleep loss. Hamet P, Tremblay J. Nunes ML, Cavalcante V. Clinical evaluation and treatment of insomnia in childhood. Pediatric obstructive sleep apnea syndrome. Arch Pediatr Adolesc Med. Reduced NREM sleep instability in children with sleep disordered breathing. Kalra M, Chakraborty R. Genetic susceptibility to obstructive sleep apnea in the obese children. Schwab RJ. Genetic determinants of upper airway structures that predispose to obstructive sleep apnea.
Respir Physiol Neurobiol. Tung A. Four to six such cycles are noted during a normal sleep period. The first two cycles are dominated by slow-wave sleep stage N3 , but in later cycles, these stages are noted only briefly and sometimes not at all. Conversely, the duration of the REM sleep cycle increases from the first to the last cycle, and toward the end of the night, the longest REM cycle may last as long as 1 hour.
Thus the first third of a normal sleep episode is dominated by slow-wave sleep, and REM sleep dominates the last third. EMG activity decreases slightly, and slow, rolling eye movements may be recorded Fig. Vertex sharp waves are noted toward the end of stage N1 sleep.
Stage N2 sleep begins after approximately 10 to 12 minutes of stage N1 sleep. Stage N2 sleep lasts for approximately 30 to 60 minutes. Toward the end of slow-wave sleep, or N3, body movements are registered as artifacts in the PSG recordings. Top 8 channels of electroencephalograms EEG show posterior dominant Hz alpha rhythm intermixed with a small amount of low-amplitude beta rhythms international nomenclature. M2, right mastoid; M1, left mastoid. Waking eye movements are seen in the electro-oculogram EOG of the left E1 and right E2 eyes, referred to the left mastoid. Chin 1 left and Chin 2 right submental electromyography EMG shows tonic muscle activity.
From Chokroverty, S. Saunders, Philadelphia, Fig. Left and right electro-oculograms EOG show slow rolling eye movements. A1, Left ear; A2, right ear; Thorax, respiratory effort chest.
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Rest of montage is same as in Fig. Note approximately Hz sleep spindles and K complexes intermixed with delta waves 0. See Fig. The first REM sleep R sleep episode is noted 60 to 90 minutes after the onset of sleep. However, this subdivision is not recognized in the recently modified staging. The EEG tracings during REM sleep are characterized by fast rhythms and theta activity, some of which may have a sawtooth appearance Fig.
A desynchronized EEG, hypotonia, or atonia of the major muscle groups and depression of monosynaptic and polysynaptic reflexes are characteristics of the tonic stage. Phasic REM sleep is characterized by rapid eye movements in all directions, as well as phasic swings in blood pressure and heart rate, irregular respiration, spontaneous middle-ear muscle activity, and tongue movements. A few periods of apnea or hypopnea may arise during REM sleep. An illustration of sleep stage distribution during the night is shown in Fig. Electroencephalogram top 8 channels shows mixed-frequency theta, low-amplitude beta, and a small amount of alpha activity.
A relaxed wakefulness is characterized by a behavioral state of quiescence and a physiological state of alpha and beta frequencies on the EEG recording, waking eye movements, and increased muscle tone. Sleep staging and scoring address normal adult sleep and the macrostructure Box In patients with sleep disorders such as sleep apnea, parasomnias, or nocturnal seizures disrupting sleep, such assessments may be difficult.
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Sleep efficiency ratio of total sleep time to total time in bed, expressed as a percentage. In , a Task Force of the American Sleep Disorders Association ASDA , now the AASM, offered descriptions of sleep microstructure that included momentary dynamic phenomena such as arousals and the cyclic alternating pattern CAP , which has been described in various publications by Terzano and co-investigators Sleep microstructure also includes K complexes and sleep spindles see Box According to the operational definition of the ASDA Task Force, an arousal is a shift in EEG frequency lasting for 3 to 14 seconds and includes alpha, beta, or theta activities but not spindles or delta waves.
The subject must be asleep for 10 consecutive seconds before an arousal can be scored. Unless accompanied by EEG frequency shifts, K complexes, delta waves, artifacts, and increased submental EMG activities are not counted as arousals. An arousal index is defined as the number of arousals per hour of sleep; up to 10 can be considered a normal arousal index. In contrast to the usual pattern of arousals signifying sleep fragmentation, the CAP indicates sleep instability.
A phase of CAP is marked by increased EEG potentials, with contributions from both synchronous high-amplitude slow and desynchronized fast rhythms in the EEG recording. During phase A, heart rate, respiration, blood pressure, and muscle tone increase. The rate of CAP cycles and arousals increase in both older individuals and a variety of sleep disorders. A period without CAP is thought to indicate a state of sustained stability. Evaluation of periods with and without a CAP is a promising technique for understanding normal and abnormal sleep.
The CAP sequence, confined between the two black arrows, shows three phase As and two phase Bs, which illustrate the minimal requirements for the definition of a CAP sequence at least three phase As in succession. Similar EEG derivation is used for the middle and lower panels. From Terzano, M. Atlas, rules and recording techniques for the scoring of cyclic alternating pattern CAP in human sleep.
Sleep Med 3, Neurological, environmental, and genetic factors, as well as comorbid medical or neurological disorders, will have significant effects on such ontogenetic changes. Sleep requirements change dramatically from infancy to old age. Newborns have a polyphasic sleep pattern with 16 hours of sleep per day.
The sleep requirement decreases to approximately 10 hours per day by age 3 to 5 years. In preschool children, sleep assumes a biphasic pattern. Adults exhibit a monophasic sleep pattern, with an average duration of 7. On falling asleep, a newborn baby goes immediately into REM sleep, or active sleep, which is accompanied by restless movements of the arms, legs, and facial muscles. In premature babies, it is often difficult to differentiate REM sleep from wakefulness.
However, the duration of the NREM-REM cycle is shorter in infants, lasting for approximately 45 to 50 minutes and increasing to 60 to 70 minutes by age 5 to 10 years, and to the normal adult cyclical pattern of 90 to minutes by age 10 years. Sleep spindles begin to appear at about 3 months of age; K complexes are seen by about 6 months. A characteristic feature of sleep in old age is marked attenuation of the amplitude of slow waves; therefore, during scoring of slow sleep, which depends not only on the rate but also on the amplitude of slow waves, the percentage of slow waves decreases.
The other characteristic feature during old age is repeated awakenings throughout the night, including early-morning awakenings. The percentage of REM sleep in normal elderly individuals remains relatively constant, and the total duration of sleep time within 24 hours is not different from that of young adults, but elderly individuals often nap during the daytime, compensating for lost sleep during the night.
Note the marked changes in REM sleep in the early years. Modified and adapted from Roffwarg, H. Ontogenic development of the human sleep-dream cycle. Science , Compared with early life, older adults spend more time awake in bed, less time in R and N3 sleep, and more time in lighter stages of sleep.
Depending on the sleep habit, two groups of individuals are recognized: evening types and morning types. These people perform best in the evening; they go to sleep late and wake up late. The body temperature rhythm shows two different curves in these two types of people. The body temperature reaches the evening peak an hour earlier in morning types than in evening types.
Morning and evening types are most likely determined by genetic factors. Sleep requirement is defined as the optimal amount of sleep required to remain alert and fully awake and to function adequately throughout the day. Sleep requirement for an average adult is approximately 7. Sleep need is determined by heredity rather than by different personality traits or other psychological factors. Social or biological factors may also play a role. Some more recent studies by Kripke and colleagues and others have confirmed these observations.
In later studies, other confounding factors such as sleep medications may have confounded these issues. There is no clear-cut conclusion yet. There is also some controversy over whether a person can extend sleep beyond the average requirement. In , Taub and Berger study showed that sleep extension beyond the average may cause exhaustion and irritability, with detriment of sleep efficiency. The overall conclusion, however, is that sleep extension has minimal effect on sleepiness and performance in absence of sleep debt , which is defined as the difference between the ideal sleep requirement and the actual duration of sleep obtained.
Modern society appears to be chronically sleep deprived. A study examining 8- to year-old adolescents between the years and showed a mean reduction of 1. There may, however, be a significant sampling error in this survey. A study by Bliwise and colleagues in healthy adults aged 50 to 65 showed a reduction of about 1 hour of sleep between and surveys. Displayed are group averages for subjects in the 8-hour diamond , 6-hour light square , and 4-hour circle chronic sleep period time in bed TIV across 2 weeks, and in the 0-hour dark square sleep condition across 3 days.
Curves through data points represent statistical nonlinear, model-based, best-fitting profiles of the response to sleep deprivation for subjects in each of the four experimental conditions. Adapted from Van Dongen, H. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation.
Sleep 26, Modern sleep scientists, however, interpret dreams in anatomical and physiological terms. Dream research has taken a new direction since the existence of REM sleep was first observed by Aserinsky and Kleitman in REM sleep is characterized by highly emotionally charged, complex, and bizarre dreams, whereas NREM dreams are more realistic and rational. During REM sleep, nerve cells, synapses, and the fibers connecting these cells become activated first in the brainstem, then the signals are transmitted to the cerebral hemisphere, which synthesizes the signals, creating colorful most of our dreams take place in natural color or black and white images during dreams.
The neurobiological significance of dreams remains unknown. Some suggestions include activation of the neural networks in the brain, restructuring and reinterpretation of data stored in memory, and removal of unnecessary and useless information from the brain of a dreamer. Dream-enacting behavior associated with abnormal movements during sleep constitutes an important REM parasomnia. Wakefulness is controlled by the ascending reticular activating system ARAS containing glutamatergic, cholinergic, aminergic, and hypocretinergic neurons Chokroverty, ; Steriade and McCarley, Projections from the ARAS terminating in the thalamus and thalamocortical projections to widespread areas of the cerebral cortex produce cerebral cortical activation during wakefulness.
Such evidence suggests that sleep-wake disturbances in early PD reflects disorder in the neural circuitry controlling circadian rhythms. PD patients also showed a sustained elevation of serum cortisol levels and reduced circulating melatonin levels compared with elderly controls, similar to previous studies Hartmann et al. A possible explanation for this is due to dysregulation in Bmal1 gene expression.
Striatal dopamine metabolism is apparently regulated by clock proteins such as Per2 Hampp et al. Stimulation of dopamine receptors also affects the rhythm of clock gene expressions of Per1 and Per2 in the striatum Imbesi et al. DA also regulates the rhythmic expression of melanopsin in retinal ganglion cells, thus influencing the entrainment of the circadian rhythm by light Sakamoto et al.
Considering that DA plays such a crucial role even in the circadian process of sleep, it should be highly plausible that the interconnecting relationships of different brain structures associated with the generation of sleep, including the SCN, can lead to different kinds of sleep disorders indefinitely.
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Alternatively, damage and degeneration to the SCN itself could be responsible for clock gene dysregulation, or even the hypothalamus. Whether circadian disruption in PD can be linked to the pathophysiology of other circadian sleep disorders such as advanced sleep phase syndrome ASPS , delayed sleep phase syndrome DSPS , nonh sleep wake syndrome, and seasonal affective disorder, poses a question as some of these disorders exhibit some of the symptoms seen in sleep disorders related to PD.
Further research will be needed to know the exact mechanisms behind the occurrence of these disorders Cermakian and Boivin, The altered timing of physiological rhythms cause internal desynchronization, leading to loss of rhythm coordination which cause negative effects on rest-activity cycles and other physiological and behavioral functions Reinberg and Ashkenazi, Circadian fluctuations also occur due to impaired retinal DA Wirz-Justice et al.
MAO-A is a clock-controlled gene Hampp et al. Loss of DA neurons in PD therefore lead to circadian disruption as it alters sleep latency and desynchronizes diurnal rhythm changes Willison et al. Blood pressure, heart rate, cortisol and melatonin hormone levels are also altered due to autonomic dysfunction, and further lead to changes in sleep structure Suzuki et al.
The ANS is subject to circadian regulation, providing a balance between sympathetic and parasympathetic tone varying in synchrony with the daily circadian cycle Jain and Goldstein, In healthy individuals, parasympathetic tone dominates during sleep to reduce heart rate and blood pressure through mechanics of the central circadian clock in the SCN via projections to the pre-autonomic neurons in the paraventricular nucleus Buijs et al.
The circadian regulation of the ANS is disrupted in PD patients, driving changes in blood pressure and heart rate Kallio et al. Anti-parkinsonian drugs also affect circadian rhythms and sleep-wake regulating systems either through direct action on sleep-wake regulating systems and circadian rhythm generators, or through indirect action meant to reduce PD symptoms during sleep Garcia-Borreguero et al.
It was found that the pineal gland undergoes compensatory up-regulation of monoaminergic transmitter systems outside of the basal ganglia, specifically in its uptake of L-DOPA, the pre-cursor of DA Ghaemi et al. This was shown in a study conducted by Ghaemi et al. This is via up-regulation of the binding site of striatal DA uptake carriers found not only in the dopaminergic system, but adrenergic and serotonergic systems as well Wiener et al. Thus dysregulation of pineal gland function not only arises from metabolism impairments in the dopaminergic systems, but from the adrenergic and serotonergic systems as well.
This consequently leads to circadian rhythm dysfunction as the pineal gland is involved in melatonin synthesis which regulates the sleep-wake rhythm. Other evidence was found in a study which showed a nocturnal melatonin peak in PD patients undergoing treatment with L-DOPA which transpired earlier compared to de novo patients and healthy controls Fertl et al. PD patients experience reduced total sleep time and sleep efficiency, increased number of awakenings, and increased wakefulness after sleep onset Wetter et al. These symptoms reflect changes in the temporal pattern of sleep due to circadian dysfunction Abbott et al.
Circadian disruption is thus a critical factor contributing to insomnia and hypersomnia in PD patients Mohawk et al. Table 1 summarizes the different sleep disorders experienced in patients with PD. It shows the causes of each disorder and the structures affected, as well as its effect and symptoms. Table 1. Summary table of the different sleep disorders in PD, the cause and brain structures affected, and its effect and symptoms. EDS is a disabling trend of rapid sleep onset without prior drowsiness in various circumstances Frucht et al.
It is associated with severe PD, PD-related disability, cognitive decline, frequent hallucinations, dementia and extended drug therapy including antihistamines, dopaminergic therapy, anxiolytics and SSRIs levodopa and dopamine agonist therapy Dhawan et al. EDS in PD is mainly due to arousal system damage, especially owing to selective orexinergic neuronal loss in the posterior lateral hypothalamus innervating central targets in advanced PD stages Arnulf, This further promotes wakefulness by up-regulating the mono-aminergic neuronal population.
Thus balance is more in favor of REM-on firing and wakefulness is impaired, which can lead to narcolepsy Siegel, ; Suzuki et al. Supplementary to orexin and histamine systems, impairments in serotoninergic, noradrenergic, and cholinergic neurons in the brainstem which serve as arousal systems that maintain wakefulness also result in EDS Suzuki et al. DA agonists however have a sedative effect due to differential selectivity for D1 and D2 receptors. D1 agonists and small doses of DA have been shown to increase firing of orexin neurons in the rat hypothalamus, while high concentrations of DA and D2 agonists decrease block this firing Alberto et al.
Thus patients with partial orexin deficiency due to low catechol o-methyl-transferase and monoamine oxidase inhibitors MAO-I activity would be sedated by D2—D3 agonists or high doses of levodopa due to prolonged action of DA in the synaptic cleft Arnulf, Insomnia exhibits prolonged sleep latency and fragmentation characterized by difficulty in falling and staying asleep, early awakening, or non-refreshing sleep despite adequate opportunities for sleep, coupled with impaired daytime functioning Suzuki et al.
This results in insomnia as wake structures fail to deactivate during the transition from wake to sleep. Figure 7. Gene dysregulation is also speculated to cause insomnia in PD. Reciprocally after phosphorylation, CREB induces gene expressions that help sustain wakefulness Cirelli and Tononi, , and may mediate cortical arousal in response to NE signals from the LC Graves et al. Thus it is possible that such a phenomenon leads to CREB gene up-regulation, which results in gene expressions that sustain wakefulness. Figure 8. This results in hypnagogic hallucinations, sleep paralysis, and most dramatically, cataplexy.
Pathophysiology is linked to Hcrt neurons carrying hypothalamic peptides mediating wakefulness via projections to the VTA, which were almost undetectable in narcoleptic patients Chaudhuri and Schapira, Thannickal et al. This occurs even before dopaminergic cell loss which result in motor symptoms. Early loss transpiring before drug treatment not only explains narcolepsy but also orthostatic hypotension in PD and abnormal body temperature regulation Thannickal et al.
As mentioned above, Hcrt promotes wakefulness by up-regulating the mono-aminergic neuronal population. As PD patients are observed to have almost complete loss of Hcrt cells, the balance is more in favor of REM-on firing and thus wakefulness is impaired, leading to narcolepsy Siegel, ; Suzuki et al. It is to be noted that this phenomenon occurs simultaneously while dysregulation of DA, NE, and SE occur at the same time, hence further impairing arousal mechanisms and inducing sleep.
RLS is manifest by the need to move due to dysethesias in the limbs that transpire at rest, and is eased by movement. The circadian pattern of periodic limb movements PLM that occur almost analogously could be secondary to the phasic influence of RLS Lewy, Sensory symptoms and PLM during wakefulness further prevent sleep onset. Although the central circadian pacemaker does not exhibit any abnormalities, the severity of symptoms might be indirectly modulated by an underlying circadian variation. RLS presents an exacerbation of symptoms at night, supporting the factor of circadian oscillation.
In a study conducted to address circadian symptom modulation, it was found that circadian oscillation of motor and sensorial symptoms can be observed under conditions of sleep deprivation as well. This suggests homeostatic sleep drive as an additional factor modulating RLS symptoms. Observations of RLS seen to be most intense late in the circadian period, and least intense several hours later early in the following circadian period suggests the presence of a generator for RLS.
Exaggerated hyperalgesia in the feet, Baier and Trenkwalder, , and neuropathic pain were also shown to be worse in the evening and night Odrcich et al.
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This evidences that both circadian phase and recovery following nocturnal sleep play a role in pain sensitization, thus postulating that endogenous fluxes in neurotransmitters and hormones succeeding circadian phases are involved in these variations Baier and Trenkwalder, The pathophysiology of brain structures involved have not been studied extensively, however animal Perlow et al.
Furthermore, circadian variation in the DA system also influences melatonin secretion, thus affecting sleep regulation. However, the circadian pattern might not be generated by the dopaminergic system itself, but by other factors that indirectly modulate it. Thus dopaminergic system dysfunction in RLS pathophysiology is most probably caused by impaired central dopaminergic transmission Trenkwalder and Paulus, ; Winkelman, , which is also the cause for PD symptoms. Pathophysiology is linked to the Adiencepalic dopaminergic nucleus which provides the main descending dopaminergic control of the spinal tract Qu et al.
Therefore, dopaminergic dysfunction in this area might contribute to the sensory symptoms of RLS. Neuroendocrine responses to dopaminergic drugs also contribute to the cause of RLS. Response changes in prolactin and growth hormone release after L-dopa administration were observed at night but not during the day in RLS patients. This indicates a consequence of circadian changes in the sensitivity of postsynaptic dopamine receptors at night Garcia-Borreguero et al.
Thus it is suggestive that there is an increase in the amplitude of circadian variation of dopaminergic function in patients with RLS compared to healthy controls. RBD is characterized by vivid and frightening dreams or nightmares, associated with muscle activity that leads to dream enactment Comella, Patients experience drastic reductions in REMS, decreased sleep efficiency, and increased sleep fragmentation due to increased stage transitions and awakenings Belaid et al.
Complex, dynamic, and violent behaviors due to dream enactment result in injuries in patients and their bed partners. Polysomnographic measurements also display excessive chin muscle tone and limb jerking during REMS Comella, Further degeneration of these structures, together with changes in locomotor generator structures, lead to obvious RBD. This chronological sequence of pathology explains why RBD precedes motor symptoms, cognitive decline and dementia in most patients who develop PD.
In the Braak stage 2 description of PD, it is stated that further Lewy body and neurite formation in the structures involved in stage 1 appear, which are the dorsal motor nucleus of the vagus nerve, olfactory bulb and anterior olfactory nucleus complex. Once the accumulation threshold is reached, changes in mood, behavior, and sleep start to develop.
Measurable changes in serotonin and noradrenaline might also be present at this stage. Figure 9. REMS onset occurs when a certain balance is reached between REMS-on and off neurons as well as inhibitory and excitatory pathways within the different brain structures. Damage and degeneration to these brain structures and their relationships lead to RBD. Based on animal studies, it is proposed that the SLD sends projections to spinal motoneurons through a direct route that causes active inhibition of skeletal muscle activity in REMS. The SLD also functions through an indirect route via the ventrolateral reticulospinal tract to reduce excitation of the MCRF, thus causing a net reduced inhibition of spinal motoneurons.
Due to dysfunction of the subcoeruleus nucleus controlling muscle atonia during REMS, reduced excitation of the MCRF and disinhibition of spinal motoneurons occur either directly or indirectly via other brainstem nuclei Boeve et al.
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It was also demonstrated that 2 systems are involved in normal REMS, where one generates muscle atonia and another suppresses locomotor activity. Muscle atonia is caused by active inhibition by the MCRF neurons in the medulla via the ventrolateral reticulospinal tract synapsing on spinal motoneurons. These MCRF neurons receive excitatory effects from the peri-LC region in the pons via the lateral tegmentoreticular tract.
Neurons in the peri-LC region are thought to inhibit the LDT and cholinergic PPN, which is interconnected with the substantia nigra, hypothalamus, thalamus, basal forebrain, and frontal cortex. These pontine structures act as locomotor generators, and are believed to receive input from supratentorial structures, especially the forebrain and thalamus, which ultimately influence spinal motoneurons.
Thus during REMS, phasic oculomotor and locomotor activity such as REMs and muscle twitches occur, however extravagant motor activity is directly or indirectly inhibited Schenck et al.
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Other studies demonstrate that lesions extending from the ventral midbrain to the medial medulla also cause RWA as activation of this system suppresses muscle tone Schenkel and Siegel, ; Lai and Siegel, ; Holmes et al. Nocturia is a condition of frequent and excess urination during the night. Autonomic dysfunction of the bladder leading to nocturia is a frequent complaint in PD patients, commonly among men Cheon et al.
Pathophysiology is linked to dopaminergic pathways affecting bladder activity as D1 receptors inhibit micturition reflex while D2 receptors activate it, therefore under-active D1 and an over-active D2 stimulation may explain this detrusor over-activity Chaudhuri and Schapira, The SCN also regulates osmotic pressure sensing cells responsible for nocturnal increase in arginine vasopression secretion, which subsequently reduces the volume of night-time urine production Colwell, ; Trudel and Bourque, It is assumed that disrupted circadian control due to dopaminergic pathway dysfunction promotes nocturnal relaxation of the bladder wall and increased urethral sphincter tone.
This leads to abnormal bladder contraction and relaxation of the urethral sphincter, thus increasing nocturia and urinary incontinence Willison et al. SAS results from a deficit in breathing drive in the brain central sleep apnea , or a problem with airflow through breathing passages, also known as obstructive sleep apnea. As breathing becomes more difficult or ceases a decrease in blood oxygen level occurs, which in turn results in awakening to restore breathing.
SAS leads to sleep disordered breathing, and is identified through a history of loud crescendo snoring and irregular snoring with snorting and gasping Mitra and Chaudhuri, As the patient remains in light sleep, they may be unaware of these awakenings, which occur numerous times a night. Consequently, the patient experiences little deep restorative sleep at night which leads to EDS. Upper airway muscle dysfunction caused by nocturnal akinesia or dyskinesia of the respiratory muscle lead to development of obstructive sleep apnea, which develops onto life-threatening nocturnal stridor caused by vocal cord abductor dysfunction Suzuki et al.
Respiratory muscle dyskinesia occurs due to dopaminergic medication excess and withdrawal Garcia-Borreguero et al. This results in dyspnea, tachypnea and irregular, erratic breathing patterns. Levodopa also induces oromandibular Kato et al. However, a wearing off effect can also be associated with respiratory complaints, particularly in advanced PD patients related to laryngeal dystonia, stridor, and appearance of chest wall muscle bradykinesia and rigidity Hartman, The pathophysiology of levodopa-related respiratory problems is not well understood, but it is very likely associated to denervation hypersensitivity of dopamine receptors to exogenous dopamine in the peripheral chemoreceptor neurons Rice et al.
Dopamine is known to be involved in both peripheral chemoreceptor and brainstem respiratory center function as hypoxia increases the synthesis and release of endogenous dopamine by carotid body glomus cells Iturriaga et al. Thus reduced peripheral chemosensitivity may explain the reduced ventilatory response to hypoxia in PD Serebrovskaya et al. PD and its symptoms are caused by various dysfunctional structures compromising many control areas in the brain, resulting in motor and non-motor abnormalities including sleep. Good comprehension and knowledge of the various brain structures involved, their relationship, and their pathophysiology in the initiation and development of these symptoms will benefit in administering innovative treatments such as deep brain stimulation.
Further studies focusing on genetics and biochemistry could also help in finding a possible cause and cure for this debilitating disease. Ms IF is the main author who wrote the manuscript in order to have a broader understanding on the pathophysiology of Parkinson's disease, especially in aspects Parkinson's disease and various brain structures in relation to sleep. KM was the author who supervised and helped in the writing of this manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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