Hector Warnes: Historical Overview of Sleep Medicine

4. Neurobiology of REM and NREM sleep

            REM and NREM sleep are controlled by the Suprachiasmatic Nuclei (SCN)and the pineal gland in animals as well as in humans. The removal of theseanatomo-physiological centers in animals causes the disappearance of mostbiological rhythms which arerestored with the implant of fetal SCN inhamsters, reviewed independently by Daniel P. Cardinali and Robert F. Ré (2006); andM.C.Moore-Ede,F.M. Sulzman and C.A. Fuller (1982).

R. W. McCarley (2007)has shown that sleepiness increases with the duration ofsleep deprivation. Eventually, a sleep debt accumulates with rebound sleepand increase of slow-wave sleep during the recovery period. It has also beenshown that caffeine and theophylline, which promote wakefulness, act byblocking adenosine receptors. The enhancement of adenosine concentrationis responsible for sleep rebound and slow-wave activity after sleepdeprivation. Adenosine inhibits the activity of hypocretin/orexin neuronsvia A1 receptor in the lateral hypothalamus and the basal forebrain resettingthe sleep homeostat, thus contributing to its sleep promoting effect.Adenosine has a proven somnogenic effect. It is a purine nucleosideprecursor of adenosine-5′-triphosphate (ATP) which serves as a buildingblock of nucleic acids.

NREM sleep is associated with reduced neuronal activity and reparativesleep usually with non-visual mentation. NREM sleep has three levels: N1with theta waves during which may occur hypnagogic hallucinations and sleepjerks; N2 with characteristic sleep spindles and K complexes; and N3 withdelta waves during which, in pathological states, may occur somnambulism,confusional arousal and sleep terrors (incubus).

During delta sleep growth hormone isreleased by the pituitary gland and alcohol, as well as the benzodiazepines,reduces delta wave activity. Cytokines exhibit peaks during early nocturnal sleep and reparative sleep enhances immune defences. Sleep deprivation suppresses immune function. Muramyl dipeptide (MDP) and delta sleep-inducingpeptides increases delta wave activity during sleep. Delta wave sleepdeprivation may also affect growth (in childhood) and may induce musculoskeletalpain and fatigue in the adult (associated with the fibromyalgia and chronicfatigue syndrome) as shown by H. Moldofsky (1993).

Parasomnias or disorders ofarousal (incomplete arousal) are defined as those behavioral, physiologicalor experiential symptoms that occur during NREM sleep.  In families ithas been discovered that the DQB1 gene is associated with sleep walking, whileHLA-DQB 1 is associated with narcolepsy. The latter has been studied inDoberman Pinschers and Labrador Retrievers.

The first REM period occurs about 70 to 90 minutes after sleep onset andis associated with lightening of sleep, desynchronization or low voltage fast EEG activity, vivid dreaming, rapid eye movement and loss of muscletone. The REM promoting neurons (REM-ON neurons) are related withcholinergic firing while REM-OFF neurons are related to norepinephrine andserotonin increase stimulation and are located in the dorsal raphe nucleus,the locus coeruleus and the dopaminergic neurons (in the cat, rat andmonkey).

A shortening of REM latency after cholinergic stimulation may reveala cholinergic sensitivity in affective disorders (Sitaram et al. 1987). RiemannnD. and Berger M. (1989) compared sleep EEG in depressive and those in remission supporting Sitaram’s findings. GABAergic neurons inhibit REM sleep. C-fos, a transcriptional regulator protein, is a marker of neuronal activity relevant to sleep homeostasis and REM information processing function. REM sleep activates c-fos expression(Pompeiano, Cirelli and Tononi 1994). Hypocretin/orexin may also play a role in REM sleep control because theyexcite the REM-OFF neurons.

            Muscarinic cholinergic receptors areresponsible for muscle atoniain the pontine reticular formation justventral to the locus coeruleus which fire the brain stem and the motorneuron. The glycine receptor are inhibitory receptors in the central nervous system which can be activated by glycine, beta alanine and taurine. Caffeine is a competitive antagonist and it has been shown (Soja2008)that glycine-mediated post synaptic inhibition is also responsible for REM sleep atonia. The brain stem is the locus of REM sleep rhythm.

A pathological condition which can be experimentally reproduced in animalsis the anatomical lesion of this area which causes oneiric and locomotorbehavior (not the normal atonia), attack behavior with restlessness andraising the head as if watching something threatening. Theseexperiments on animals conducted by MichelJouvet(2004)in Lyon, France led to the clinical observations of a similar state of REM sleep without atonia which they called REM behavior disorder (Mahowald and Schenck 2015). The patients literally acted out their dreamssometimes in a violent way. The disorder may precede the onset of Parkinson’s disease or be induced by psychotropic drugs. The condition is seen more often in elderly patients which requires a complete neurological examination.

 Innarcolepsy the appearance of REM-like sleep associated with cataplexiaduring the day was associated with a loss of orexinergic neurons.These neurons excite GABAergic, aminergic and glutamatergic neurons ininteraction with neurotransmitters. Intranasal orexin A has been tested innarcolepsy with cataplexy and has been shown that it increases the quality ofsleep, wakefulness and attention (Weinhold et al.2014).

The narcoleptic tetrad has been called the Westphal Gélineau’s syndrome. Karl Friedrich Otto Westphal (1885)was the first to describe agoraphobiaand was also the first to describe cases of narcolepsy with cataplexy. Symonds (1926) described cases of narcolepsy as a symptom of encephalitis lethargica. Schenck, Basetti, Arnulf and Mignot in a 2007 paper were of the opinion that the patients with narcolepsy-cataplexia, described by Westphal and later by Jean-Baptiste-Édouard Gélineau (1828-1906),were likely to be HLA-DQBI.

Mammals spend a large amount of time is REM sleep in utero as well asafter birth (raging from 50 to 80% during sleep), while this percentagedecreases gradually to about 25% while delta waves (NREM sleep) areminimally present in the newborns and increases slowly during the firstcouple of years of life, reaching its maximum at age 10 and graduallydecreasing to a minimum with aging.

The elderly tend to sleep earlier and wake up earlier due to a phase advance in the circadian sleep cycle. They show a reduction of delta and K complex (NREM2) and of REM sleep and frequently an increase of sleep associated apneas andimmune dysfunctions (Edwards et al. 2010;Besedovsky, Langeand Born 2012) mostly due to the relative sleep deprivation, the sharp decline of delta sleep ( which promotes reparative sleep) with aging and the fragmentation of sleep along with the increase of sleep apneas.



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Cardinali, DP,Ré RF.Ritmosbiológicosenpsiquiatría.In:Marchant M, Monchablon A, eds.Tratado de Psiquiatría,Vol. 1 Chapter 48. Buenos Aires: Grupo Guía SA: 2006.

Edwards BA, O'Driscoll DM, Ali A, Jordan AS, Trinder J, Malhotra A. Aging and sleep: Physiology and Pathophysiology. Semn Respir. Crit. Care Med 2010; 31: 618-33.

Jouvet, M. How sleep was dissociated into two states: telencephalic and rhombencephalicsleep. Arch. Ital. Biol 22004; 142: 317-26.

Mahowald MW, Schenck, CH.  REM sleep behaviour disorder: a window on the sleeping brain Brain 2015; 138: 1131- 3.

Moore-Ede MC, Sulzman, FM, Fuller CA. The clock that times us: physiology of the circadian system. Cambrdge: Harvard University Press; 1982.

McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med 2007; 8: 302-30.

Moldofsky H. Fibromyalgia, sleep disorders and chronic fatigue syndrome. In Bock G, Whelan J, ed.Chronic Fatigue Syndrome (Ciba foundation Symposium 173). Chichester: Wiley, pp. 262-79.

Pompeiano M,Cirelli C, Tononi G. Immediate-early genes in spontaneous wakefulness and sleep: expression of c-fos protein and mRNA levels. J. Sleep Research 1994; 3: 80-96.

RiemannD, Berger M. EEG sleep in depression and in remission and the REM sleep response to the cholinergic agonist RS86. Neuropsychopharmacology 1989; 2: 145-52.

Schenck CH, Bassetti CL, Arnulf I, Mignot E.English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary.J Clin Sleep Med. 2007; 15;301-11.

Sitaram N, Dube S,Keshavan M, Davies A, Reynal P. The association of supersensitive cholinergic REM-induction and affective illness within pedegrees. J. Psychiatr. Res 1987; 21: 487-97.

Soja, PJ. Glycine-mediated post synaptic inhibition is responsible for REM sleep atonia.2008; 31: 1483 – 6.

Symonds CP. Narcolepsy as a symptom of encephalitis lethargica. Lancet 1926; 2: 1214-5.

Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav. Brain Res 2014; 262: 8-13.

Westphal KFO. Uebereinenmerkwürdigen Fall von periodischerLähmungallervierExtremitäten. mitgleichzeitigemErlöschen der elektrischenErregbarkeitwährend der Lähmung. Berl. klin. Wchnschr 1885; 22: 489 - 91 & 509 -11..


June 21, 2018