Lack of sleep and health outcomes: coping with chronic sleep deprivation

Lack of sleep and health outcomes: coping with chronic sleep deprivation

Sleep deprivation is a relevant health problem in modern societies.

Sleep of sufficient duration, continuity, and depth without circadian disruption is necessary to prevent physiological changes that may predispose individuals to adverse health outcomes.

Sleep deprivation is linked to a number of negative health outcomes, including psychiatric, metabolic, and cardiovascular problems.

Sleep deprivation occurs when inadequate sleep leads to decreased performance, inadequate alertness, and deterioration in health.

Sleep deprivation may be a result of the contemporary lifestyle or works requiring continuous performance for extended periods and affects many people. Without adequate sleep, people usually experience difficulties in performing effectively at work, carrying out habitual home duties or driving a vehicle safely. Sleep loss reduces the vigilance or arousal level, producing a general worsening in cognitive performance.

The mechanism of these alterations in normal homeostasis is related to the strain of maintaining wakefulness under conditions of sleep deficit, and at times when the biological clocks are primed for sleep. It is not known if these changes are short-lived and these systems are able to adapt over time.

Independently of its primary cause, sleep deprivation can impinge upon several biological pathways, such as oxidative stress, cardiovascular autonomic control, inflammatory responses and endothelial function.

With short-term sleep deprivation, blood pressure, inflammation, autonomic tone, and hormones are all altered in a direction that is recognized to contribute to the development of cardiovascular disease, most importantly, atherosclerosis.

Chronic sleep deprivation may contribute to the establishment of basal elevations in inflammatory mediators and coagulatory factors, thereby priming otherwise healthy individuals for development of disease.

 Causes of sleep deprivation

  • related to our lifestyle: the use of electronic devices before going to sleep, which alter the physiological secretion of melatonin, hard work schedule, shift work;
  • related to aging process: aging is associated with a reduction of total sleep time and a disruption of physiological sleep;
  • related to sleep disorders: sleep disordered breathing, insomnia, periodic limb movements, restless leg syndrome.

Pathological sleep deprivation

Pathological sleep deprivation can be the consequence of:

  • sleep disorders such as insomnia, sleep disordered-breathing, obstructive sleep apnea syndrome,
  • neurological disorders such as periodic limb movements and restless leg syndrome.

One of the most important common element of these sleep disorders is the condition of chronic sleep deprivation, which has a complex series of biological consequences.

Obstructive sleep apnea

Obstructive sleep apnea is associated with:

  • increasing age
  • male gender
  • obesity

It is most common in men over the age of 40 years. The incidence in women increases after menopause.

The prevalence of obstructive sleep apnea in the general adult population is approximately 24% in men and 9% in women.

Obstructive sleep apnea occurs when there are repetitive episodes of complete or near-complete cessation of airflow during sleep, with continued respiratory effort against a closed airway. The result may be either a decline in oxygen saturation or a cortical arousal from sleep.

Obstructive events can occur in any stage of sleep but are most severe during REM sleep, when muscle atonia is present.

Symptoms of obstructive sleep apnea are present during both the night and day.

Nocturnal symptoms include:

  • snoring – can be the only symptom
  • gasping or choking
  • cessation of breathing
  • frequent arousals
  • nocturia
  • excessive movement in sleep
  • hyperhidrosis.

Patients are often unaware of any symptoms.

Upon awakening, patients report:

  • dry mouth
  • nasal congestion
  • headaches
  • heartburn

Excessive daytime sleepiness is usually present as a result of respiratory events causing disturbed nighttime sleep. Patients report dozing off when sedentary and have difficulty with concentration and attention. Obstructive sleep apnea is particularly concerning in commercial drivers and pilots.

Patients with cardiovascular diseases have a higher prevalence of obstructive sleep apnea.

The pathophysiological cascade leading from obstructive sleep apnea to cardiovascular events has been extensively studied. There are described 3 main mechanisms:

  1. the upper airways collapse several times during sleep inducing the occurrance of microarousals and a fragmentation of the physiological sleep.
  2. during each apneic episode, hypoxia-hypercapnia followed by reoxigenation occur, thus altering the physiological blood gases exchange. Chemoreflex activation is associated with the occurrence of EEG alterations (microarousals);
  3. each inspiration effort against the occluded upper airways induces an increase in negative intrathoracic pressure which leads to important consequences on the heart anatomy (atria enlargement and remodelling and stretch of the pulmonary vein ostia).

Consequences:

  • the activation of chemoreflexes leads to deregulation of the autonomic nervous system, with repetitive bursts of sympathetic activity. Also there is continuous sympathetic and parasympathetic coactivation during apneas which can be a key factor in triggering major life-threatening arrhythmias
  • a series of intermediate mechanisms are activated by apneic events: oxidative stress, systemic inflammatory response, platelet activation and aggregation, endothelial dysfunction and metabolic alterations

Patients with obstructive sleep apnea are at risk for stroke, congestive heart failure, myocardial infarction. The apnea/hypopnea index (AHI), an index that sum the amount of apneic and hypopneic events during the sleep period, is the only independent predictor of adverse events.

Insomnia is defined as a subjective difficulty in initiating and/or maintaining sleep or a sensation of non-restorative sleep. It affects approximately 10–15% of general population.

Studies suggests that patients with insomnia have a higher prevalence of hypertension, congestive heart failure, and coronary artery disease. Studies show that insomnia symptoms were associated with an increased risk of cardiovascular mortality, mostly in men with difficulty in initiating sleep.
Restless legs syndrome and periodic limb movements have also been associated with cardiovascular diseases. Few data are available but some evidences suggest that these patients are at increased risk of developing hypertension, heart disease and stroke.

Sleep deprivation effects

Most of the biological functions of the body changes during sleep compared to wake, such as:

  • heart rate
  • arterial blood pressure
  • temperature
  • hormonal secretion
  • immune function.

Cardiovascular regulation is profoundly modified during sleep. The interconnection between sleep processes and cardiovascular system must be considered as a bidirectional link.

Cardiovascular diseases are associated with alterations of physiological sleep and vice versa sleep disorders can alter the cardiovascular system, leading to an increased cardiovascular risk.
Unfortunately sleep deprivation can activate several pathophysiological pathways, such as:

  • autonomic nervous system dysfunction
  • endothelial dysfunction
  • increased inflammation
  • coagulation and oxidative stress responses
  • deregulation of hormones secretion
  • accelerated atherosclerosis.

An early assessment of a condition of sleep deprivation and its treatment is clinically relevant to prevent the harmful consequences of a very common condition in adult population.
Epidemiological studies have shown that sleep deprivation is associated with important health outcomes including:

  1. type 2 diabetes
  2. hypertension
  3. cardiovascular diseases
  4. stroke
  5. arrhythmias
  6. coronary heart diseases
  7. obesity
  8. depression
  9. dyslipidemia

National Institutes of Health recommends at least:

  • 10 h of sleep for children
  • 9–10 h for teenagers
  • 7–8 h for adults.

Sleep deprivation has become a huge health care problem in modern societies. It has been reported that in 2014 almost 1/3 of the adults slept less than 6 h per night.

The dose–response of sleep deprivation in mortality has also been studied. Studies found a linear association between a statistically significant increase in mortality and sleep duration at less than six hours. Although short sleep is associated with increased mortality and other health outcomes, there is no rigorous evidence that lengthening sleep duration can lead to smaller frequency of these outcomes.
Short sleepers were likely to be associated with greater mortality than normal sleepers with a reported risk of around a 12% absolute increase. For the other outcomes, short sleepers were likely to have a point estimate of an absolute increase of:

  • 37% for type 2 diabetes
  • 17% for hypertension
  • 16% for cardiovascular disease
  • 26% for coronary heart disease
  • 38% for obesity.

In terms of depression and dyslipidemia, no sufficient evidence from meta-analyses existed to conclude whether short sleep was associated with an increase in the incidents in the meta-analyses.

Sleep deprivation and immune function

Sleep plays a key role in maintaining homeostasis of physiological systems. It is reassuring that host defense mechanisms are intact in the face of acute short-lasting deprivation. In the long term, both chronic partial sleep deprivation and severe acute sleep deprivation are associated with increased inflammation which in turn is associated with the development of many diseases.

Sleep deprivation alters basal metabolic function, which is likely to contribute to changes in immunological homeostasis.
The immune responses associated with healthy sleep support growth and development of immunological memory. Monocyte production of IL-12, a key cytokine involved in the development of cellular (type 1) memory, is increased during sleep in humans.

Total sleep deprivation studies have found monocytes and neutrophils to be increased and lymphocytes decreased.

Studies of prolonged partial sleep deprivation have also found increased white blood cells due to deprivation.

Both total and partial sleep deprivation studies have found that circulating levels of IL-6 and C-reactive protein are increased in healthy volunteers.

The soluble tumoral necrosis factor receptor 1 has been shown to increase during acute total sleep deprivation.

Although the IL-6 and C-reactive protein elevations are small, they may be very important in long-term health. IL-6 and C-reactive protein are important acute phase markers of the innate immune system- the type of immunity that humans have without requiring exposure and development of immunological memory. These acute phase markers are known to be elevated in overweight individuals. Also, they have been linked to the development of future cardiovascular disease and diabetes, even independent of their relationship with adiposity.

Even very small subclinical elevations in inflammatory mediators have been linked to future risk for the development of disease.

Epidemiological studies show that there are risks associated with habitual short sleep duration.

Individuals who sleep less than 6 h per night are at increased risk for developing future cardiovascular disease and diabetes, independent of other known risk factors such as body mass index.

Individuals with sleep-disordered breathing have higher levels of inflammatory mediators, including IL-6 and C-reactive protein. Even healthy individuals with very low-level basal increases in C-reactive protein and IL-6 have a higher likelihood of developing future cardiovascular disease. C-reactive protein is particularly useful to examine in population-based studies because it is stable, it has a long half-life (between 15 and 19 h) and it doesn’t have a diurnal rhythm.

Individuals with disturbed sleep due to sleep apnea have been reported to show elevated basal levels of proinflammatory cytokines.

Sleep deprivation may cause:

  • increased production of pro-inflammatory plasma cytokines (IL-21, IL-1, TNF-alpha, PCR and IFN-gamma)
  • endothelial-dependent vasodilatation
  • alteration of adhesion molecule function.

Monocytes and neutrophils are elevated during acute sleep deprivation.

Sleep deprivation also affect the tumor necrosis factor system. Type 1 (but not type 2) soluble tumor necrosis factor receptor is influenced by acute complete sleep loss.

Studies have shown that after a single night of sleep reduced by 50% there has been an increase in monocyte production of IL-6 and tumor necrosis factor-α messenger RNA.

One of the explanations for why inflammatory mediators are elevated in cardiovascular disease is that the increased blood pressure increases endothelial shear stresses, resulting in endothelial production of inflammatory mediators. During sleep, endothelial markers drop to their lowest point in the day, coinciding with the nocturnal dip in blood pressure.

Endothelial selectin and intracellular adhesion molecule-I have been reported to increase under conditions of sleep deprivation. These findings support the hypothesis that activated vasculature, related to elevated blood pressure, leads to activation of an inflammatory cascade.

As well, autonomic system activation also contributes to elevated inflammation via multiple pathways. Catecholamine elevation is associated with increased inflammatory mediators. Noradrenaline stimulates production of inflammatory mediators including IL-6 and tumor necrosis factor-α.

One study reported a decreased immune response to influenza virus vaccination in individuals suffering from chronic sleep loss. Antibody titers were decreased by more than 50% after 10 days in subjects who were vaccinated for influenza immediately after 6 nights of sleep restricted to 4 hours per night, compared with those who were vaccinated after habitual sleep duration. But by 3 to 4 weeks after the vaccination, there was no difference in antibody level between the two subject groups. Therefore, sleep loss appeared to alter the acute immune response to vaccination. Although associated with elevated markers of inflammation, sleep loss results in a functional state of immunodeficiency.

Regarding patient response, studies of acute sleep deprivation show that there are individual differences in the vulnerability for developing short-sleep-induced inflammation, both in the short and the long term. Once it is developed, there may be further individual differences in tolerance to increased inflammation and resistance to the development of disease.

Inflammation and Cardiovascular Disease

Studies show that acute sleep deprivation is able to modify hemodynamic control and autonomic cardiovascular regulation in healthy subjects, together with an altered inflammatory response and endothelial function.

During experimental sleep deprivation of healthy individuals, white blood cells and other markers of inflammation increase. A relationship between inflammation and future development of cardiovascular disease has long been recognized.

Patients with congestive heart failure also have high leukocyte numbers. Studies have identified an association between risk, in asymptomatic individuals, for the development of cardiovascular disease and leukocyte counts.

The production of interleukin 6 (IL-6) and other inflammatory mediators stimulates the production of C-reactive protein.

Hypoxia is a hallmark of the sleep apnea syndrome and is strongly associated with elevations in inflammatory mediators.

Interleukin 6 is produced by the monocyte/macrophage leukocyte cell line and by activated endothelial cells lining vascular and lymph beds.

Interleukin 6 is a potent stimulator of C-reactive protein production. Although IL-6 is predictive of the development of cardiovascular disease, C-reactive protein has an advantage in that it is more stable, with a much longer half-life and is without diurnal rhythm.

C-reactive protein is an independent predictor of a first cardiovascular event in asymptomatic individuals. Furthermore it is also associated with adversity of that event.

Sleep deprivation and congestive heart failure

Congestive heart failure is defined as the inability of the heart to fulfil the oxygen demand of the periphery and is a pathological condition. It can be caused by the inability of the ventricles to contract properly.

Sleep disorder breathing must be considered a very important comorbidity in patients with congestive heart failure. Sleep disorder breathing affects more than 50% of the congestive heart failure patients with systolic heart failure.
Congestive heart failure is characterized by a progressive loss of sympathetic rhythmical oscillation, accompanied by a consensual reduction in heart rate variability. This fact supports the hypothesis of a cardiac system less able to respond adaptively to stressors stimuli. In addition to this autonomic deregulation, patients with comorbid obstructive sleep apnea also have:

  • repetitive bursts of sympathetic activity during apneas due to the activation of chemoreflexes
  • an increased vagal activity due to hypoxia and upper airway obstruction;

This phenomenon causes a reflex bradycardia, which is then followed by a post-event sympathoexcitation.

This coactivation, together with pulmonary vasoconstriction induced by hypoxia, acute stretch of the atria wall and pulmonary vein stretch, and right ventricular hypertension could trigger the onset of arrhythmias in congestive hert failure patients, especially atrial fibrillation.

The optimal therapy for obstructive sleep apnea is the use of continuous positive airways pressure (CPAP), which is able to reduce symptoms and improve quality of life and to significantly reduce the incidence of fatal and non fatal cardiovascular events.

Insomnia has a high prevalence in congestive heart failure. It has been recently shown that in subject initially free from congestive heart symptoms, insomnia symptoms were associated with an increased incidence of congestive heart failure development during a 10 years follow-up in a dose-dependent manner.

Effects of sleep deprivation on blood pressure

Several studies have found that sleep deprivation leads to increased blood pressure.

An important role in development of hypertension is played by sympathetic nervous system overactivity and changes in circadian rhythm.

Hypertension affects about 26.5% of the adult population worldwide. It ranks as the leading chronic risk factor for mortality. Half of all strokes and ischemic heart disease events are attributable to high blood pressure.

Patients sleeping less than 6 hours per night are 66% more likely to have hypertension than individuals sleeping between 7 and 8 hours per night.

Even half a night of sleep loss has been reported to increase blood pressure in subjects with hypertension or prehypertension.
Blood pressure is physiologically regulated via several mechanisms. Some of the major determinants of blood pressure are:

  • cardiac contractility
  • cardiac output
  • peripheral vascular resistance

These are under autonomic nervous control. They are linked to blood pressure via a feedback loop termed the baroreflex which involves a series of receptors, located in the heart itself as well as in the carotid artery and aortic arch, which sense blood pressure.

If blood pressure needs to be adjusted, sympathetic or parasympathetic output then can influence cardiac contractility, heart rate, and peripheral vascular resistance.

Increased sympathetic activation and decreased parasympathetic activation are seen during stress and increased work expenditure. Similar autonomic changes, consistent with a kind of stress response are also seen when sleep is of inadequate quantity or quality.

Staying awake beyond the normal 16-hour wake day, even when it is not accompanied by stressful conditions, involves exertion of energy, a fight against an accumulating sleep deficit.

Motivation and circumstance influence the level of energy in the short term.

To maintain wakefulness against sleep deficit and a strong circadian drive for sleep requires effort which is aided by social interaction. Motivation must hold back the decline in optimism-sociability caused by sleep deprivation. By 1 week of sleep reduction to about 50% of normal daily amount, self-reported optimism-sociability declines by about 10% compared with normal sleep conditions. As a result, autonomic system is activated during the resisting phase of an extended vigil.

Sympathetic Activation

Studies show that sleep is more important for sympathetic nervous system regulation of the heart in comparison with the parasympathetic system that appeares to be more under circadian control.

Blood pressure is increased during sleep deprivation because of:

  • increased sympathetic outflow to the heart or periphery
  • changes in baroreflex sensitivity
  • baroreflex resetting to a higher level.

Another study showed that after sleep deprivation forearm vascular resistance and plasma catecholamines were not affected, mean arterial blood pressure did increase. Furthermore, the arterial baroreflex was reset upward by 12 mm Hg toward a higher blood pressure by a single night of sleep deprivation.

Studies suggest that increased blood pressure is because of baroreflex set-point change and that sympathetic outflow is dampened as a protective response. Sympathovagal balance is elevated by sleep loss, during the morning through midday hours.

The sympathetic nervous system and blood pressure are modulated by the activities undertaken and environmental conditions. Body posture, ambient temperature, emotional stress, cognitive and physical workload, fluid levels, and food and salt intake influence regulating factors such as hormones and catecholamines that control blood pressure.

Sleep deprivation causes increased sympathetic cardiac and blood pressure modulation and decreased baroreflex sensitivity.

Values greater than or equal to 140/90 mmHg are considered as “hypertension”.

A normal blood pressure profile is characterized by a 10% fall in mean systolic blood pressure values whilst sleeping compared to when awake.

It is of note that the mean nocturnal blood pressure level is a major indicator of cardiovascular

morbidity and mortality irrespective of the 24-h blood pressure levels. Sleep and sleep disorders can impact blood pressure values and profile throughout 24 h.

Autonomic cardiovascular control changes across sleep stages. Thus, blood pressure (BP), heart rate and peripheral vascular resistance progressively decrease in non-rapid eye movement sleep. Any deterioration in sleep quality or quantity may be associated with an increase in nocturnal blood pressure which could participate in the development or poor control of hypertension.

Obstructive sleep apnea is clearly associated with the development of hypertension. Unfortunately is only slightly reduced by continuous positive airway pressure treatment. Shorter and longer sleep durations are both associated with prevalent or incident hypertension.

Obstructive sleep apnea has been considered as the first identifiable cause of hypertension. The prevalence of moderate-to-severe obstructive sleep apnea in patients with primary hypertension is approximately 30%, while in those with resistant hypertension is 80%.

The last European Society of Hypertension guidelines strongly recommend the obstructive sleep apnea screening for all patients with resistant hypertension.

The autonomic nervous system control is altered during night-time, with a continuous waxing and waining of sympathetic bursts during apneic events, and also during day-time, with a constant predominance of sympathetic modulation to the sinus node and the vessels.

Insomnia is also a potential risk factor for arterial hypertension.

Studies report that, compared to subjects with normal sleep, subjects who sleep less than 5 hours per night due to insomnia have the highest risk of hypertension, followed by the group who sleep 5–6 hours per night. In conclusion, insomnia with short sleep duration is associated with an enhanced risk of developing hypertension, similarly to sleep disordered breathing.

Prospective studies also provided evidence of increased incidence of new-onset hypertension in patients with insomnia or short sleep duration, this fact being more prevalent in women than in men.

Mechanisms involved in resistant hypertension development might be gender-specific with sleep quality being crucial in women, whereas traditional cardiovascular risk factors play a major role in men.

The cause for the development of hypertension is a hyperarousal state induced by insomnia. Another major problem in determining the relevance of insomnia in hypertension is the high prevalence of depression in insomniacs.
The effects of periodic limb movements with hypertension found inconclusive results. Periodic limb movements seem to be associated with daytime hypertension and patients with daytime hypertension have a greater number of periodic limb movements.
Sleep quality rather than sleep duration was found to be associated with resistant hypertension.

Studies have found a gender-specific relationship between sleep quality and resistant hypertension. There is an association between sleep loss and hypertension incidence in women. The prevalence of poor sleep quality in women is higher than in men. The actual sources of this difference are unknown.
To conclude, sleep loss has been indicated as a new modifiable cardiovascular risk factor.

Sleep deprivation acts as a neurobiologic stressor, leading to sympathetic nervous system and hypothalamus–pituitary–adrenal axis activation, proinflammatory responses, and endothelial dysfunction, thus favoring hypertension development and maintenance. Sleep deprivation increases daytime blood pressure and amplifies systolic blood pressure increases due to psychologic stress through sympathetic activation. Acute psychologic stress can induce sodium retention and blood pressure increase, mediated by renin–angiotensin and sympathetic nervous system activation. Thus, the different sleep loss conditions acting as chronic stressors can conceivably induce and sustain hypertension. This mechanism is gender-specific, as postmenopausal women have an increased susceptibility to salt-induced rise in blood pressure. A number of pathophysiologic mechanisms of hypertension development and maintenance have been described in order to show gender differences. Muscle sympathetic nerve activity has a steeper increase with age in women than in men, and women with elevated blood pressure and metabolic syndrome showed a disturbed sympathetic firing pattern, which is proportional to trait anxiety and depressive symptoms scores.

Menopause status is associated with hormonal changes, psychosocial stress and also with increased cardiovascular risk. It is closely related to increased incidence of insomnia and other sleep disorders.

Poor sleep quality may be a mechanism involved in resistance to antihypertensive treatment in women.
Poor sleep quality is highly prevalent in resistant hypertensive patients and is associated with resistant hypertension in women but not in men, even independent of sleep duration and cardiovascular and psychiatric comorbidities.

Sleep deprivation and coronary artery disease

Epidemiological studies showed that approximately 50% of patients with coronary artery diseases have moderate to severe obstructive sleep apnea. In addition, an important gender difference has been noticed: obstructive sleep apnea is a risk factor for coronary artery diseases in men but this result has not been confirmed in women.
In addition to hypoxia, disruption of physiological sleep and autonomic deregulation with bursts of sympathetic over activity, and the repetitive episodes of upper airways collapse lead to the uncoupling of myocardial workload and coronary blood flow.

Blood flow increases after each apneic event but with a certain delay with respect to the increase in myocardial workload. This phenomenon could be responsible for the strong link between obstructive sleep apnea and ischemic events in subjects with coronary artery disease.
The comorbidity of obstructive sleep apnea impacts on the clinical progression of the myocardial infarction. In the early phases of acute myocardial infarction, in patients with obstructive sleep apnea, heart is more sensitive to the increased intrathoracic negative pressure induced by apneas, thus leading to a worse recovery from acute events. Patients with obstructive sleep apnea have prolonged myocardial ischemia, altered ventricular remodelling and lower ventricular function. Obstructive sleep apnea is a significant risk factor for the incidence of an acute coronary artery disease, such as acute myocardial infarction, revascularization procedure, and death for cardiac causes.

Obstructive sleep apnea has a high prevalence in patients with coronary artery disease. Also, it is a significant independent risk factor for the development of ischemic heart disease.
Studies show that insomnia, especially manifested by difficulties initiating sleep were associated with deaths for coronary artery diseases in males but not in females, after the adjustment for the most important risk factors. However, short sleep duration was independent from the risk of coronary artery diseases or total mortality, suggesting a relationship between troubles falling asleep and mortality for coronary artery diseases in males.

Conclusive results on the effects of sleep loss secondary to insomnia and coronary artery diseases are still debated. However, one study has shown a dose dependent association between the symptoms of insomnia and acute myocardial infarction risk especially for patients with difficulties initiating sleep. This study was accompanied by an editorial suggesting that sleep is one of the ten modifiable cardiovascular risk factor. Recently, a further prospective study in men confirmed that insomnia symptoms were associated with an increased risk of cardiovascular mortality.

Sleep deprivation and atrial fibrillation

Obstructive sleep apnea is characterized by repetitive episodes of upper airways collapse, which lead to sleep fragmentation, alteration of blood gases exchange and significant changes in intrathoracic pressures. These mechanisms, through an autonomic derangement and changes in cardiac anatomy, are responsible for an increase risk of atrial fibrillation.

Patients with obstructive sleep apnea are at higher risk to develop atrial fibrillation.

Commonly, patients with atrial fibrillation have a greater prevalence of obstructive sleep apnea.

There are many detrimental consequences of patological sleep deprivation induced by obstructive sleep apnea and atrial fibrillation, not only regarding the increased risk of developing atrial fibrillation for patients with obstructive sleep apnea and higher incidence of recurrence but also long term outcomes. In addition to the negative effects induced by the hypoxia—reoxigenation episodes during apneas, a major role might be played by the coactivation of the autonomic nervous system during hypoxiemic episodes. Vagal activation induces an impaired refractoriness of the cardiac conducting system, and creates an electrogenic background for triggering atrial fibrillation.

Apneic events induce changes in intrathoracic pressures which causes atria enlargement and tissue stretch and remodeling at the pulmonary vein ostia, leading to a “mechanical” trigger for atrial fibrillation onset.

The efficacy of atrial fibrillation treatment is affected by the presence of obstrucitve sleep apnea.

An effective obstructive sleep apnea treatment with continuous positive airway pressure improves atrial fibrillation outcomes. A prompt identification of obstructive sleep apnea in patients with atrial fibrillation and adequate therapeutic options should be considered in order to significantly improve the long-term outcomes in these patients.

Correlation between sleep deprivation and risk of stroke

Stroke is defined as an abrupt onset of a neurologic deficit because of disturbance in the blood supply to the brain. World Health Organization has defined stroke as ‘‘rapidly developed clinical signs of focal disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than vascular origin.’’

Obstructive sleep apnea has been reported to significantly increase the risk of stroke. Both short and long sleep durations are related to increased likelihood of diabetes and hypertension, which themselves are risk factors for stroke.

Clinical studies have indicated that the incidence and high mortality of cerebrovascular diseases can be prevented to a large extent. Thus, prevention is an effective strategy and highlights the need for awareness regarding stroke risk factors and warning signs.

Risk factors for stroke include:

  • advanced age
  • hypertension
  • atrial fibrillation
  • previous stroke or transient ischemic attack
  • diabetes
  • high cholesterol
  • cigarette smoking

Sleep has been associated with stroke because most of the risk factors are modified by sleep and sleep-related disorders.

There are several risk factors that link sleep patterns and stroke:

1. Circadian Variation: the incidence of stroke has shown a 24-hour pattern irrespective of stroke subtype, and the presence or the absence of predisposing risk factors. Studies have indicated an

association between circadian variations and stroke onset because the stroke onset peaks in morning hours.

Circadian rhythms are controlled by the body’s biological clock and are influenced by sleep, being responsible for changes in blood pressure and rhythmic occurrence of some cardiovascular diseases. During NREM sleep sympathetic activity decreases and parasympathetic activity predominates. The result is a decrease in heart rate, blood pressure, cardiac output, peripheral vascular resistance, and respiratory frequency.

On the other hand, during REM sleep have been reported variations in the activity of both the sympathetic and parasympathetic systems resulting in a net increased parasympathetic tone

and decreased sympathetic influence. REM sleep is characterized by increased cerebral cortical and spinal blood flow, variable heart rate and arterial blood pressure.

As most individuals experience a nocturnal dip in blood pressure followed by a morning surge,

it has been suggested that this morning surge may disrupt vulnerable plaques causing rupture and thrombosis leading to a cardiovascular or cerebrovascular incident.

As circadian rhythms are influenced by sleep, the duration of sleep produces circadian variations, which thereby alter the stroke incidence. Studies have reported that rotating night shift work disrupts circadian rhythms and is an independent risk factor for ischemic stroke.

2. Aging affects the cardiovascular system, which increases the risks of both ischemic stroke and intracerebral hemorrhage. As a result of age-related brain atrophy and increased cerebral vascular resistance secondary to cerebral arteriosclerosis, it has been demonstrated a 20% reduction in regional cerebral blood flow. Moreover, both sleep duration and the alterations during sleep act as predisposing factors. Insomnia and hypertension are common problems in the elderly both of them leading to an important risk factor for stroke. Short duration of sleep has been associated with an increased risk of stroke events in hypertensive patients.

The sleep stage analyses have indicated a nocturnal increase in serum interleukin 6 levels in association with stage 1-2 and REM sleep with no difference in the levels during slow wave sleep. As aging involves a relative increase in REM sleep at the expense of slow wave sleep, the abnormal increase in interleukin 6 is a risk factor for stroke in geriatric population. Furthermore, elderly people have lower oxygen retention during sleep in the supine position as a result of reduced hypoventilation. This may be caused by:

  • decreased lung elasticity resulting from advancing age
  • depressed respiratory regulation due to autonomic dysfunction
  • underventilation caused by cardiac, lung, and brain diseases.

Studies have shown that arterial oxyhemoglobin levels decline in most people during sleep, and the compensatory vascular responses prevent cerebral oxyhemoglobin saturation from falling during sleep. Thus, elderly persons with lower baseline cerebral oxyhemoglobin saturation levels and greater declines in cerebral oxygenation during sleep are at greater risk for stroke or other forms of disabling cerebrovascular disease.

3. Hypertension is a major risk factor for stroke as high blood pressure puts stress on the blood vessel walls and causes blood clots or hemorrhage. Even small increases in blood pressure, particularly night-time blood pressure levels, are associated with significant increases in cardiovascular morbidity and mortality. Furthermore, sleep deprivation and insomnia have been reported to increase the incidence of hypertension. Sleep and blood pressure level are closely associated. The different sleep stages modulate autonomous functions such as blood pressure and heart rate. Sleep apnea increases blood pressure and may cause low levels of oxygen in the blood while carbon dioxide levels rise, which may lead to blood clots or strokes.

Short-term sleep restriction is associated with impairment in blood pressure regulation. An impaired daily rhythm is closely related to the development of hypertension. Regulation of sympathetic nerve alterations may prove helpful in the treatment of hypertension and circadian rhythm disorder. Studies have shown that poor sleep quality is related with resistant hypertension and serves as an independent predictor of non-dipping in newly diagnosed stage 1 hypertensive patients.

Higher morning hypertension has been associated with stroke risk independently of nocturnal blood pressure falls, ambulatory blood pressure, and silent infarct in elderly hypertensive patients.

Recent studies have shown that sleep deprivation is associated with an increased risk of hypertension with possibly stronger effects among women than those among men.
It has been reported that sleep disturbances impair stroke recovery. Sleep deprivation produce detrimental effects on functional and structural outcomes after stroke. This indicates a potential role of sleep in the modulation of recovery processes and neuroplasticity.

Sleep apnea, characterized by prolonged exposures to intermittent hypoxia during sleep, causes an increase in brain susceptibility to acute ischemic events. The sleep discontinuity caused by sleep apnea is another factor that rises the question whether sleep duration is another factor involved in stroke.

Experimental sleep deprivation has been found to induce a functional alteration of the monocyte proinflammatory cytokine response. Previous studies have also reported that sleep deprivation produces a proinflammatory and pro-oxidative environment and activates stress responses. Thus, it can be hypothesized that acute sleep deprivation exacerbates neuroinflammation and neurodegeneration after global ischemia.

A potential role of sleep-modulating treatments on stroke outcomes has been suggested as the results of an experimental study have demonstrated that at the early phase of stroke, sleep disruption aggravates brain damage and increases expression of genes that inhibit poststroke axonal sprouting. Sleep-enhancing drugs like sodium oxybate have demonstrated neuroprotective action against ischemia and brain damage and also have been shown to accelerate motor recovery after stroke in a mouse model.

Both short and long sleep durations have been associated with increased risk of stroke.

Excessive daytime sleepiness has been reported as a significant risk factor for stroke. Prolonged sleep duration which triggers increased REM sleep has been associated with increase in the incidence of stoke.

Insomnia is also a risk factor for ischemic cerebrovascular disease and possibly ischemic cardiac events. Studies have reported that the risk of an ischemic stroke is increased in men whose sleep is frequently disturbed, and the daytime sleepiness is associated with a significant increase in ischemic heart disease events.
From the findings of experimental and epidemiologic studies, it may be concluded that sleep duration affects the stroke incidence directly and indirectly through the modulation of certain risk factors for stroke like sleep disordered breathing, circadian variations, hypertension, and diabetes. This implication of sleep suggests that prevention of sleep disturbances, improvement of sleep quality, and sleep-modulating treatments may play a potential role in the management of stroke.

 

Sleep deprivation and diabetes

Type 2 diabetes mellitus is a major public health problem, which affects approximately 8% of the United States population, with an incidence that has doubled over the last 30 years (American Diabetes Association, 2010).

In general, both short sleep duration (6 h or less) and long sleep duration (9 h or more) are associated with increased prevalence of type 2 diabetes and impaired glucose tolerance, even in absence of evident signs of insomnia.

Sleep loss is associated with hyperactivation of sympathetic nervous system. In patients with obstructive sleep apnea, intermittent hypoxia and sleep fragmentation leads to inflammation, oxidative stress, adipokines changes and insuline resistance, which predispose to an increased risk of type 2 diabetes development.

Studies show that all-night selective suppression of slow wave sleep (SWS), without any change in total sleep time, leads to a marked decrease in insulin sensitivity without an adequate compensatory increase in insulin release. The result is a reduced glucose tolerance and increased diabetes risk.

The magnitude of the decrease in insulin sensitivity is strongly correlated with the magnitude of the reduction in slow wave sleep. Moreover, loss of slow wave sleep is associated with a shift of the nighttime sympathovagal balance towards a sympathetic predominance. These findings suggest that slow wave sleep has an important role in the maintenance of normal glucose homeostasis through autonomic nervous system modulation.

Studies have shown that obstructive sleep apnea is an independent risk factor for the development of type 2 diabetes. More severe obstructive sleep apnea, higher the probability of a worse glycemic control and of type 2 diabetes incidence. For instance, the percentage of HbA1c, which is a marker of long-term glucose control in diabetic individuals, was positively correlated with the severity of obstructive sleep apnea.

The treatment with continuous positive airway pressure has been shown to be effective on glycemic control in type 2 diabetes. Several evidences showed significant improvements in insulin sensitivity in patients with obstructive sleep apnea who are treated with continuous positive airway pressure.
Sleep loss due to insomnia was also associated with a higher risk for diabetes. Objective sleep duration may predict cardiometabolic morbidity of chronic insomnia, independently of age, gender, race, obesity, diabetes, smoking, alchool consumption, depression and the presence of sleep disordered breathing. The highest risk of diabetes was in subjects with insomnia and less than 5 hours of sleep and in insomniacs who slept 5–6 hours per night compared with the normal sleeping of more than 6 h.

The prevalence of restless leg movements is 28.5% in diabetes, without sex differences. This suggests a significant association between restless leg movements and diabetes which must be taking into account in evaluating the potential detrimental effects in diabetic patients.

Mechanisms between sleep deprivation and glucose regulation

Several mechanisms have been suggested to explain why inadequate sleep leads to impaired glucose regulation and type 2 diabetes:

  1. Sleep deprivation leads to a reduced glucose uptake by the brain.
  2. Hormonal regulation is impaired by sleep deprivation leading to higher levels of growth hormone and nocturnal cortisol, which in turn alter glucose metabolism.
  3. Sleep loss results in an activation of the sympathetic nervous system, which then leads to less insulin secretion and higher glucose levels. Studies have shown that in experimentally induced sleep loss in healthy volunteers, insulin sensitivity is decreased without adequate compensation in beta-cell function, which results in impaired glucose tolerance and increased diabetes risk. Short sleep duration has been associated with an elevated risk of incident-impaired fasting glucose through insulin resistance.
  4. Sleep loss was shown to be associated with weight gain, which is a well-established risk factor for type 2 diabetes. Sleep loss may further translate into weight gain by daytime fatigue and a subsequent decrease in energy expenditure, by an increase in time to eat, and by an increase in levels of leptin and ghrelin, which regulate appetite and satiety. The lack of sleep downregulates the satiety hormone leptin, upregulates the appetite-stimulating hormone ghrelin, and increases hunger and food intake.

Cardiovascular diseases can be caused by complex combinations of these metabolic and circulatory abnormalities.

The increasing incidence of diabetes along with a decrease in sleep duration has indicated that diabetes is a risk factor for stroke modifiable by sleep duration.

Endocrine and metabolic changes associated with sleep loss

Anabolic hormones are altered by sleep deprivation.

Growth hormone reaches its daily maximum in the first half of the sleep period. Up to about 70% of the daily growth hormone secretion occurs during this window of time. During sleep deprivation, the sleep-associated growth hormone pulse is substantially dampened or abolished.
Sleep deprivation also alters the output of metabolic hormones as measured in peripheral circulation. Glucose metabolism is slowed during sleep deprivation. Insufficient sleep may be a potentially contributing mechanism in the clinical development of insulin resistance, increased accrual of adipocytes, and resulting elevated inflammatory mediators.

Leptin, an adipocyte hormone that signals satiety to the brain, is reduced in diurnal rhythm amplitude and peak amount as measured in peripheral circulation during sleep deprivation.

Ghrelin, a hormone that signals hunger to the brain, and subjective appetite are increased during sleep deprivation. The combination of slowed metabolism produced by sleep deprivation and increased appetite may lead to weight gain and contribute to the increasing prevalence of obesity and metabolic syndrome.

Sleep plays a role in thermoregulation. Sleep deprivation also represents a reduction in the normal nocturnal drop in both body temperature and blood pressure.

In concert with this drop in temperature, the thyroid-stimulating hormone level is elevated and also the free thyroid hormones T3 and T4 during sleep deprivation. The elevations seen in short-term experimental sleep deprivation studies are without clinical sequelae and resolve quickly with recovery sleep. The thyroid is a major regulator of metabolic rate, affects carbohydrate metabolism, modulates oxygen consumption, heart contractility, and cardiac output. It also raises the rate at which the gastrointestinal tract absorbs glucose, which increases insulin resistance. In case of chronic sleep deprivation, the small thyroid-stimulating hormone changes may nonetheless contribute to the development of disease.

Studies have also found increased stress markers during sleep deprivation such as elevations in cortisol in the late afternoon and into the early nighttime hours, when cortisol is typically at its lowest level.

In sleep deprivation studies, catecholamine results (both adrenaline and nordrenaline) also showed increased levels. Hormones such as noradrenaline, prolactin, ghrelin, and growth hormone, which are dependent on sleep for their circadian rhythmicity or appearance, lose their periodic pattern of excretion during sleep loss. Rebounds in growth hormone and adrenocorticotropic hormone (ACTH) during recovery sleep are seen after sleep loss or slow wave sleep deprivation.

Sleep, particularly deep sleep, has an inhibitory influence on the hypothalamic–pituitary–adrenal axis. Activation of the hypothalamic–pituitary–adrenal axis or administration of glucocorticoids can lead to arousal and sleeplessness. Insomnia, the most common sleep disorder, is associated with a 24-hour increase in ACTH and cortisol secretion, consistent with a disorder of central nervous system hyperarousal.

The effects of sleep deprivation on emotional control

Sleep plays an important role in regulating emotional control. Partial sleep deprivation negatively affects emotional stability. This is important since insufficient sleep is common in today’s society.

Sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation is that negative events elicit more attentive behavior and thus stable responding under sleep deprivation conditions. Sleep deprivation impacts reactivity to emotional stimuli through automated attentional and self-regulatory processes.

Sleep loss adversely affects functioning in many ways. Sleep deprivation negatively impacts health, performance, daytime sleepiness, and subjective effort. Recent research shows that partial sleep deprivation negatively affects performance and health, and that daytime fatigue is related to sleep habits, sleepiness, and feelings of stress.

The lack of sleep is associated with negative changes in mood, increased irritability, and emotional instability as well as physiological changes associated with a stress response. Sleep deprivation increases negative mood states, worsens emotional regulation, and induces extra sensitivity to emotional and stressful events. Poor sleep quality is also related to increased perceived stress, negative affect, and amygdala reactivity as well as decreased emotional regulation.

Emotions can affect sleep architecture and sleep affects consolidation of emotional memories but can also lead to habituation and decreased reactions to past aversive events.

There is a bidirectional relationship between sleep and emotions such that sleep affects emotions and emotions affect sleep. Many clinical-based studies have shown that sleep disturbances are related to mood and anxiety disorders suggesting a relationship between sleep and affective stability that may exceed the short-term effects due to acute sleep deprivation.

Sleep-deprived persons report more stress, anxiety, and anger when exposed to low-stress conditions but not when exposed to high-stress conditions. Sleep deprivation reduces positive affect and increases anxiety during a stressful task.

Experimentally, sleep deprivation increases reactions to angry and fearful facial expressions that can be attenuated by naps rich in rapid eye movement sleep. These effects of sleep deprivation on mood and affect can have negative repercussions in real-world settings. For example, a study on sleep-deprived medical residents reported that sleep loss magnified the negative emotive effects of disruptive daytime work.

It is clear that emotional stability in sleep-deprived persons is compromised.

Being more focused on the negative stimuli could be an indication of a lack of self-control in sleep-deprived persons. Self-control has been shown to affect emotional responses if people consciously pursue emotional control. Sleep deprivation makes it less likely that people will choose to regulate their emotions. Sleep is necessary to replenish the internal resources necessary for self-control.

Sleep-deprived persons are less capable of monitoring and controlling their self-regulatory behavior as well as their attentional states. Sleep deprivation could contribute to a decrease in positive affect and subsequently lower workplace morale and motivation.
Studies indicate that both partial and total sleep deprivation have a greater negative effect on subjective ratings to positive events than negative events. Negative events automatically elicit more attentive behavior under sleep deprivation conditions.

Poor sleep quality and insufficient sleep lead to low positive affect among healthy, depression-free individuals.

Animal studies suggest a potential causal link by which chronic sleep restriction leads to a gradual and persistent desensitization of the 5-HT1A receptor system. If also true in humans, and given that depression is associated with altered serotonergic neurotransmission, desensitization of the serotonin system could explain the increased risk of depression among individuals with persistent sleep problems.

Sleep deprivation may lead to increased impulsivity.

The effect of sleep duration on impulsivity—acting quickly and without thorough consideration of consequences—is of particular interest because impulsivity is associated with many behavioral problems such as addiction, attention deficit disorder, oppositional defiant disorder, conduct disorder and overeating.

There are a number of cognitive factors contributing to impulse control, many of which are impacted by sleep deprivation such as vigilance, attention, perception, higher order processes such as learning and executive functions.

Impulsivity has been delineated into two separable constructs: impulsive action and impulsive decision-making or choice. Impulsive action is the failure to inhibit inappropriate responses.

Impulsive decision-making (or choice) involves decisions based on evaluation of potential outcomes (risks and rewards) and is associated with the tendency to favor more immediate rather than delayed rewards. Partial sleep deprivation impacts impulsive action but not impulsive decision-making.

Negative impact of short sleep on impulsive action was strongest in those individuals who reported that they typically had longer time in bed at baseline.
A pathway through which short sleep may specifically impact impulsive action is via impairments in vigilance and sustained attention. Attention suffers with sleep deprivation, as evidenced by lapses in vigilance and decreased reaction time.

There are important individual differences in tolerance to short sleep. Those who typically achieve longer time in bed are most at risk for impairment when sleep must be restricted.

Sleep deprivation and depression

Sleep serves an important role in mood and emotional homeostasis. Sleep deprivation is associated with high negative and low positive emotions. Longitudinal studies that examined poor sleep as a predictor of a depressive episode showed that after 1-3 years of sleep deprivation people who were not currently depressed had a significant vulnerability risk for a future depressive episode (a twofold risk of developing depression when reassessed 1 year or more later, compared to those with no sleep difficulties at baseline).

Individuals prone to experience poor sleep in response to stress might also be prone to developing a depressive episode under stress.

A large epidemiological study found that the most common temporal pattern between sleep and mood disturbances among those with a first major depressive episode and insomnia was for insomnia symptoms to have emerged before MDD (41% of participants). In contrast, insomnia symptoms emerged at the same time as the MDD in 29% and after the depressive episode in 29%.

Poor sleep is one of the first depressive symptoms to emerge, thus representing an early stage in the link between stress and depression.

Regarding anxiety disorder, studies have reported that insomnia emerges at the same time as or after the anxiety disorder.

Studies have reported that subjects deprived of sleep for 56 h showed significant elevations on clinical scales measuring depression, anxiety, paranoia and somatic complaints.

In general, when sleep deprived, healthy subjects were more likely to report increased feelings of worthlessness, inadequacy, powerlessness, failure, low self-esteem and reduced life satisfaction.

Moreover, the change in scores was large enough to meet criteria for a ‘clinically significant’ increase in depression scores for 25% of the sample, while 17% of subjects showed clinically significant elevations on scales measuring anxiety, mania and borderline features, suggesting that sleep loss has profound impacts on emotional functioning in healthy individuals.

Evaluation of emotional stimuli is also affected by sleep deprivation. A study presented normally rested healthy subjects with a series of pleasant, neutral and unpleasant photographs and asked them to rate each of the images for emotional quality. Subjects then rated a matched set of images again following either a night of normal sleep at home or one night of total sleep deprivation. Loss of sleep did not alter ratings of pleasant or unpleasant images, but neutral images were rated significantly more negatively following sleep deprivation, an effect that was independent of self-rated mood. Sleep deprivation alters the affective perception of neutral stimuli, biasing emotional processing toward greater negativity.

Perception of humour also appears to be affected by sleep loss. The ability to appreciate humour is a highly complex cognitive capacity that requires the ability to integrate contextual information with emotional processes. Studies show that, despite the fact that caffeine leads to increased alertness and vigilance performance it did not improve humour ratings above placebo. Therefore, the effects of sleep deprivation do not appear to be accounted for by a general deficit in alertness.

Even a single night of sleep deprivation leads to a significant increase in negative self-rated mood scores compared to subjects receiving a normal night of sleep.

Sleep-deprived individuals report worse moods and show evidence of more frequent and amplified negative cognitions and intolerant responses to frustrating social situations. Sleep deprivation affects emotional responses to frustrating events, reduces self-reported coping capacities and emotional intelligence skills. Specifically, two nights of sleep deprivation were associated with a reduced tendency to think positively, decreased willingness to take effective behavioural action to solve problems, and a greater reliance on unproductive coping strategies such as superstitious and magical thinking processes.

Moreover, total scores on an emotional intelligence scale declined as a function of sleep deprivation, particularly with regard to ratings of self-esteem, empathy toward others, understanding of interpersonal dynamics, impulse control, and the ability to delay gratification.

Sleep-deprived individuals appear to be more easily frustrated, intolerant, unforgiving, less caring, and more self-focused than when fully rested.

Neuroimaging studies of the effects of sleep deprivation on brain function showed significant declines in prefrontal metabolic activity during sleep deprivation, which correlated with declines in attention and cognitive processing. The prefrontal cortex is important for regulating attentional resources and also plays an important role in emotional processing and personality.

The medial prefrontal cortex also has extensive inhibitory connections with primitive emotional processing areas such as the amygdala and other limbic structures. Reductions in medial prefrontal metabolic activity impair normal modulation of emotion-related amygdala responses, leading to elevations in negative affective processing.

Sleep deprivation is associated with significantly reduced functional connectivity between the medial prefrontal cortex and the amygdala during emotional processing relative to rested controls.

This critical finding suggests that sleep deprivation weakens top-down inhibitory control over the amygdala by the prefrontal cortex, leading to dysregulation of emotional processing. One critical function of sleep is to optimize neuronal connectivity. Without optimal cortico-limbic connectivity, the lower order emotional processing regions of the limbic system may be effectively ‘cut-off’ from the modulatory control regions of the prefrontal cortex during periods of sleep deprivation.

Sleep deprivation and obesity

Epidemiological studies suggest that adults and children who are habitual short sleepers tend to have a higher body mass index, fat percentage and abdominal circumference when compared to average-duration sleepers. Sleep restriction may lead to increased food intake but does not appear to result in decreased energy expenditure.

Sleep deprivation has been reported to increase evening cortisol levels, which decreases insulin sensitivity the next morning. This notion was further supported by studies, which noted decreases in the effectiveness of insulin-mediated glucose uptake the following morning. Short sleepers have glucose responses that are similar to average-duration sleepers, but at the cost of an increase in insulin release, which may be the result of decreased insulin sensitivity over time.

Sleep restriction enhances susceptibility to food stimuli, especially for energy-dense, high-carbohydrate foods.

Although the magnitude of weight gain is not substantial, a slight but persistent change in sleep duration may negatively affect body weight.

Inadequate sleep, in both quality and quantity, should be regarded as a plausible risk factor for the development of obesity and type 2 diabetes. In addition to other health promotion measures, a good night’s sleep should be seen as a critical health component in the prevention and treatment of obesity and type 2 diabetes. A study indicated that 3—5% of obesity in adults can be attributed to short sleep duration, highlighting the crucial role of inadequate sleep in the prevalence of obesity.

The pathogenesis of obesity is complicated. Investigating the contribution of only a single risk factor to obesity is difficult. Obesity results from complex multifactorial interactions, such as those involving eating habits, sedentary lifestyle environment and genes. A family history of obesity is considered a crucial risk factor for obesity.

 

Physiological mechanism underlying the association of sleep deprivation with obesity:

  1. the shortening of sleep duration is associated with appetite regulating hormone changes, which can increase the appetite and food intake, leading to weight gain (changes in orexins, including increased ghrelin and decreased leptin).
  2. a short sleep duration increases fatigue and reduces activity during the daytime, which results in more sedentary time without adequate energy expenditure.
  3. a decrease in sleep duration is often accompanied by irregular eating habits and increased caloric intake. In particular, the preferential intake of fat-containing, high-carbohydrate, and energy-dense food is significantly increased. Although the caloric intake is increased, the daytime energy expenditure remains unchanged, leading to weight gain.

Sleep has a major role in the regulation of glucose metabolism and neuroendocrine function in adults.

Normal sleep duration has less risk of obesity than short or long sleep duration.

Sleep deprivation and driving

Drowsiness and falling asleep at the wheel are the reasons for many fatal crashes and traffic accidents. Falling asleep at the wheel associated with sleep deprivation and nocturnal driving has been incriminated in 20% of traffic accidents. Sleep hygiene and countermeasures (naps and coffee) could significantly improve road safety.

Of all sleep disorders, obstructive sleep apnea syndrome is the most studied pathologic process with regard to traffic accidents. Medical treatments such as continuous positive airway pressure and uvulopalatopharyngoplasty are effective to decrease accidental risk in those with sleep apnea.

Although cold air or listening to the radio has not demonstrated any efficacy, coffee and naps are very efficient in combating sleepiness at the wheel. A cup of coffee containing 200 mg of caffeine significantly improves performance in both young (20 to 25 years) and middle-aged individuals (40 to 50 years) on nighttime highway driving performances. A 30-minute nap is more efficient in younger than in middle-aged drivers.

Alcohol use has been found to consistently reduce alertness. One difficulty in assessing the magnitude of performance effects associated with sleep loss is the lack of a clear standard of pathology for most measures. The fact that society has established very specific rules for blood alcohol content with respect to driving has led to the use of impairment associated with blood alcohol level as a standard reference for sleep deprivation as well.

Several studies of alcohol use in direct comparison with sleep deprivation have shown decrements on different tasks. After a night of sleep deprivation subjects averaged one off-road (vehicle driving off the road) incident every 5 minutes. This same level of off-road driving was reached with a blood alcohol content of 0.08%. Studies also suggest that the changes in response speed, visual tracking, and driving commonly found during the first night of total sleep deprivation are equivalent to changes associated with legal intoxication. Such metrics provide useful understanding of the consequences associated with short periods of sleep loss. While being sleepy or sleep-deprived it is totally contraindicated alcohol consumption. Even if the level of blood alcohol content is below the legal limit, sleepiness enhances its effects. The result could be the same as for a legal intoxication.

Effects of sleep deprivation on cognition

Insufficient sleep leads to a general slowing of response speed particularly for simple measures of alertness, attention and vigilance and also affects many higher level cognitive capacities, including perception, memory and executive functions.

Alertness and vigilance are the cognitive capacities most consistently and dramatically impacted by insufficient sleep. These basic capacities serve as the foundation for complex cognitive processing.

The most commonly used metric for evaluating alertness and vigilance during sleep loss is the Psychomotor Vigilance Test, a 10-min simple reaction time test that repeatedly presents a visual cue at random intervals ranging from 2 to 10 s. At each cue presentation, the subject simply presses a button as quickly as possible to register a response.

When wakefulness is pushed beyond about16 h, most individuals begin to show a substantial slowing of reaction time and worsening of performance accuracy on tests of psychomotor vigilance, declines that continue to worsen as wakefulness is sustained throughout the night into the early morning hours. Restricting sleep by 6 h per night can lead to significant slowing of response times that, if prolonged for up 2 weeks, can reach impairment levels that are comparable to about two nights of total sleep deprivation. Sleep deprivation leads to an increase in the number and duration of attentional lapses (periods during which the subject fails to respond to the cue, usually defined as a response of 500 ms or longer) as well as an increase in errors of commission or false alarms (responses when no cue has been presented or incorrect responses). Longer lapses represent ‘microsleeps’, or brief periods where sleep-like brain activity may momentarily interrupt ongoing wakefulness. During sleep deprivation, performance degradation will be most severe at the circadian nadir during the early morning hours.

A particularly compelling and practically relevant account of the decline in vigilance and attention was demonstrated by a study that equated hours of wakefulness with blood alcohol concentration during a simple test of hand–eye tracking and coordination.

The study showed that after 10 h of continuous wakefulness, each additional hour awake was equivalent to an increase of 0.004% blood alcohol concentration until about 26 h of wakefulness. In practical terms, by 17-h of wakefulness performance was equivalent to a blood alcohol concentration of 0.05%, while 24 h awake was roughly equivalent to performance at 0.10%, a level meeting or exceeding the legal limit for intoxication in all states in the United States. The implications are clear – a person who has gone for even one single night without sleep is about as impaired on early morning hand–eye coordination as an individual drinking alcohol to the legal limit of intoxication.

The explanation is that sleep deprivation is associated with reduced metabolic activity within a network of brain regions important for attention, information processing and executive control, including the prefrontal cortex, anterior cingulate, thalamus, basal ganglia and cerebellum.

Total sleep deprivation was also associated with significant increases in ratings of spontaneous pain, including general physical discomfort, body pain, headache, muscle pain and stomach pain. The exact mechanisms for hyperalgesia during sleep deprivation is not clearly understood, but it is conceivable that dysregulation of affective processing systems may contribute to this effect.
Sleep is critical to learning and memory. When sleep is hindered, memory processing is correspondingly degraded. Sleep appears to be important for memory processing in two major ways:

  1. sleep is important before learning or encoding to prepare the brain to effectively acquire new information.
  2. sleep is important following learning to facilitate the consolidation (stabilization) and integration (assimilation) of newly learned information into existing memory structures.

Sleep deprivation adversely affect temporal lobe regions typically involved in memory processing.

Sleep is necessary to prepare the brain for subsequent learning. When the brain is deprived of sleep, normal hippocampal functioning becomes impaired and the formation of new memories is hindered.

Studies have reported that sleep deprivation significantly impairs encoding and retention of positive and neutral stimuli. Memory for negative stimuli appeared to be relatively impervious to sleep loss. This may result in a bias favouring negative memories over neutral and positive ones when sleep deprived, which could have implications for the development and maintenance of pathological mood conditions such as depression.

The neuroprotective effect of vitamin E and C on chronic sleep deprivation

Sleep deprivation induces oxidative stress and impairs learning and memory processes. Vitamin E is a strong antioxidant that has neuroprotective effect on the brain, preventing memory impairment probably through its antioxidant action in the hippocampus.

A central cognitive function of sleep is to consolidate newly acquired memories for long-term storage. Several studies have shown that sleep, and namely REM sleep, is vital for learning and memory consolidation. The duration of REM sleep increases after learning tasks.

The mechanism of memory impairment is still unknown but in general, sleep deprivation increases oxidative stress in the hippocampus and many regions in the brain that are usually detoxified by sleep. This hippocampal oxidative stress reflects on neuronal excitability, molecular signaling, and cognitive functions.

Vitamin E is a powerful antioxidant that reduces free radicals and reactive oxygen species activity, preventing oxidative stress. Oxidative stress has been linked to cognitive impairments in several health conditions. Like other antioxidants, vitamin E slows or prevents memory impairments that accompany several conditions such as diabetes, cerebral ischemic injury, stroke, Alzheimer’s disease, mental stress and aging. Also, vitamin C is a potent antioxidant and reduces learning and memory impairment associated with Alzheimer’s diseases, chronic stress, diabetes, exposure to fluoride and melamine and the aging process. Majority of reports underling cognitive impairment in Alzheimer disease relate impairment to oxidative stress via decreased levels of antioxidant enzymes.

Studies shows that chronic vitamin C and E administration prevent short- and long-term memory impairment induced by chronic sleep deprivation.

Current results indicate that chronic sleep deprivation decrease the antioxidant defense mechanism.

The antioxidative stress mechanisms are important for cognition because they function in multiple brain areas where elevated oxidative stress leads to neuronal damage. An imbalance between reactive oxygen species and antioxidant enzymes may lead to oxidative stress state.

Vitamin C and E normalize levels of oxidative stress markers such as glutathione/glutathione disulfide ratio, and enzymatic systems including glutathione peroxidase, catalase and superoxide dismutase that are reduced during chronic sleep deprivation. Vitamin C does not act alone in the brain. It is well known that vitamin C is needed to regenerate vitamin E.

Oxidative stress contributes to the cellular damage and leads to cognitive impairments of both short- and long-term memory.

The mechanisms that link oxidative stress with impaired cognitive functions during sleep deprivation could be related to oxidative stress responsive signaling molecules such as CREB and CaMKIV. Oxidative stress is accompanied with reduced levels of CaMKIV and phosphorylated CREB. Both CREB and CaMKIV are essential signaling molecules for memory functions. Thus, increased oxidative stress during sleep deprivation leads to suppression of signaling molecules important for memory functions such as CREB and CaMKIV, leading to memory impairment. As an antioxidant, vitamin E is capable of preventing this sequence of events.

Vitamin E is not an enhancing agent, and it might work only if there is an impairment in memory functions.

Oxidative stress seem to be acutely associated with a compensatory increase in antioxidant defense mechanism. With chronic exposure to oxidative stress, these compensatory mechanisms start to fade, and reductions in antioxidant defense mechanisms is usually detected.

The impairment of learning and memory during sleep deprivation is not due to release of stress hormones. Stress influences the hippocampus in a considerably different manner than sleep deprivation. As an example, one study reported that psychosocial stress for 6 weeks did not affect long-term memory, which was markedly impaired by chronic sleep deprivation. Psychosocial stress does not impair dentate gyrus related memory function.

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