With the use of the tryptophan depletion paradigm and the catecholamine depletion we assessed the role of brain serotonergic and catacholaminergic systems respectively. “We found that disturbances in brain serotonin systems play a key role in the pathogenesis of seasonal affective disorder and that light therapy may compensate for the underlying deficit” (Edelman, p. 45). Moreover other is evidence that catecholaminergic systems may be involved in the mechanism of action of light therapy. Tryptophan depletion studies suggest that sleep deprivation does not exert its antidepressant effects by involving brain serotonin system alone. Interestingly, tryptophan depletion prevented the relapse after the recovery might, possibly by enhancing brain serotonin transmission after the depletion procedure. Therefore, the paper will analyze the effects of Sleep Deprivation on the Brain.

The Effects of Sleep Deprivation on the Brain

Mathematical models of sleep propensity have been developed by Kronauer and coworkers, who emphasize circadian control and by Borbely, who emphasize the extent of prior wakefulness. Borbely and coworkers model postulates that the intensity and amplitude of delta wave activity indexes the level of sleep factors and slow-wave sleep drive. In this model the time course of delta activity over the night, a declining exponential, reflects the dissipation of the sleep factor. These workers have not specified the nature of the underlying sleep factor. The main short-term functional consequence of deprivation of sleep seems to be the presence of “micro sleeps” that is, very brief episodes of sleep during which sensory input from the outside is diminished and cognitive function is markedly altered. Furthermore, there are also long-duration effects of sleep loss/restriction on performance and physiology, termed “sleep debt,” which persist even after a night of recovery sleep. Sleep loss-induced transcriptional changes may underlie the presence of sleep debt.  “A growing body of evidence supports the role of purine nucleoside adenosine as a mediator of the sleepiness following prolonged wakefulness, a role in which its inhibitory actions on the basal forebrain wakefulness promoting neurons may be especially important” Borque , (1996) commonsense evidence for an adenosine role in sleepiness comes from the nearly universal use of coffee and tea to increase alertness, since these beverages contain the adenosine receptor antagonists caffeine and theophylline.

Adenosine, a ubiquitous nucleoside, serves as a building block of nucleic side, serves as a substrate for multiple enzymes, and, most importantly for this review, as an extracellular modulator of cellular activity. “Since its first description in 1929 by Drury and Szent-Gyorgyi, adenosine has been widely investigated in different tissues” (Blakemore, p.126). “The endogenous release of adenosine exerts powerful effects in a wide range of organ systems” (Hale-Evans, 2006). For example, adenosine has a predominantly hyperpolarizing effect on the membrane potential of excitable cells, producing inhabitation in smooth muscle cells both in the myocardium and coronary arteries, as well as in neurons in brain. From an evolutionary point of view, adenosine’s postulated promotion of sleep following activity could be considered as an extension of its systemic role in protecting against over activity, as seen most clearly in the heart. Adenosine in the central nervous system functions both as a neuromodulator and as a neuroprotector. The modulatory function, reviewed as early as 1981 by Phillis and Wu, is exerted under physiological conditions both as a homoeostatic modulator as well as a modulator at the synaptic level. The most profound effect of adenosine is inhibitory modulation of cellular activity and neurotransmitter release, and it consequently has been described as a “retaliatory modulator”. In terms of a neuroprotective response, extracellular adenosine levels have been shown to increase under abnormal cell-threatening conditions such as cell injury, trauma, ischemia, or hypoxia, and adenosine is widely studied as an endogenous neuroprotective agent in the central nervous system. The increased levels of extracellular adenosine exert neuroprotective agent in the central nervous system.

The increased levels of extra cellular adenosine exert neuroprotective effects by reducing excitatory amino acid release and calcium ion influx, as well as by reducing cellular activity and hence metabolism. Pharmacological agents which enhance extracellular adenosine levels have been shown to reduce neuronal damage in animal models of cerebral ischemia. An increase in adenosine levels and adenosine A1 receptor activation has been described as essential to development of ischemic tolerance. In addition, adenosine has also been implicated in locomotion, analgesia, chronic drug use, and mediation of the effects of ethanol.  Initial evidence that adenosine, a purine nucleoside, was a sleep factor came from pharmacological studies describing the sleep-inducing effects of systemic or intracerebral injections of adenosine and adenosine agonist drugs. The hypnogenic effects of adenosine were first described in cats by Feldberg and Sherwood and later in dogs by Haulica. Since then the seductive, sleep-inducing effects of systemic and central administrations of adenosine have been the fact that adenosine is a byproduct of energy metabolism, led to postulates that adenosine may serve as a homoeostatic regulator of energy in brain during sleep, since energy restoration has been proposed as one of the functions of sleep. The figure below schematizes adenosine metabolism and its relationship to adenosine triphosphate.

Reasoning that adenosine’s control of sleepiness might best be understood as an inhibition of wakefulness promoting neuronal activity, Bottcher,  (1995) used micro dialysis to apply adenosine to the cholinergic neuronal zones of the feline basal forebrain and LDT/PPT, known to be important in production of wakefulness.  At both sites, adenosine produced a decrease in wakefulness land in the activated EEG.  There is indirect evidence that hypoxia is the main trigger of acute BP elevation during apnea. Shepard found a positive correlation between the level of desaturation and the corresponding elevation of intra-arterial BP in 10 patients with spontaneous apnea. Blakemore, and Frith, (2005) examined simulated apneas in normal males with voluntary breath hold under hypoxic conditions and during pretreatment with 100% oxygen. Intraapneic BP rose to abnormal values during the hypoxic breath holds but remained stable during hyperoxic apneas, indicating that hypoxia was a necessary component for intra-apneic BP rise. Bottcher, (1995) found a strong correlation between the nadir Sao2 reached and acute nocturnal BP elevation in 17 apnea subjects studied. These authors also found that regardless of resting BP level, OSA patients have an increased pressure response to induced hypoxia, which is not present in nonsnoring, nonapneic controls. Other investigators fond a role for arousal and sleep state change in the acute response to apnea. Goswami, Pandi-Perumal, and Thorpy, (2009) examined 11 obstructive apnea patients during sleep and found that apneas recorded during oxygen supplementation were associated with equivalent postapneic mean arterial BP elevations compared to apneas without oxygen supplementation.

 A subsequent study by the same authors had subjects simulate timed obstructive apneas while awake, comparing BP changes during wakefulness to those during sleep apneas of similar duration and negative intrathoracic pressure change. Apneas during sleep produced higher acute BP changes than those produced by apneas while awake, implying that arousal is an important stimulus to acute elevation of in fluctuations in intrathoracic pressure during obstructed breathing; generalized stress from disruption of sleep; genetic factors; and age.  In addition, the table illustrates that the sleep needed by someone to have good health, depends with someone’s age and environment.

New born infants should have at least              -          20-22 hours of sleep, while

1-4 years old                                                  -          12 hours

4-12 years old (at least)                                  -          10 hours

13-19 years old (adolescents)                         -          8-10 hours

Adults                                                             -          7-8 hours

Elderly people                                                 -          5-7 hours

Several animal models of genetic and renal hypertension are believed to have chronically increased sympathetic activity. It is theorized that perhaps an analogous situa-lion in humans exists in response to recurrent obstructive apneas over a period of years. Recurrent activation of the sympathetic nervous system could theoretically lead to a sustained increase in sympathetic activity with either increased vascular tone or some humoral change such as increased catecholamine or rennin-angiotensisn system activity.

Recent studies in humans indeed show that peripheral sympathetic activity may continue after cessation of hypoxia. Stickgold, & Walker, (2009) administered intermittent asphyxia to five healthy, awake humans over a 20-min period. Muscle sympathetic nerve activity climbed throughout the period of asphyxia and remained elevated above control levels for up to 20 min after release of the stimulus. These authors hypothesize that the carotid chemoreceptors are “sensitized” or reset in response to hypoxia. This fits with the theory that long after the nocturnal episodic asphyxia stimulus is terminated, sympathetic activity to the adrenals or peripheral vasculature remains high, promoting diurnal elevation of BP. Patients with sleep apnea have high levels of sympathetic drive, whether assessed by plasma catecholamine or by direct intraneural records using microneurography. This is increased sympathetic activity as apparent even when sleep apnea patients are awake and breathing normally and in the absence of any oxygen desaturation. During sleep, sympathetic activity increases further with consequent increases in nocturnal blood pressure levels. Acute treatment with CPAP lowers both sympathetic activity and blood pressure during sleep. Hyperoxia lowers blood pressure and sympathetic activity in awake sleep apneic patients, but not in matched control subjects. Thus, the sympathetic system is an attractive candidate mechanism to explain higher long-term blood pressure levels in sleep apnea patients.  For the reasons stated earlier, definitive proof of this is lacking. In an attempt to examine the effects of CPAP therapy on sympathetic activity and blood pressure, MacKenzie, (1994) and colleagues found that long-term CPAP was accompanied by reductions in plasma norepinephrine but no reduction in blood pressure. Unfortunately, a cohort of untreated sleep apneic patients was not followed.  

A new and potentially exciting area of investigation in the chronic cardiovascular changes of sleep apnea is the change in coagulation that might be induced by chronic episodic hypoxia. Two studies indicate reversible clotting abnormalities that may accompany obstructive sleep apnea. Lee-Chiong, (2006) examined spontaneous platelet aggregation and platelet activation in six sleep apnea subjects before and after nasal CPAP. Both aggregation and activation were abnormally high on the apnea night and returned to baseline control values after a night of CPAP treatment.  In a similar study, Eysenck, (2001) examined plasma fibrinogen, hematocrit, and total plasma protein, the latter two parameters used to calculate whole blood viscosity. Plasma apnea and returned to control levels following the application of nasal CPAP. Cardiovascular events such as stroke, angina, and myocardial infarction may be more common in apnea patients. The implication of these studies is that hypercoagulability is more likely during sleep in patients with episodic hypoxia and cyclic sympathetic nervous system activation. Elimination of this stressful cyclic hypoxia may reduce the risk of vascular occlusion. On the other side, another non- pharmacological intervention that alleviates depression is the therapeutic sleep deprivation for the whole night or for the second half of the night. Other forms of sleep deprivation include the selective rapid eye movement sleep deprivation and the phase advance therapy. Total sleep deprivation is effective in approximately 60% of all patients. However, the rapid and often dramatic antidepressant effects of sleep deprivation are in general short-lived, the relapse usually occurs after the recovery night. Interventions to prolonge the antidepressant effects of sleep deprivation include the concomitant administration of antidepressants, especially those enhancing serotonergic transmission, but also lithium or light therapy. During the recent years there has been increasing interest which role brain monoaminergic systems play in the pathophysiology of SAD and the mechanism of action of light therapy. With the use of the tryptophan depletion paradigm and the catecholamine depletion paradigm several groups tried to evaluate which role serotonergic and catecholaminergic systems, respectively, play in the mechanism of action of light therapy and in the pathophysiology of SAD. During recent years studies of neurobiological mechanisms underlying the antidepressant properties of sleep deprivation have also examined serotonergic mechanisms. Evidence can be inferred as follows: (1) a number of studies indicate those antidepressants with a serotonergic mechanism of action, for example fluvoxamine or clomipramine, but also light therapy or lithium prevent at least partially the depressive relapse after sleep deprivation, ( 2 ) sleep deprivation had a robust effect on peak change in prolactin levels after intravenous administration of levels after intravenous administration of tryptophan, a finding that was confined to women only, ( 3 ) the flenfluramine stimulation test performed prior to sleep deprivation as found to be capable of predicting the clinical response to sleep deprivation as found to be capable of predicting the clinical response to sleep deprivation, ( 4 ) Animal studies suggest that sleep deprivation induces an increase of serotonergic activity in the dorsal raphe nucleus. However, all the noted evidence is indirect and thus there was clearly a need for a more direct approach to study serotonergic mechanisms in sleep deprivation. In a more recent study the hypothesis was tested that sleep deprivation exerts its antidepressant effects by enhancing serotonergic transmission.  

With the use of the tryptophan depletion paradigm the authors studied a group of drug free sleep depressed patients who responded to a single night of total sleep deprivation. In the morning after sleep deprivation the patients received in a double-blind fashion either a tryptophan- free amino acid beverage would reverse the antidepressant effects of sleep deprivation. As expected tryptophan depletion significantly reduced plasma total and free tryptophan concentrations. Both levels increased during same depletion were found. Interestingly, tryptophan depletion prevented the depressive relapse after the recovery might. Although no final conclusions were drawn about the mechanisms that prevented the depressive relapse after the recovery night but the authors argued that it is likely that on the day after tryptophan depletion a rebound effect occurred with an enhancement of serotonergic transmission. Moreover the authors concluded that it seems to be unlikely that serotonin alone mediates the antidepressant effects of sleep deprivation.

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