Cellular network

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cellular_network 

 

Top of a cellular radio tower

 

Indoor cell site in Germany

 

Part of a series on
Antennas

A cellular network or mobile network is a communication network where the link to and from end nodes is wireless. The network is distributed over land areas called "cells", each served by at least one fixed-location transceiver (typically three cell sites or base transceiver stations). These base stations provide the cell with the network coverage which can be used for transmission of voice, data, and other types of content. A cell typically uses a different set of frequencies from neighboring cells, to avoid interference and provide guaranteed service quality within each cell.

When joined together, these cells provide radio coverage over a wide geographic area. This enables numerous portable transceivers (e.g., mobile phones, tablets and laptops equipped with mobile broadband modems, pagers, etc.) to communicate with each other and with fixed transceivers and telephones anywhere in the network, via base stations, even if some of the transceivers are moving through more than one cell during transmission.

Cellular networks offer a number of desirable features:

• More capacity than a single large transmitter, since the same frequency can be used for multiple links as long as they are in different cells
• Mobile devices use less power than with a single transmitter or satellite since the cell towers are closer
• Larger coverage area than a single terrestrial transmitter, since additional cell towers can be added indefinitely and are not limited by the horizon

Major telecommunications providers have deployed voice and data cellular networks over most of the inhabited land area of Earth. This allows mobile phones and mobile computing devices to be connected to the public switched telephone network and public Internet access. Private cellular networks can be used for research or for large organizations and fleets, such as dispatch for local public safety agencies or a taxicab company.

Concept

Example of frequency reuse factor or pattern 1/4

In a cellular radio system, a land area to be supplied with radio service is divided into cells in a pattern dependent on terrain and reception characteristics. These cell patterns roughly take the form of regular shapes, such as hexagons, squares, or circles although hexagonal cells are conventional. Each of these cells is assigned with multiple frequencies (f₁ – f₆) which have corresponding radio base stations. The group of frequencies can be reused in other cells, provided that the same frequencies are not reused in adjacent cells, which would cause co-channel interference.

The increased capacity in a cellular network, compared with a network with a single transmitter, comes from the mobile communication switching system developed by Amos Joel of Bell Labs that permitted multiple callers in a given area to use the same frequency by switching calls to the nearest available cellular tower having that frequency available. This strategy is viable because a given radio frequency can be reused in a different area for an unrelated transmission. In contrast, a single transmitter can only handle one transmission for a given frequency. Inevitably, there is some level of interference from the signal from the other cells which use the same frequency. Consequently, there must be at least one cell gap between cells which reuse the same frequency in a standard frequency-division multiple access (FDMA) system.

Consider the case of a taxi company, where each radio has a manually operated channel selector knob to tune to different frequencies. As drivers move around, they change from channel to channel. The drivers are aware of which frequency approximately covers some area. When they do not receive a signal from the transmitter, they try other channels until finding one that works. The taxi drivers only speak one at a time when invited by the base station operator. This is a form of time-division multiple access (TDMA).

History

See also: History of mobile phones

The first commercial cellular network, the 1G generation, was launched in Japan by Nippon Telegraph and Telephone (NTT) in 1979, initially in the metropolitan area of Tokyo. Within five years, the NTT network had been expanded to cover the whole population of Japan and became the first nationwide 1G network. It was an analog wireless network. The Bell System had developed cellular technology since 1947, and had cellular networks in operation in Chicago and Dallas prior to 1979, but commercial service was delayed by the breakup of the Bell System, with cellular assets transferred to the Regional Bell Operating Companies.

The wireless revolution began in the early 1990s, leading to the transition from analog to digital networks. This was enabled by advances in MOSFET technology. The MOSFET, originally invented by Mohamed M. Atalla and Dawon Kahng at Bell Labs in 1959, was adapted for cellular networks by the early 1990s, with the wide adoption of power MOSFET, LDMOS (RF amplifier), and RF CMOS (RF circuit) devices leading to the development and proliferation of digital wireless mobile networks.

The first commercial digital cellular network, the 2G generation, was launched in 1991. This sparked competition in the sector as the new operators challenged the incumbent 1G analog network operators.

Cell signal encoding

To distinguish signals from several different transmitters, frequency-division multiple access (FDMA, used by analog and D-AMPS systems), time-division multiple access (TDMA, used by GSM) and code-division multiple access (CDMA, first used for PCS, and the basis of 3G) were developed.

With FDMA, the transmitting and receiving frequencies used by different users in each cell are different from each other. Each cellular call was assigned a pair of frequencies (one for base to mobile, the other for mobile to base) to provide full-duplex operation. The original AMPS systems had 666 channel pairs, 333 each for the CLEC "A" system and ILEC "B" system. The number of channels was expanded to 416 pairs per carrier, but ultimately the number of RF channels limits the number of calls that a cell site could handle. Note that FDMA is a familiar technology to telephone companies, that used frequency-division multiplexing to add channels to their point-to-point wireline plants before time-division multiplexing rendered FDM obsolete.

With TDMA, the transmitting and receiving time slots used by different users in each cell are different from each other. TDMA typically uses digital signaling to store and forward bursts of voice data that are fit into time slices for transmission, and expanded at the receiving end to produce a somewhat normal-sounding voice at the receiver. TDMA must introduce latency (time delay) into the audio signal. As long as the latency time is short enough that the delayed audio is not heard as an echo, it is not problematic. Note that TDMA is a familiar technology for telephone companies, that used time-division multiplexing to add channels to their point-to-point wireline plants before packet switching rendered FDM obsolete.

The principle of CDMA is based on spread spectrum technology developed for military use during World War II and improved during the Cold War into direct-sequence spread spectrum that was used for early CDMA cellular systems and Wi-Fi. DSSS allows multiple simultaneous phone conversations to take place on a single wideband RF channel, without needing to channelize them in time or frequency. Although more sophisticated than older multiple access schemes (and unfamiliar to legacy telephone companies because it was not developed by Bell Labs), CDMA has scaled well to become the basis for 3G cellular radio systems.

Other available methods of multiplexing such as MIMO, a more sophisticated version of antenna diversity, combined with active beamforming provides much greater spatial multiplexing ability compared to original AMPS cells, that typically only addressed one to three unique spaces. Massive MIMO deployment allows much greater channel re-use, thus increasing the number of subscribers per cell site, greater data throughput per user, or some combination thereof. Quadrature Amplitude Modulation (QAM) modems offer an increasing number of bits per symbol, allowing more users per megahertz of bandwidth (and decibels of SNR), greater data throughput per user, or some combination thereof.

Frequency reuse

The key characteristic of a cellular network is the ability to re-use frequencies to increase both coverage and capacity. As described above, adjacent cells must use different frequencies, however, there is no problem with two cells sufficiently far apart operating on the same frequency, provided the masts and cellular network users' equipment do not transmit with too much power.

The elements that determine frequency reuse are the reuse distance and the reuse factor. The reuse distance, D is calculated as

${\displaystyle D=R{\sqrt {3N}}}$,

where R is the cell radius and N is the number of cells per cluster. Cells may vary in radius from 1 to 30 kilometres (0.62 to 18.64 mi). The boundaries of the cells can also overlap between adjacent cells and large cells can be divided into smaller cells.

The frequency reuse factor is the rate at which the same frequency can be used in the network. It is 1/K (or K according to some books) where K is the number of cells which cannot use the same frequencies for transmission. Common values for the frequency reuse factor are 1/3, 1/4, 1/7, 1/9 and 1/12 (or 3, 4, 7, 9 and 12 depending on notation).

In case of N sector antennas on the same base station site, each with different direction, the base station site can serve N different sectors. N is typically 3. A reuse pattern of N/K denotes a further division in frequency among N sector antennas per site. Some current and historical reuse patterns are 3/7 (North American AMPS), 6/4 (Motorola NAMPS), and 3/4 (GSM).

If the total available bandwidth is B, each cell can only use a number of frequency channels corresponding to a bandwidth of B/K, and each sector can use a bandwidth of B/NK.

Code-division multiple access-based systems use a wider frequency band to achieve the same rate of transmission as FDMA, but this is compensated for by the ability to use a frequency reuse factor of 1, for example using a reuse pattern of 1/1. In other words, adjacent base station sites use the same frequencies, and the different base stations and users are separated by codes rather than frequencies. While N is shown as 1 in this example, that does not mean the CDMA cell has only one sector, but rather that the entire cell bandwidth is also available to each sector individually.

Recently also orthogonal frequency-division multiple access based systems such as LTE are being deployed with a frequency reuse of 1. Since such systems do not spread the signal across the frequency band, inter-cell radio resource management is important to coordinate resource allocation between different cell sites and to limit the inter-cell interference. There are various means of inter-cell interference coordination (ICIC) already defined in the standard. Coordinated scheduling, multi-site MIMO or multi-site beamforming are other examples for inter-cell radio resource management that might be standardized in the future.

Directional antennas

Cellular telephone frequency reuse pattern. See U.S. Patent 4,144,411

Cell towers frequently use a directional signal to improve reception in higher-traffic areas. In the United States, the Federal Communications Commission (FCC) limits omnidirectional cell tower signals to 100 watts of power. If the tower has directional antennas, the FCC allows the cell operator to emit up to 500 watts of effective radiated power (ERP).

Although the original cell towers created an even, omnidirectional signal, were at the centers of the cells and were omnidirectional, a cellular map can be redrawn with the cellular telephone towers located at the corners of the hexagons where three cells converge. Each tower has three sets of directional antennas aimed in three different directions with 120 degrees for each cell (totaling 360 degrees) and receiving/transmitting into three different cells at different frequencies. This provides a minimum of three channels, and three towers for each cell and greatly increases the chances of receiving a usable signal from at least one direction.

The numbers in the illustration are channel numbers, which repeat every 3 cells. Large cells can be subdivided into smaller cells for high volume areas.

Cell phone companies also use this directional signal to improve reception along highways and inside buildings like stadiums and arenas.

Broadcast messages and paging

Practically every cellular system has some kind of broadcast mechanism. This can be used directly for distributing information to multiple mobiles. Commonly, for example in mobile telephony systems, the most important use of broadcast information is to set up channels for one-to-one communication between the mobile transceiver and the base station. This is called paging. The three different paging procedures generally adopted are sequential, parallel and selective paging.

The details of the process of paging vary somewhat from network to network, but normally we know a limited number of cells where the phone is located (this group of cells is called a Location Area in the GSM or UMTS system, or Routing Area if a data packet session is involved; in LTE, cells are grouped into Tracking Areas). Paging takes place by sending the broadcast message to all of those cells. Paging messages can be used for information transfer. This happens in pagers, in CDMA systems for sending SMS messages, and in the UMTS system where it allows for low downlink latency in packet-based connections.

Movement from cell to cell and handing over

In a primitive taxi system, when the taxi moved away from a first tower and closer to a second tower, the taxi driver manually switched from one frequency to another as needed. If communication was interrupted due to a loss of a signal, the taxi driver asked the base station operator to repeat the message on a different frequency.

In a cellular system, as the distributed mobile transceivers move from cell to cell during an ongoing continuous communication, switching from one cell frequency to a different cell frequency is done electronically without interruption and without a base station operator or manual switching. This is called the handover or handoff. Typically, a new channel is automatically selected for the mobile unit on the new base station which will serve it. The mobile unit then automatically switches from the current channel to the new channel and communication continues.

The exact details of the mobile system's move from one base station to the other vary considerably from system to system (see the example below for how a mobile phone network manages handover).

Mobile phone network

WCDMA network architecture

The most common example of a cellular network is a mobile phone (cell phone) network. A mobile phone is a portable telephone which receives or makes calls through a cell site (base station) or transmitting tower. Radio waves are used to transfer signals to and from the cell phone.

Modern mobile phone networks use cells because radio frequencies are a limited, shared resource. Cell-sites and handsets change frequency under computer control and use low power transmitters so that the usually limited number of radio frequencies can be simultaneously used by many callers with less interference.

A cellular network is used by the mobile phone operator to achieve both coverage and capacity for their subscribers. Large geographic areas are split into smaller cells to avoid line-of-sight signal loss and to support a large number of active phones in that area. All of the cell sites are connected to telephone exchanges (or switches), which in turn connect to the public telephone network.

In cities, each cell site may have a range of up to approximately 1⁄2 mile (0.80 km), while in rural areas, the range could be as much as 5 miles (8.0 km). It is possible that in clear open areas, a user may receive signals from a cell site 25 miles (40 km) away.

Since almost all mobile phones use cellular technology, including GSM, CDMA, and AMPS (analog), the term "cell phone" is in some regions, notably the US, used interchangeably with "mobile phone". However, satellite phones are mobile phones that do not communicate directly with a ground-based cellular tower but may do so indirectly by way of a satellite.

There are a number of different digital cellular technologies, including: Global System for Mobile Communications (GSM), General Packet Radio Service (GPRS), cdmaOne, CDMA2000, Evolution-Data Optimized (EV-DO), Enhanced Data Rates for GSM Evolution (EDGE), Universal Mobile Telecommunications System (UMTS), Digital Enhanced Cordless Telecommunications (DECT), Digital AMPS (IS-136/TDMA), and Integrated Digital Enhanced Network (iDEN). The transition from existing analog to the digital standard followed a very different path in Europe and the US. As a consequence, multiple digital standards surfaced in the US, while Europe and many countries converged towards the GSM standard.

Structure of the mobile phone cellular network

A simple view of the cellular mobile-radio network consists of the following:

• A network of radio base stations forming the base station subsystem.
• The core circuit switched network for handling voice calls and text
• A packet switched network for handling mobile data
• The public switched telephone network to connect subscribers to the wider telephony network

This network is the foundation of the GSM system network. There are many functions that are performed by this network in order to make sure customers get the desired service including mobility management, registration, call set-up, and handover.

Any phone connects to the network via an RBS (Radio Base Station) at a corner of the corresponding cell which in turn connects to the Mobile switching center (MSC). The MSC provides a connection to the public switched telephone network (PSTN). The link from a phone to the RBS is called an uplink while the other way is termed downlink.

Radio channels effectively use the transmission medium through the use of the following multiplexing and access schemes: frequency-division multiple access (FDMA), time-division multiple access (TDMA), code-division multiple access (CDMA), and space-division multiple access (SDMA).

Small cells

Main article: Small cell

Small cells, which have a smaller coverage area than base stations, are categorised as follows:

• Microcell -> less than 2 kilometres,
• Picocell -> less than 200 metres,
• Femtocell -> around 10 metres,
• Attocell -> 1–4 metres

Cellular handover in mobile phone networks

Main article: Handover

As the phone user moves from one cell area to another cell while a call is in progress, the mobile station will search for a new channel to attach to in order not to drop the call. Once a new channel is found, the network will command the mobile unit to switch to the new channel and at the same time switch the call onto the new channel.

With CDMA, multiple CDMA handsets share a specific radio channel. The signals are separated by using a pseudonoise code (PN code) that is specific to each phone. As the user moves from one cell to another, the handset sets up radio links with multiple cell sites (or sectors of the same site) simultaneously. This is known as "soft handoff" because, unlike with traditional cellular technology, there is no one defined point where the phone switches to the new cell.

In IS-95 inter-frequency handovers and older analog systems such as NMT it will typically be impossible to test the target channel directly while communicating. In this case, other techniques have to be used such as pilot beacons in IS-95. This means that there is almost always a brief break in the communication while searching for the new channel followed by the risk of an unexpected return to the old channel.

If there is no ongoing communication or the communication can be interrupted, it is possible for the mobile unit to spontaneously move from one cell to another and then notify the base station with the strongest signal.

Cellular frequency choice in mobile phone networks

Main article: Cellular frequencies

The effect of frequency on cell coverage means that different frequencies serve better for different uses. Low frequencies, such as 450  MHz NMT, serve very well for countryside coverage. GSM 900 (900 MHz) is suitable for light urban coverage. GSM 1800 (1.8  GHz) starts to be limited by structural walls. UMTS, at 2.1 GHz is quite similar in coverage to GSM 1800.

Higher frequencies are a disadvantage when it comes to coverage, but it is a decided advantage when it comes to capacity. Picocells, covering e.g. one floor of a building, become possible, and the same frequency can be used for cells which are practically neighbors.

Cell service area may also vary due to interference from transmitting systems, both within and around that cell. This is true especially in CDMA based systems. The receiver requires a certain signal-to-noise ratio, and the transmitter should not send with too high transmission power in view to not cause interference with other transmitters. As the receiver moves away from the transmitter, the power received decreases, so the power control algorithm of the transmitter increases the power it transmits to restore the level of received power. As the interference (noise) rises above the received power from the transmitter, and the power of the transmitter cannot be increased anymore, the signal becomes corrupted and eventually unusable. In CDMA-based systems, the effect of interference from other mobile transmitters in the same cell on coverage area is very marked and has a special name, cell breathing.

One can see examples of cell coverage by studying some of the coverage maps provided by real operators on their web sites or by looking at independently crowdsourced maps such as Opensignal or CellMapper. In certain cases they may mark the site of the transmitter; in others, it can be calculated by working out the point of strongest coverage.

A cellular repeater is used to extend cell coverage into larger areas. They range from wideband repeaters for consumer use in homes and offices to smart or digital repeaters for industrial needs.

Cell size

The following table shows the dependency of the coverage area of one cell on the frequency of a CDMA2000 network:

Frequency (MHz)	Cell radius (km)	Cell area (km2)	Relative cell count
450	48.9	7521	1
950	26.9	2269	3.3
1800	14.0	618	12.2
2100	12.0	449	16.2

Delayed sleep phase disorder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Delayed_sleep_phase_disorder 

Delayed sleep phase disorder
Other names	Delayed sleep–wake phase disorder, delayed sleep phase syndrome, delayed sleep phase type
Comparison of standard (green) and DSPD (blue) circadian rhythms
Specialty	Psychiatry, sleep medicine

Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a chronic dysregulation of a person's circadian rhythm (biological clock), compared to those of the general population and societal norms. The disorder affects the timing of sleep, peak period of alertness, the core body temperature, rhythm, hormonal as well as other daily cycles. People with DSPD generally fall asleep some hours after midnight and have difficulty waking up in the morning. People with DSPD probably have a circadian period significantly longer than 24 hours. Depending on the severity, the symptoms can be managed to a greater or lesser degree, but no cure is known, and research suggests a genetic origin for the disorder.

Affected people often report that while they do not get to sleep until the early morning, they do fall asleep around the same time every day. Unless they have another sleep disorder such as sleep apnea in addition to DSPD, patients can sleep well and have a normal need for sleep. However, they find it very difficult to wake up in time for a typical school or work day. If they are allowed to follow their own schedules, e.g. sleeping from 4:00 am to 1:00 pm, their sleep is improved and they may not experience excessive daytime sleepiness. Attempting to force oneself onto daytime society's schedule with DSPD has been compared to constantly living with jet lag; DSPD has been called "social jet lag".

Researchers in 2017 linked DSPD to at least one genetic mutation. The syndrome usually develops in early childhood or adolescence. An adolescent version may disappear in late adolescence or early adulthood; otherwise, DSPD is a lifelong condition. The best estimate of prevalence among adults is 0.13–0.17% (1 in 600). Prevalence among adolescents is as much as 7–16%.

DSPD was first formally described in 1981 by Elliot D. Weitzman and others at Montefiore Medical Center.^[9] It is responsible for 7–13% of patient complaints of chronic insomnia. However, since many doctors are unfamiliar with the condition, it often goes untreated or is treated inappropriately; DSPD is often misdiagnosed as primary insomnia or as a psychiatric condition. DSPD can be treated or helped in some cases by careful daily sleep practices, morning light therapy, evening dark therapy, earlier exercise and meal times, and medications such as aripiprazole, melatonin, and modafinil; melatonin is a natural neurohormone partly responsible for the human body clock. At its most severe and inflexible, DSPD is a disability. A chief difficulty of treating DSPD is in maintaining an earlier schedule after it has been established, as the patient's body has a strong tendency to reset the sleeping schedule to its intrinsic late times. People with DSPD may improve their quality of life by choosing careers that allow late sleeping times, rather than forcing themselves to follow a conventional 9-to-5 work schedule.

Presentation

Comorbidity

Depression

In the DSPD cases reported in the literature, about half of the patients have suffered from clinical depression or other psychological problems, about the same proportion as among patients with chronic insomnia. According to the ICSD:

Although some degree of psychopathology is present in about half of adult patients with DSPD, there appears to be no particular psychiatric diagnostic category into which these patients fall. Psychopathology is not particularly more common in DSPD patients compared to patients with other forms of "insomnia." ... Whether DSPD results directly in clinical depression, or vice versa, is unknown, but many patients express considerable despair and hopelessness over sleeping normally again.

A direct neurochemical relationship between sleep mechanisms and depression is another possibility.

It is conceivable that DSPD has a role in causing depression because it can be such a stressful and misunderstood disorder. A 2008 study from the University of California, San Diego found no association of bipolar disorder (history of mania) with DSPD, and it states that

there may be behaviorally-mediated mechanisms for comorbidity between DSPD and depression. For example, the lateness of DSPD cases and their unusual hours may lead to social opprobrium and rejection, which might be depressing.

The fact that half of DSPD patients are not depressed indicates that DSPD is not merely a symptom of depression. Sleep researcher Michael Terman has suggested that those who follow their internal circadian clocks may be less likely to suffer from depression than those trying to live on a different schedule.

DSPD patients who also suffer from depression may be best served by seeking treatment for both problems. There is some evidence that effectively treating DSPD can improve the patient's mood and make antidepressants more effective.

Vitamin D deficiency has been linked to depression. As it is a condition which comes from lack of exposure to sunlight, anyone who does not get enough sunlight exposure during daylight hours (about 20 to 30 minutes three times a week, depending on skin tone, latitude, and the time of year) could be at risk, without adequate dietary sources or supplements.

Attention deficit hyperactivity disorder

DSPD is genetically linked to attention deficit hyperactivity disorder by findings of polymorphism in genes in common between those apparently involved in ADHD and those involved in the circadian rhythm and a high proportion of DSPD among those with ADHD.

Overweight

A 2019 study from Boston showed a relationship of evening chronotypes and greater social jet lag with greater body weight / adiposity in adolescent girls, but not boys, independent of sleep duration.

Obsessive–compulsive disorder

Persons with obsessive–compulsive disorder are also diagnosed with DSPD at a much higher rate than the general public.

Mechanism

Main article: Circadian rhythm sleep disorder

DSPD is a disorder of the body's timing system—the biological clock. Individuals with DSPD might have an unusually long circadian cycle, might have a reduced response to the resetting effect of daylight on the body clock, and/or may respond overly to the delaying effects of evening light and too little to the advancing effect of light earlier in the day. In support of the increased sensitivity to evening light hypothesis, "the percentage of melatonin suppression by a bright light stimulus of 1,000 lux administered 2 hours prior to the melatonin peak has been reported to be greater in 15 DSPD patients than in 15 controls."

The altered phase relationship between the timing of sleep and the circadian rhythm of body core temperature has been reported previously in DSPD patients studied in entrained conditions. That such an alteration has also been observed in temporal isolation (free-running clock) supports the notion that the etiology of DSPD goes beyond simply a reduced capacity to achieve and maintain the appropriate phase relationship between sleep timing and the 24-hour day. Rather, the disorder may also reflect a fundamental inability of the endogenous circadian timing system to maintain normal internal phase relationships among physiological systems, and to properly adjust those internal relationships within the confines of the 24-hour day. In normal subjects, the phase relationship between sleep and temperature changes in temporal isolation relative to that observed under entrained conditions: in isolation, tmin tends to occur toward the beginning of sleep, whereas under entrained conditions, tmin occurs toward the end of the sleep period—a change in phase angle of several hours; DSPD patients may have a reduced capacity to achieve such a change in phase angle in response to entrainment.

Possibly as a consequence of these altered internal phase relationships, that the quality of sleep in DSPD may be substantially poorer than that of normal subjects, even when bedtimes and wake times are self-selected. A DSPD subject exhibited an average sleep onset latency twice that of the 3 control subjects and almost twice the amount of wakefulness after sleep onset (WASO) as control subjects, resulting in significantly poorer sleep efficiency. Also, the temporal distribution of slow wave sleep was significantly altered in the DSPD subject. This finding may suggest that, in addition to abnormal circadian clock function, DSPD may be characterized by alteration(s) in the homeostatic regulation of sleep, as well. Specifically, the rate with which Process S is depleted during sleep may be slowed. This could, conceivably, contribute to the excessive sleep inertia upon awakening that is often reported by DSPD sufferers. It has also been hypothesized that, due to the altered phase angle between sleep and temperature observed in DSPD, and the tendency for longer sleep periods, these individuals may simply sleep through the phase-advance portion of the light PRC. Though quite limited in terms of the total number of DSPD patients studied, such data seem to contradict the notion that DSPD is merely a disorder of sleep timing, rather than a disorder of the sleep system itself.

People with normal circadian systems can generally fall asleep quickly at night if they slept too little the night before. Falling asleep earlier will in turn automatically help to advance their circadian clocks due to decreased light exposure in the evening. In contrast, people with DSPD have difficulty falling asleep before their usual sleep time, even if they are sleep-deprived. Sleep deprivation does not reset the circadian clock of DSPD patients, as it does with normal people.

People with the disorder who try to live on a normal schedule cannot fall asleep at a "reasonable" hour and have extreme difficulty waking because their biological clocks are not in phase with that schedule. Non-DSPD people who do not adjust well to working a night shift have similar symptoms (diagnosed as shift-work sleep disorder).

In most cases, it is not known what causes the abnormality in the biological clocks of DSPD patients. DSPD tends to run in families, and a growing body of evidence suggests that the problem is associated with the hPer3 (human period 3) gene and CRY1 gene. There have been several documented cases of DSPD and non-24-hour sleep–wake disorder developing after traumatic head injury. There have been cases of DSPD developing into non-24-hour sleep–wake disorder, a severe and debilitating disorder in which the individual sleeps later each day.

Diagnosis

A sleep diary with nighttime at the top and the weekend in the middle, to better notice trends

DSPD is diagnosed by a clinical interview, actigraphic monitoring, and/or a sleep diary kept by the patient for at least two weeks. When polysomnography is also used, it is primarily for the purpose of ruling out other disorders such as narcolepsy or sleep apnea.

DSPD is frequently misdiagnosed or dismissed. It has been named as one of the sleep disorders most commonly misdiagnosed as a primary psychiatric disorder. DSPD is often confused with: psychophysiological insomnia; depression; psychiatric disorders such as schizophrenia, ADHD or ADD; other sleep disorders; or school refusal. Practitioners of sleep medicine point out the dismally low rate of accurate diagnosis of the disorder, and have often asked for better physician education on sleep disorders.

Definition

According to the International Classification of Sleep Disorders, Revised (ICSD-R, 2001), the circadian rhythm sleep disorders share a common underlying chronophysiologic basis:

The major feature of these disorders is a misalignment between the patient's sleep-wake pattern and the pattern that is desired or regarded as the societal norm... In most circadian rhythm sleep disorders, the underlying problem is that the patient cannot sleep when sleep is desired, needed or expected.

Incorporating minor updates (ICSD-3, 2014), the diagnostic criteria for delayed sleep phase disorder are:

1. An intractable delay in the phase of the major sleep period occurs in relation to the desired clock time, as evidenced by a chronic or recurrent (for at least three months) complaint of inability to fall asleep at a desired conventional clock time together with the inability to awaken at a desired and socially acceptable time.
2. When not required to maintain a strict schedule, patients exhibit improved sleep quality and duration for their age and maintain a delayed phase of entrainment to local time.
3. Patients have little or no reported difficulty in maintaining sleep once sleep has begun.
4. Patients have a relatively severe to absolute inability to advance the sleep phase to earlier hours by enforcing conventional sleep and wake times.
5. Sleep–wake logs and/or actigraphy monitoring for at least two weeks document a consistent habitual pattern of sleep onsets, usually later than 2 am, and lengthy sleeps.
6. Occasional noncircadian days may occur (i.e., sleep is "skipped" for an entire day and night plus some portion of the following day), followed by a sleep period lasting 12 to 18 hours.
7. The symptoms do not meet the criteria for any other sleep disorder causing inability to initiate sleep or excessive sleepiness.
8. If one of the following laboratory methods is used, it must demonstrate a significant delay in the timing of the habitual sleep period: 1) 24-hour polysomnographic monitoring (or two consecutive nights of polysomnography and an intervening multiple sleep latency test), 2) Continuous temperature monitoring showing that the time of the absolute temperature nadir is delayed into the second half of the habitual (delayed) sleep episode.

Some people with the condition adapt their lives to the delayed sleep phase, avoiding morning business hours as much as possible. The ICSD's severity criteria are:

• Mild: Two-hour delay (relative to the desired sleep time) associated with little or mild impairment of social or occupational functioning.
• Moderate: Three-hour delay associated with moderate impairment.
• Severe: Four-hour delay associated with severe impairment.

Some features of DSPD which distinguish it from other sleep disorders are:

• People with DSPD have at least a normal—and often much greater than normal—ability to sleep during the morning, and sometimes in the afternoon as well. In contrast, those with chronic insomnia do not find it much easier to sleep during the morning than at night.
• People with DSPD fall asleep at more or less the same time every night, and sleep comes quite rapidly if the person goes to bed near the time they usually fall asleep. Young children with DSPD resist going to bed before they are sleepy, but the bedtime struggles disappear if they are allowed to stay up until the time they usually fall asleep.
• DSPD patients usually sleep well and regularly when they can follow their own sleep schedule, e.g., on weekends and during vacations.
• DSPD is a chronic condition. Symptoms must have been present for at least three months before a diagnosis of DSPD can be made.

Often people with DSPD manage only a few hours sleep per night during the working week, then compensate by sleeping until the afternoon on weekends. Sleeping late on weekends, and/or taking long naps during the day, may give people with DSPD relief from daytime sleepiness but may also perpetuate the late sleep phase.

People with DSPD can be called "night owls". They feel most alert and say they function best and are most creative in the evening and at night. People with DSPD cannot simply force themselves to sleep early. They may toss and turn for hours in bed, and sometimes not sleep at all, before reporting to work or school. Less-extreme and more-flexible night owls are within the normal chronotype spectrum.

By the time those who have DSPD seek medical help, they usually have tried many times to change their sleeping schedule. Failed tactics to sleep at earlier times may include maintaining proper sleep hygiene, relaxation techniques, early bedtimes, hypnosis, alcohol, sleeping pills, dull reading, and home remedies. DSPD patients who have tried using sedatives at night often report that the medication makes them feel tired or relaxed, but that it fails to induce sleep. They often have asked family members to help wake them in the morning, or they have used multiple alarm clocks. As the disorder occurs in childhood and is most common in adolescence, it is often the patient's parents who initiate seeking help, after great difficulty waking their child in time for school.

The current formal name established in the third edition of the International Classification of Sleep Disorders (ICSD-3) is delayed sleep-wake phase disorder. Earlier, and still common, names include delayed sleep phase disorder (DSPD), delayed sleep phase syndrome (DSPS), and circadian rhythm sleep disorder, delayed sleep phase type (DSPT).

Management

Treatment, a set of management techniques, is specific to DSPD. It is different from treatment of insomnia, and recognizes the patients' ability to sleep well on their own schedules, while addressing the timing problem. Success, if any, may be partial; for example, a patient who normally awakens at noon may only attain a wake time of 10 or 10:30 with treatment and follow-up. Being consistent with the treatment is paramount.

Before starting DSPD treatment, patients are often asked to spend at least a week sleeping regularly, without napping, at the times when the patient is most comfortable. It is important for patients to start treatment well-rested.

Non-pharmacological

One treatment strategy is light therapy (phototherapy), with either a bright white lamp providing 10,000 lux at a specified distance from the eyes or a wearable LED device providing 350–550 lux at a shorter distance. Sunlight can also be used. The light is typically timed for 30–90 minutes at the patient's usual time of spontaneous awakening, or shortly before (but not long before), which is in accordance with the phase response curve (PRC) for light. Only experimentation, preferably with specialist help, will show how great an advance is possible and comfortable. For maintenance, some patients must continue the treatment indefinitely; some may reduce the daily treatment to 15 minutes; others may use the lamp, for example, just a few days a week or just every third week. Whether the treatment is successful is highly individual. Light therapy generally requires adding some extra time to the patient's morning routine. Patients with a family history of macular degeneration are advised to consult with an eye doctor. The use of exogenous melatonin administration (see below) in conjunction with light therapy is common.

Light restriction in the evening, sometimes called darkness therapy or scototherapy, is another treatment strategy. Just as bright light upon awakening should advance one's sleep phase, bright light in the evening and night delays it (see the PRC). It is suspected that DSPD patients may be overly sensitive to evening light. The photopigment of the retinal photosensitive ganglion cells, melanopsin, is excited by light mainly in the blue portion of the visible spectrum (absorption peaks at ~480 nanometers).

A formerly popular treatment, phase delay chronotherapy, is intended to reset the circadian clock by manipulating bedtimes. It consists of going to bed two or more hours later each day for several days until the desired bedtime is reached, and it often must be repeated every few weeks or months to maintain results. Its safety is uncertain, notably because it has led to the development of non-24-hour sleep-wake rhythm disorder, a much more severe disorder.

A modified chronotherapy is called controlled sleep deprivation with phase advance, SDPA. One stays awake one whole night and day, then goes to bed 90 minutes earlier than usual and maintains the new bedtime for a week. This process is repeated weekly until the desired bedtime is reached.

Earlier exercise and meal times can also help promote earlier sleep times.

Pharmacological

Aripiprazole (brand name Abilify) is an atypical antipsychotic that has been shown to be effective in treating DSPD by advancing sleep onset, sleep midpoint, and sleep offset at relatively low doses.

Phase response curves for light and for melatonin administration

Melatonin taken an hour or so before the usual bedtime may induce sleepiness. Taken this late, it does not, of itself, affect circadian rhythms, but a decrease in exposure to light in the evening is helpful in establishing an earlier pattern. In accordance with its phase response curve (PRC), a very small dose of melatonin can also, or instead, be taken some hours earlier as an aid to resetting the body clock; it must then be small enough not to induce excessive sleepiness.

Side effects of melatonin may include sleep disturbance, nightmares, daytime sleepiness, and depression, though the current tendency to use lower doses has decreased such complaints. Large doses of melatonin can even be counterproductive: Lewy et al. provide support to "the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." The long-term effects of melatonin administration have not been examined. In some countries, the hormone is available only by prescription or not at all. In the United States and Canada, melatonin is on the shelf of most pharmacies and herbal stores. The prescription drug Rozerem (ramelteon) is a melatonin analogue that selectively binds to the melatonin MT₁ and MT₂ receptors and, hence, has the possibility of being effective in the treatment of DSPD.

A review by the US Department of Health and Human Services found little difference between melatonin and placebo for most primary and secondary sleep disorders. The one exception, where melatonin is effective, is the "circadian abnormality" DSPD. Another systematic review found inconsistent evidence for the efficacy of melatonin in treating DSPD in adults, and noted that it was difficult to draw conclusions about its efficacy because many recent studies on the subject were uncontrolled.

Modafinil (brand name Provigil) is a stimulant approved in the US for treatment of shift-work sleep disorder, which shares some characteristics with DSPD. A number of clinicians prescribe it for DSPD patients, as it may improve a sleep-deprived patient's ability to function adequately during socially desirable hours. It is generally not recommended to take modafinil after noon; modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day can make it harder to fall asleep at bedtime.

Vitamin B₁₂ was, in the 1990s, suggested as a remedy for DSPD, and is still recommended by some sources. Several case reports were published. However, a review for the American Academy of Sleep Medicine in 2007 concluded that no benefit was seen from this treatment.

Prognosis

Risk of relapse

A strict schedule and good sleep hygiene are essential in maintaining any good effects of treatment. With treatment, some people with mild DSPD may sleep and function well with an earlier sleep schedule. Caffeine and other stimulant drugs to keep a person awake during the day may not be necessary and should be avoided in the afternoon and evening, in accordance with good sleep hygiene. A chief difficulty of treating DSPD is in maintaining an earlier schedule after it has been established. Inevitable events of normal life, such as staying up late for a celebration or deadline, or having to stay in bed with an illness, tend to reset the sleeping schedule to its intrinsic late times.

Long-term success rates of treatment have seldom been evaluated. However, experienced clinicians acknowledge that DSPD is extremely difficult to treat. One study of 61 DSPD patients, with average sleep onset at about 3:00 am and average waking time of about 11:30 am, was followed with questionnaires to the subjects after a year. Good effect was seen during the six-week treatment with a large daily dose of melatonin. After ceasing melatonin use over 90% had relapsed to pre-treatment sleeping patterns within the year, 29% reporting that the relapse occurred within one week. The mild cases retained changes significantly longer than the severe cases.

Adaptation to late sleeping times

Working the evening or night shift, or working at home, makes DSPD less of an obstacle for some. Many of these people do not describe their pattern as a "disorder". Some DSPD individuals nap, even taking 4–5 hours of sleep in the morning and 4–5 in the evening. DSPD-friendly careers can include security work, the entertainment industry, hospitality work in restaurants, theaters, hotels or bars, call center work, manufacturing, healthcare or emergency medicine, commercial cleaning, taxi or truck driving, the media, and freelance writing, translation, IT work, or medical transcription. Some other careers that have an emphasis on early morning work hours, such as bakers, coffee baristas, pilots and flight crews, teachers, mail carriers, waste collection, and farming, can be particularly difficult for people who naturally sleep later than is typical. Some careers, such as over-the-road truck drivers, firefighters, law enforcement, nursing, can be suitable for both people with delayed sleep phase syndrome and people with the opposite condition, advanced sleep phase disorder, as these workers are needed both very early in the morning and also late at night.

Some people with the disorder are unable to adapt to earlier sleeping times, even after many years of treatment. Sleep researchers Dagan and Abadi have proposed that the existence of untreatable cases of DSPD be formally recognized as a "sleep-wake schedule disorder (SWSD) disability", an invisible disability.

Rehabilitation for DSPD patients includes acceptance of the condition and choosing a career that allows late sleeping times or running a home business with flexible hours. In a few schools and universities, students with DSPD have been able to arrange to take exams at times of day when their concentration levels may be good.

Patients suffering from SWSD disability should be encouraged to accept the fact that they suffer from a permanent disability, and that their quality of life can only be improved if they are willing to undergo rehabilitation. It is imperative that physicians recognize the medical condition of SWSD disability in their patients and bring it to the notice of the public institutions responsible for vocational and social rehabilitation.

In the United States, the Americans with Disabilities Act requires that employers make reasonable accommodations for employees with sleeping disorders. In the case of DSPD, this may require that the employer accommodate later working hours for jobs normally performed on a "9 to 5" work schedule. The statute defines "disability" as a "physical or mental impairment that substantially limits one or more major life activities", and Section 12102(2)(a) itemizes sleeping as a "major life activity".

Impact on patients

Lack of public awareness of the disorder contributes to the difficulties experienced by people with DSPD, who are commonly stereotyped as undisciplined or lazy. Parents may be chastised for not giving their children acceptable sleep patterns, and schools and workplaces rarely tolerate chronically late, absent, or sleepy students and workers, failing to see them as having a chronic illness.

By the time DSPD sufferers receive an accurate diagnosis, they often have been misdiagnosed or labelled as lazy and incompetent workers or students for years. Misdiagnosis of circadian rhythm sleep disorders as psychiatric conditions causes considerable distress to patients and their families, and leads to some patients being inappropriately prescribed psychoactive drugs. For many patients, diagnosis of DSPD is itself a life-changing breakthrough.

As DSPD is so little-known and so misunderstood, peer support may be important for information, self-acceptance, and future research studies.

People with DSPD who force themselves to follow a normal 9–5 workday "are not often successful and may develop physical and psychological complaints during waking hours, e.g., sleepiness, fatigue, headache, decreased appetite, or depressed mood. Patients with circadian rhythm sleep disorders often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."

Epidemiology

There have been several studies that have attempted to estimate the prevalence of DSPD. Results vary due to differences in methods of data collection and diagnostic criteria. A particular issue is where to draw the line between extreme evening chronotypes and clinical DSPD. Using the ICSD-1 diagnostic criteria (current edition ICSD-3) a study by telephone questionnaire in 1993 of 7,700 randomly selected adults (aged 18–67) in Norway estimated the prevalence of DSPD at 0.17%. A similar study in 1999 of 1,525 adults (aged 15–59) in Japan estimated its prevalence at 0.13%. A somewhat higher prevalence of 0.7% was found in a 1995 San Diego study. A 2014 study of 9100 New Zealand adults (age 20–59) using a modified version of the Munich Chronotype Questionnaire found a DSPD prevalence of 1.5% to 8.9% depending on the strictness of the definition used. A 2002 study of older adults (age 40–65) in San Diego found 3.1% had complaints of difficulty falling asleep at night and waking in the morning, but did not apply formal diagnostic criteria. Actimetry readings showed only a small proportion of this sample had delays of sleep timing.

A marked delay of sleep patterns is a normal feature of the development of adolescent humans. According to Mary Carskadon, both circadian phase and homeostasis (the accumulation of sleep pressure during the wake period) contribute to a DSPD-like condition in post-pubertal as compared to pre-pubertal youngsters. Adolescent sleep phase delay "is present both across cultures and across mammalian species" and "it seems to be related to pubertal stage rather than age." As a result, diagnosable DSPD is much more prevalent among adolescents. with estimates ranging from 3.4% to 8.4% among high school students.

Phase response curve

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Phase_response_curve 

A phase response curve (PRC) illustrates the transient change (phase response) in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received. PRCs are used in various fields; examples of biological oscillations are the heartbeat, circadian rhythms, and the regular, repetitive firing observed in some neurons in the absence of noise.

In circadian rhythms

Phase response curves for light and for melatonin administration

In humans and animals, there is a regulatory system that governs the phase relationship of an organism's internal circadian clock to a regular periodicity in the external environment (usually governed by the solar day). In most organisms, a stable phase relationship is desired, though in some cases the desired phase will vary by season, especially among mammals with seasonal mating habits.

In circadian rhythm research, a PRC illustrates the relationship between a chronobiotic's time of administration (relative to the internal circadian clock) and the magnitude of the treatment's effect on circadian phase. Specifically, a PRC is a graph showing, by convention, time of the subject's endogenous day along the x-axis and the amount of the phase shift (in hours) along the y-axis. Each curve has one peak and one trough in each 24-hour cycle. Relative circadian time is plotted against phase-shift magnitude. The treatment is usually narrowly specified as a set intensity and colour and duration of light exposure to the retina and skin, or a set dose and formulation of melatonin.

These curves are often consulted in the therapeutic setting. Normally, the body's various physiological rhythms will be synchronized within an individual organism (human or animal), usually with respect to a master biological clock. Of particular importance is the sleep–wake cycle. Various sleep disorders and externals stresses (such as jet lag) can interfere with this. People with non-24-hour sleep–wake disorder often experience an inability to maintain a consistent internal clock. Extreme chronotypes usually maintain a consistent clock, but find that their natural clock does not align with the expectations of their social environment. PRC curves provide a starting point for therapeutic intervention. The two common treatments used to shift the timing of sleep are light therapy, directed at the eyes, and administration of the hormone melatonin, usually taken orally. Either or both can be used daily. The phase adjustment is generally cumulative with consecutive daily administrations, and — at least partially — additive with concurrent administrations of distinct treatments. If the underlying disturbance is stable in nature, ongoing daily intervention is usually required. For jet lag, the intervention serves mainly to accelerate natural alignment, and ceases once desired alignment is achieved.

Note that phase response curves from the experimental setting are usually aggregates of the test population, that there can be mild or significant variation within the test population, that individuals with sleep disorders often respond atypically, and that the formulation of the chronobiotic might be specific to the experimental setting and not generally available in clinical practice (e.g. for melatonin, one sustained-release formulation might differ in its release rate as compared to another); also, while the magnitude is dose-dependent, not all PRC graphs cover a range of doses. The discussions below are restricted to the PRCs for the light and melatonin in humans.

Light

The time shown on the x-axis is vague: dawn – mid-day – dusk – night – dawn. These times do not refer to actual sun-up etc. nor to specific clock times. Each individual has her/his own circadian "clock" and chronotype, and dawn in the illustration refers to a person's time of spontaneous awakening when well-rested and sleeping regularly. The PRC shows when a stimulus, in this case light to the eyes, will effect a change, an advance or a delay. The curve's highest point coincides with the subject's lowest body temperature.

Starting about two hours before an individual's regular bedtime, exposure of the eyes to light will delay the circadian phase, causing later wake-up time and later sleep onset. The delaying effect gets stronger as evening progresses; it is also dependent on the wavelength and illuminance ("brightness") of the light. The effect is small if indoor lighting is dim (< 3 Lux).

About five hours after usual bedtime, coinciding with the body temperature trough (the lowest point of the core body temperature during sleep) the PRC peaks and the effect changes abruptly from phase delay to phase advance. Immediately after this peak, light exposure has its greatest phase-advancing effect, causing earlier wake-up and sleep onset. Again, illuminance greatly affects results; indoor light may be less than 500 lux while light therapy uses up to 10,000 lux. The effect diminishes until about two hours after spontaneous wake-up time, when it reaches approximately zero.

During the period between two hours after usual wake-up time and two hours before usual bedtime, light exposure has little or no effect on circadian phase (slight effects generally cancelling each other out).

Another image of the PRC for light is here (Figure 1). Within that image, the explanatory text is

• Delay region: evening light shifts sleepiness later and
• Advance region: morning light shifts sleepiness earlier.

Light therapy, typically with a light box producing 10,000 lux at a prescribed distance, can be used in the evening to delay or in the morning to advance a person's sleep timing. Because losing sleep to obtain bright light exposure is considered undesirable by most people, and because it is very difficult to estimate exactly when the greatest effect (the PRC peak) will occur in an individual, the treatment is usually applied daily just prior to bedtime (to achieve phase delay), or just after spontaneous awakening (to achieve phase advance).

In addition to its use in the adjustment of circadian rhythms, light therapy is used as treatment for several affective disorders including seasonal affective disorder (SAD).

In 2002 Brown University researchers led by David Berson announced the discovery of special cells in the human eye, ipRGCs (intrinsically photosensitive retinal ganglion cells), which many researchers now believe control the light entrainment effect of the phase response curve. In the human eye, the ipRGCs have the greatest response to light in the 460–480 nm (blue) range. In one experiment, 400 lux of blue light produced the same effects as 10,000 lux of white light from a fluorescent source. A theory of spectral opponency, in which the addition of other spectral colors renders blue light less effective for circadian phototransduction, was supported by research reported in 2005.

Melatonin

The phase response curve for melatonin is roughly twelve hours out of phase with the phase response curve for light. At spontaneous wake-up time, exogenous (externally administered) melatonin has a slight phase-delaying effect. The amount of phase-delay increases until about eight hours after wake-up time, when the effect swings abruptly from strong phase delay to strong phase advance. The phase-advance effect diminishes as the day goes on until it reaches zero about bedtime. From usual bedtime until wake-up time, exogenous melatonin has no effect on circadian phase.

The human body produces its own (endogenous) melatonin starting about two hours before bedtime, provided the lighting is dim. This is known as dim-light melatonin onset, DLMO. This stimulates the phase-advance portion of the PRC and helps keep the body on a regular sleep-wake schedule. It also helps prepare the body for sleep.

Administration of melatonin at any time may have a mild hypnotic (sleep-inducing) effect. The expected effect on sleep phase timing, if any, is predicted by the PRC.

Additive effects

In a 2006 study Victoria L. Revell et al. showed that a combination of morning bright light and afternoon melatonin, both timed to phase advance according to the respective PRCs, produce a larger phase advance shift than bright light alone, for a total of up to 21⁄2 hours. All times are approximate and vary from one person to another. In particular, there is no convenient way to accurately determine the times of the peaks and zero-crossings of these curves in an individual. Administration of light or melatonin close to the time at which the effect is expected to change sense abruptly may, if the changeover time is not accurately known, produce an opposite effect to that desired.

Exercise

In a 2019 study Shawn D. Youngstedt et al., showed that in humans "Exercise elicits circadian phase‐shifting effects, but additional information is needed. [...] Significant phase–response curves were established for aMT6(melatonin derivative) onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm"

Origin

The first published usage of the term "phase response curve" was in 1960 by Patricia DeCoursey. The "daily" activity rhythms of her flying squirrels, kept in constant darkness, responded to pulses of light exposure. The response varied according to the time of day – that is, the animals' subjective "day" – when light was administered. When DeCoursey plotted all her data relating the quantity and direction (advance or delay) of phase-shift on a single curve, she created the PRC. It has since been a standard tool in the study of biological rhythms.

In neurons

Further information: Phase precession

Phase response curve analysis can be used to understand the intrinsic properties and oscillatory behavior of regular-spiking neurons. The neuronal PRCs can be classified as being purely positive (PRC type I) or as having negative parts (PRC type II). Importantly, the PRC type exhibited by a neuron is indicative of its input–output function (excitability) as well as synchronization behavior: networks of PRC type II neurons can synchronize their activity via mutual excitatory connections, but those of PRC type I can not.

Experimental estimation of PRC in living, regular-spiking neurons involves measuring the changes in inter-spike interval in response to a small perturbation, such as a transient pulse of current. Notably, the PRC of a neuron is not fixed but may change when firing frequency or neuromodulatory state of the neuron is changed.

Circadian rhythm sleep disorder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Circadian_rhythm_sleep_disorder 

Circadian rhythm sleep disorder
Other names	Circadian rhythm sleep-wake disorders
Specialty	Neurology, chronobiology

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.

Overview

Humans, like most living organisms, have various biological rhythms. These biological clocks control processes that fluctuate daily (e.g., body temperature, alertness, hormone secretion), generating circadian rhythms. Among these physiological characteristics, the sleep-wake propensity can also be considered one of the daily rhythms regulated by the biological clock system. Human's sleeping cycles are tightly regulated by a series of circadian processes working in tandem, allowing for the experience of moments of consolidated sleep during the night and a long wakeful moment during the day. Conversely, disruptions to these processes and the communication pathways between them can lead to problems in sleeping patterns, which are collectively referred to as circadian rhythm sleep disorders.

Normal rhythm

A circadian rhythm is an entrainable, endogenous, biological activity that has a period of roughly twenty-four hours. This internal time-keeping mechanism is centralized in the suprachiasmatic nucleus (SCN) of humans, and allows for the internal physiological mechanisms underlying sleep and alertness to become synchronized to external environmental cues, like the light-dark cycle. The SCN also sends signals to peripheral clocks in other organs, like the liver, to control processes such as glucose metabolism. Although these rhythms will persist in constant light or dark conditions, different Zeitgebers (time givers such as the light-dark cycle) give context to the clock and allow it to entrain and regulate expression of physiological processes to adjust to the changing environment. Genes that help control light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY. A full circadian cycle can be described as a twenty-four hour circadian day, where circadian time zero (CT 0) marks the beginning of a subjective day for an organism and CT 12 marks the start of subjective night.

Humans with regular circadian function have been shown to maintain regular sleep schedules, regulate daily rhythms in hormone secretion, and sustain oscillations in core body temperature. Even in the absence of Zeitgebers, humans will continue to maintain a roughly 24-hour rhythm in these biological activities. Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the day's activities, and rest at night.

Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway. Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals. Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance one's circadian cycle earlier in the day, leading to an earlier wake time.

Diagnosis

The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population suffers from a CRSD, many people are often misdiagnosed with insomnia instead of a CRSD. Of adults diagnosed with sleep disorders, an estimated 10% have a CRSD and of adolescents with sleep disorders, an estimated 16% may have a CRSD. Patients diagnosed with circadian rhythm sleep disorders typically express a pattern of disturbed sleep, whether that be excessive sleep that intrudes on working schedules and daily functions, or insomnia at desired times of sleep. Note that having a preference for extreme early or late wake times are not related to a circadian rhythm sleep disorder diagnosis. There must be distinct impairment of biological rhythms that affects the person's desired work and daily behavior. For a CRSD diagnosis, a sleep specialist gathers the history of a patient's sleep and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO). Gathering this data gives insight into the patient's current schedule, as well as the physiological phase markers of the patient's biological clock.

The start of the CRSD diagnostic process is a thorough sleep history assessment. A standard questionnaire is used to record the sleep habits of the patient, including typical bedtime, sleep duration, sleep latency, and instances of waking up. The professional will further inquire about other external factors that may impact sleep. Prescription drugs that treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants are associated with abnormal sleep behaviors. Other daily habits like work schedule and timing of exercise are also recorded—because they may impact an individual's sleep and wake patterns. To measure sleep variables candidly, patients wear actigraphy watches that record sleep onset, wake time, and many other physiological variables. Patients are similarly asked to self-report their sleep habits with a week-long sleep diary to document when they go to bed, when they wake up, etc. to supplement the actigraphy data. Collecting this data allows sleep professionals to carefully document and measure patient's sleep habits and confirm patterns described in their sleep history.

Other additional ways to classify the nature of a patient's sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep. Questionnaires like the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of sleep disruption. Specifically, these questionnaires can help the professional assess the patient's problems with sleep latency, undesired early-morning wakefulness, and problems with falling or staying asleep. Tayside children's sleep questionnaire is a ten-item questionnaire for sleep disorders in children aged between one and five years old.

Types

Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders.

CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs.

Intrinsic

• Delayed sleep phase disorder (DSPD): Individuals who have been diagnosed with delayed sleep phase disorder have sleep-wake times which are delayed when compared to normal functioning individuals. People with DSPD typically have very long periods of sleep latency when they attempt to go to sleep during conventional sleeping times. Similarly, they also have trouble waking up at conventional times.
• Advanced sleep phase disorder (ASPD): People with advanced sleep phase disorder exhibit characteristics opposite to those with delayed sleep phase disorder. These individuals have advanced sleep wake times, so they tend to go to bed and wake up much earlier as compared to normal individuals. ASPD is less common than DSPD, and is most prevalent within older populations.
  • Familial Advanced Sleep Phase Syndrome (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G). Families that have this mutation in PER2 experience extreme phase advances in sleep, waking up around 2 AM and going to bed around 7 PM.
• Irregular sleep–wake rhythm disorder (ISWRD) is characterized by a normal 24-hr sleeping period. However, individuals with this disorder experience fragmented and highly disorganized sleep that can manifest in the form of waking frequently during the night and taking naps during the day, yet still maintaining sufficient total time asleep. People with ISWRD often experience a range of symptoms from insomnia to excessive daytime sleepiness.
• Non-24-hour sleep–wake disorder (N24SWD): Most common in individuals that are blind and unable to detect light, is characterized by chronic patterns of sleep/wake cycles which are not entrained to the 24-hr light-dark environmental cycle. As a result of this, individuals with this disorder will usually experience a gradual yet predictable delay of sleep onset and waking times. Patients with DSPD may develop this disorder if their condition is untreated.

Extrinsic

• Shift work sleep disorder (SWSD): Approximately 9% of Americans who work night or irregular work shifts are believed to experience Shift work sleep disorder. Night shift work directly opposes the environmental cues that entrain our biological clock, so this disorder arises when an individual's clock is unable to adjust to the socially imposed work schedule. Shift work sleep disorder can lead to severe cases of insomnia as well as excessive daytime sleepiness.
• Jet lag: Jet lag is best characterized by difficulty falling asleep or staying asleep as a result of misalignment between one's internal circadian system and external, or environmental cues. It is typically associated with rapid travel across multiple time zones.

Alzheimer's disease

CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimer's disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments. On one hand, it has been stated that people with AD have melatonin alteration and high irregularity in their circadian rhythm that lead to a disrupted sleep-wake cycle, probably due to damage on hypothalamic SCN regions typically observed in AD. On the other hand, disturbed sleep and wakefulness states have been related to worsening of an AD patient's cognitive abilities, emotional state and quality of life. Moreover, the abnormal behavioural symptoms of the disease negatively contribute to overwhelming patient's relatives and caregivers as well.

However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood. Therefore, further studies exploring this field have been highly recommended, mainly considering the increasing life expectancy and significance of neurodegenerative diseases in clinical practices.

Treatment

Possible treatments for circadian rhythm sleep disorders include:

• Chronotherapy, best shown to effectively treat delayed sleep phase disorder, acts by systematically delaying an individual's bedtime until their sleep-wake times coincide with the conventional 24-hr day.
• Light therapy utilizes bright light exposure to induce phase advances and delays in sleep and wake times. This therapy requires 30–60 minutes of exposure to a bright (5,000–10,000 lux) white, blue, or natural light at a set time until the circadian clock is aligned with the desired schedule. Treatment is initially administered either upon awakening or before sleeping, and if successful may be continued indefinitely or performed less frequently. Though proven very effective in the treatment of individuals with DSPD and ASPD, the benefits of light therapy on N24SWD, shift work disorder, and jet lag have not been studied as extensively.
• Hypnotics have also been used clinically alongside bright light exposure therapy and pharmacotherapy for the treatment of CRSDs such as Advanced Sleep Phase Disorder. Additionally, in conjunction with cognitive behavioral therapy, short-acting hypnotics also present an avenue for treating co-morbid insomnia in patients suffering from circadian sleep disorders.
• Melatonin, a naturally occurring biological hormone with circadian rhythmicity, has been shown to promote sleep and entrainment to external cues when administered in drug form (0.5–5.0 mg). Melatonin administered in the evening causes phase advances in sleep-wake times while maintaining duration and quality of sleep. Similarly, when administered in the early morning, melatonin can cause phase delays. It has been shown most effective in cases of shift work sleep disorder and delayed phase sleep disorder, but has not been proven particularly useful in cases of jet lag.
• Dark therapy, for example, the use of blue-blocking goggles, is used to block blue and blue-green wavelength light from reaching the eye during evening hours so as not to hinder melatonin production.