Gianluca Rinaldi
Raffaele Ramonda
DEFINITION
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms resulting from rapid long-distance transmeridian (east–west or west–east) travel on a (typically jet) aircraft. It is classified as one of the circadian rhythms sleep disorders.
The condition of jet lag may last several days until one is fully adjusted to the new time zone, and a recovery rate of one day per time zone crossed is a suggested guideline. The issue of jet lag is especially pronounced for airline pilots, crew, and frequent travelers. Airlines have regulations aimed at combating pilot fatigue caused by jet lag.
(wikipedia)
(PMC)
(medical-dictionary)
EPIDEMIOLOGY
A 2002 study of international business travelers (IBTs) found that jet lag was one of the most common health problems reported, affecting as many as 74% of IBTs.
SYMPTOMS
Traveling through a few time zones at a time is not as disruptive to circadian rhythms as traveling around the world can be. The foremost symptom of jet lag is altered sleep pattern—sleepiness during the day, and insomnia during the night. Individuals afflicted by jet lag will alternate in and out of a normal day-night cycle.
Other Symptoms include daytime anergia, emotional disturbances, and gastrointestinal distress. The severity depends on the degree and the duration of dyssynchrony, as well as on innate factors such as age and whether the patient is an “early bird” or a “night owl.”
DIAGNOSIS
When assessing for jet lag disorder, ask about:
• the patient’s degree of sleep deprivation before and during travel;
• his or her innate circadian preference ( whether he or she is a “night owl” or “early bird”);
• patterns of alcohol and caffeine consumption.
Tools:
1) Sleep diary: in a sleep diary or log, patients record the times that they take naps, maintain consolidated sleep, and subsequently arise. The diary also prompts the patient for information about sleep latency, wakefulness after sleep onset, time in bed, medication and caffeine intake, and the restorative quality of sleep. Compliance is often limited. Therefore, the sleep diary is best used in conjunction with actigraphy;
2) Actigraphy: an actigraph is a wristwatch-size motion detector, typically worn continuously for 7 days or longer. The data it gathers and stores serve as a surrogate measure of various sleep-wake variables.
Either a sleep diary or actigraphy is required to demonstrate the stability of sleep patterns and circadian preference, but the actigraph typically generates more reliable data. It is also valuable in assessing the response to treatment of circadian rhythm sleep disorders.
PATHOGENESIS
When people are without clocks in a compartment that is completely closed to sunlight, most of them fall into a circadian cycle of about 25 hours. Every morning the sunlight resets the cycle, stimulating the leading chemicals and thus compensating for the difference between the 24-hour day and the 25-hour innate rhythm.
Circadian rhythm sleep disorders are the result of dyssynchrony between the body’s internal clock and the external 24-hour light-dark cycle.
Sleep and wakefulness are conceptually governed by two processes, “process S” and “process C”. The homeostatic drive to sleep (process S) is proportional to the duration of sleep restriction (which causes an accumulation of DSIP), and it becomes maximal at about 40 hours. In contrast, process C creates a drive for wakefulness that variably opposes process S and depends on circadian rhythms intrinsic to the organism. The homeostatic process (process S, blue line) is limited to a range of values determined by a clock-like circadian process (process C, red lines) that varies with the biological time of day. (Jet lag and shift work sleep disorders: How to help reset the internal clock 2017)
Coordinating this sleep-wake rhythm (and numerous other behavioral and physiologic processes) are the neurons of the suprachiasmatic nuclei (SCN) of the hypothalamus, a tiny region on the brain's midline responsible for controlling circadian rhythms: neurons in the SCN fire action potentials in a 24-hour rhythm. At mid-day, the firing rate reaches a maximum, and, during the night, it falls. SCN has got connections with photosensitive ganglion cells in the retina, which stimulate it helping the resetting of the circadian rhythm. SCN stimulates the nocturnal secretion of the pineal hormone melatonin. Once secreted by the pineal gland, melatonin initiates a cascade of physiological events that are sleep promoting in humans. Melatonin binding to melatonin receptors(MT2) in the SCN reduces SCN neuronal firing rates and this is hypothesized to quiet the circadian brain arousal signal and therefore promote sleep. Melatonin and melatonin receptor agonists also affect other physiological systems that promote sleep, such as reducing core body temperature and increasing peripheral heat loss. However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear, but some results suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN.
The intrinsic human circadian period is typically slightly longer than 24 hours, due to the intrinsic rhythm of SCN, but it is synchronized to the 24-hour day by various environmental inputs, or zeitgebers (German for “time-givers”), the most important of which is light exposure.
When the internal clock is out of sync with the sun, in particular after long-distance air travel, this overwhelms the ability of the intrinsic clock to adjust rapidly enough, and the result is jet lag sleep disorder.
(Circadian and wakefulness-sleep modulation of cognition in humans)
The role of glucocorticoids (GCs)
In some experiments, cortisol concentrations were measured in jet-lagged hamsters throughout the course of the treatment, on Day 8 jet lag hamsters exhibited cortisol concentrations comparable to stress-induced values in this species. On subsequent days, cortisol concentrations in the jet-lagged hamsters were lower than those seen in stressed animals but greater than daily maximum values.
SCN regulates the circadian release of GC via input to the hypothalamo-pituitary-adrenal axis (ACTH circadian rhythmic release) and via a second regulatory pathway, which likely involves sympathetic innervation of the adrenal.
The SCN signals primarily though neuronal connections to the adrenal, thereby regulating adrenal clock gene expression. In turn, the adrenal clock feeds back to the SCN, where it stabilizes SCN-controlled activity rhythms. GCs are part of this adrenal to SCN feedback, which most likely uses indirect pathway of transmission, as SCN neurons themselves do not express GC receptors.
Such a feedback control mechanism would prevent uncoordinated resetting of the circadian system, for example in response to sporadic light exposure, and thus serves as a protection from Zeitgeber noise. In the case of jet lag, however, this feedback loop becomes a problem, preventing rapid adaptation of behavioral rhythms to the new time zone. In fact exposure to sunlight keeps the cortisol levels up in the body when they should be going down. When the adrenal clock is compromised, for example by adrenalectomy or transplantation of a clock-deficient adrenal, then adrenal-SCN feedback is affected. The SCN pacemaker thus becomes less resistant to external perturbation and hence more rapidly relays the external resetting signal to subordinated clocks and tissues, resulting in accelerated reentrainment. Because GC rhythmicity markedly influenced photic resetting during jet lag, modulating these rhythms by timed inhibition of GC synthesis might be an attractive therapeutic alternative because of its minor side effects.
Moreover GCs reduce adult hippocampal neurogenesis so, since there is an association between the production of new hippocampal neurons and hippocampal-dependent cognitive processes, the cognitive impairment seen during phase advancements may result from increased cortisol production in jet-lagged animals.
The degree of reduction in neurogenesis depends upon the direction, a greater decrease in neurogenesis is observed when the phase is advanced (eastward travel), and duration of the shifts.
(Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior)
(Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters)
(Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag)
(Jet lag and shift work sleep disorders: How to help reset the internal clock)
(Electrophysiological effects of melatonin on mouse Per1 and non-Per1 suprachiasmatic nuclei neurones in vitro)
(Circadian regulation of cortisol release in behaviorally split golden hamsters)
TREATMENT
10 Tips On How To Get Over Jet Lag Fast by Alisa Paliano
No drugs
Frequent shifts to different time zones, often required in business travel, are very difficult to accommodate, and business travelers actually may do better if they remain on their home-based schedule. If the traveler intends to remain at the destination long enough, he or she can adjust better via strategic avoidance of and exposure to light.
Generally, shifts earlier in time are required for eastward flights, and shifts later in time are required for westward flights. However, advances of 8 hours or more are more readily accomplished by a phase delay.
Our core body temperature dips to its lowest point about 2 to 3 hours before we habitually awake. Exposure to bright light in the hours leading up to the patient’s minimum core body temperature tends to push the internal clock later in time, whereas bright light in the hours immediately afterward pushes the clock earlier in time.
As a consequence, people travelling east, who want to set their clocks ahead (a phase advance), need to keep to the dark in the 3 hours leading up to the time they reach their minimum core body temperature, and then expose themselves to light in the 3 hours immediately after. Requirements for darkness can be met with protective eyewear, or by remaining in a dark room.
The following precautions taken during an international flight can help to limit or prevent jet lag:
• Stay hydrated. Drink plenty of water and juices to prevent dehydration. Beverages and foods with caffeine should be avoided because of their stimulant properties. Alcohol should also be avoided.
• Stretch and walk. As much movement as possible during a flight helps circulation, which moves nutrients and waste through the body and aids in elimination.
• Stay on time. Set watches and clocks ahead to the time in the destination city to start adjusting to the change.
• Sleep smart. Draw the shade and sleep during the evening hours in the destination city, even if it is still daylight outside of the airplane. Earplugs and sleep masks may be helpful in blocking noise and light. Many airlines provide these items on international flights.
• Dress comfortably. Wear or bring comfortable clothes and slippers that will make sleeping during the flight easier.
Drugs
Melatonin
Most field studies have found that nightly doses of melatonin (2–8 mg) improve the quality of sleep or alleviate daytime symptoms of jet lag: melatonin administration in the morning shifts rhythms later while melatonin administration in the evening shifts rhythms earlier.
The study involving solely westward travel found that significantly better jet lag outcomes were found in the group of partecipants who received melatonin beginning only on arrival than people who received melatonin before departure and continuing for 5 days after arrival.
Benzodiazepine
The use of standard hypnotics during periods of circadian realignment appears to be commonplace
in counteracting jet-lag-induced insomnia, but the evidence is less clear for daytime symptoms.
however, adverse effects (such as nausea, vomiting, and confusion) are more frequent in people who take benzodiazepines.
Stimulants (caffeine)
In one study, people took preparations (pills) at a daily dosage of 300 mg after an eastward flight traversing seven time zones, every day for 5 days. Curiously, alertness and other jet lag symptoms were not assessed, but circadian rhythms (determined by levels of cortisol in saliva) were re-entrained at a more rapid rate, to a degree comparable with that achieved by exogenous melatonin. As a consequence, those receiving caffeine were objectively less sleepy but had significantly more nocturnal sleep complaints, as assessed both objectively and subjectively.
(Jet lag and shift work sleep disorders: How to help reset the internal clock)
(Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders)
COMPLICATIONS
The related disruption of the human circadian time organization leads in the short-term to an array of jet-lag-like symptoms, and in the long-run it may contribute to weight gain/obesity, metabolic syndrome/type II diabetes, and cardiovascular disease. Epidemiologic studies also suggest increased cancer risk, especially for breast cancer.
Experimental 'jet lag' causes sympathoexcitation via oxidative stress through angiotensin II type 1 receptor in the cardiovascular center of the brainstem (rostral ventrolateral medulla; RVLM) especially in hypertension.
Furthermore ROS genes exhibit a time-of-day-specific phase of expression under diurnal and circadian conditions, this means that there is a role of the circadian clock in the transcriptional regulation of these genes; a mutation in the circadian rhythm affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress.
(Experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT1 receptor in the brainstem)
(Shift work and cancer risk: Potential mechanistic roles of circadian disruption, light at night, and sleep deprivation.)
(CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses.)
