Neotrophic Factors and BDNF

Brain-derived neurotrophic factor

From what I read in 101 Theory Drive, one promising area for potential new treatments of mental illlness may be that of the Neotrophic factors such as BDNF.


From yee Wiki: Brain-derived neurotrophic factor, also known as BDNF, is a secreted protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF. Neurotrophic factors are found in the brain and the periphery.

Function

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF itself is important for long-term memory. BDNF was the second neurotrophic factor to be characterized after nerve growth factor (NGF).

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.

Tissue distribution

Despite its name, BDNF is actually found in a range of tissue and cell types, not just in the brain. It is also expressed in the retina, the central nervous system, motor neurons, the kidneys, and the prostate. BDNF is present in high concentration in hippocampus and cerebral cortex. BDNF is also found in human saliva.

Mechanism of action

BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB (pronounced "Track B") and the LNGFR (for low-affinity nerve growth factor receptor, also known as p75). It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor.

TrkB is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkB is the primary receptor for BDNF and NT-4, TrkA is the receptor for NGF, and TrkC is the primary receptor for NT-3. NT-3 binds to TrkA and TrkB as well, but with less affinity (thus the caveat "primary receptor").

The other BDNF receptor, the p75, plays a somewhat less clear role. Some researchers have shown that the p75NTR binds and serves as a "sink" for neurotrophins. Cells that express both the p75NTR and the Trk receptors might, therefore, have a greater activity, since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that the p75NTR may signal a cell to die via apoptosis; so, therefore, cells expressing the p75NTR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.

Secretion

BDNF is made in the endoplasmic reticulum and secreted from dense-core vesicles. It binds carboxypeptidase E (CPE), and the disruption of this binding has been proposed to cause the loss of sorting of BDNF into dense-core vesicles. The phenotype for BDNF knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons.

Exercise has been shown to increase the secretion of BDNF at the mRNA and protein levels in the rodent hippocampus, suggesting the potential increase of this neurotrophin after exercise in humans.

Caffeine improves recognition memory, and this effect may be related to an increase of the BDNF and TrkB immunocontent in the hippocampus.

Genetics

The BDNF protein is coded by the gene that is also called BDNF. In humans this gene is located on chromosome 11. Val66Met (rs6265) is a single nucleotide polymorphism in the gene where adenine and guanine alleles vary, resulting in a variation between valine and methionine at codon 66.

As of 2008, Val66Met is probably the most investigated SNP of the BDNF gene, but, besides this variant, other SNPs in the gene are C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442.

The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome.

In 2009, variants close to the BDNF gene were found to be associated with obesity in two very large genome wide-association studies of body mass index (BMI).

Disease

Various studies have shown possible links between BDNF and conditions, such as depression, schizophrenia, obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease, Rett syndrome, and dementia, as well as anorexia nervosa, and bulimia nervosa.

Short bouts of exercise can produce an increase in serum BDNF which is hypothesized to be cancelled by exposure to air pollution.

Increased levels of BDNF can induce a change to an opiate-dependent-like reward state when expressed in the ventral tegmental area in rats.

Depression

Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and, if exposure is persistent, this leads to an eventual atrophy of the hippocampus. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from chronic depression. In addition, rats bred to be heterozygous for BDNF, therefore reducing its expression, have been observed to exhibit similar hippocampal atrophy. This suggests that an etiological link between the development of depression and BDNF exists. Supporting this, the excitatory neurotransmitter glutamate, voluntary exercise, caloric restriction, intellectual stimulation, curcumin, and various treatments for depression (such as antidepressants and electroconvulsive therapy and sleep deprivation increase expression of BDNF in the brain. In the case of some treatments such as drugs and electroconvulsive therapy this has been shown to protect or reverse this atrophy.

Decreased level of BDNF in the hypothalamus has been implicated in development of depression and hyperphagy that may lead to obesity.

Eczema

High levels of BDNF and Substance P have been found associated with increased itching in eczema.

Epilepsy

Epilepsy has also been linked with polymorphisms in BDNF. Given BDNF's vital role in the development of the landscape of the brain, there is quite a lot of room for influence on the development of neuropathologies from BDNF.

Levels of both BDNF mRNA and BDNF protein are known to be up-regulated in epilepsy. BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor-mediated post-synaptic currents. This provides a potential mechanism for the observed up-regulation.

Alzheimer's disease

Post mortem analysis has shown lowered levels of BDNF in the brain tissues of people with Alzheimer's disease, although the nature of the connection remains unclear. Studies suggest that neurotrophic factors have a protective role against amyloid beta toxicity. A connection, however has been seen in a link with depression and BDNF. Depression causes shrinkage of the hippocampus. When antidepressants are administered, the levels of BDNF are raised to protect and increase the volume of hippocampal and other cells. In Alzheimer's, the hippocampus is also damaged, lowering levels of the neurotrophic factor.

Drug Addiction

BDNF is a critical regulator of drug dependency. Animals chronically exposed to drugs of abuse show increased levels of BDNF in the ventral tegmental area (VTA) of the brain, and when BDNF is injected directly into the VTA of rats, the animals act as if they are dependent on opiates.

Interactions

Brain-derived neurotrophic factor has been shown to interact with TrkB. BDNF has also been shown to interact with the reelin signaling chain. The expression of reelin by Cajal-Retzius cells goes down during development under the influence of BDNF. The latter also decreases reelin expression in neuronal culture.

Tormenting Thoughts and Secret Rituals

Not my real cube, but not far from the truth.

This weekend I took some much needed time away from the funnybook cubical of power. Naturally since I don’t hunt or fish, I instead spent quite a few hours tracking down new treasures as a “book scout.” Among other titles, I picked up a new book on OCD, Tormenting Thoughts and Secret Rituals by Ian Osborn, M. D.

You might think as many books as I’ve already read on the subject, this was a bit redundant -- that I’d already “caught my limit.” Ah, but herein lies the beauty of the cheap book score. When I collected “how to” art books, I found that if I could garner even only one or two new approaches or techniques out of a book, it was a terrific way to build up my overall knowledge base. But, the books do have to be cheap -- or you might go broke.

Books, books, books!

Ian Osborn’s title is a first-rate book about OCD, and he suffers from the condition himself. I particularly applaud his lucid explanations of the biological basis of the illness and for me, the sometimes-nettlesome topic of medication. He challenges the complete, anti-drug stance of celebrated psychiatric critic Dr. Peter Breggin whose contrarian views often provoke uncertainty in me. I think it’s worth excerpting a few passages from Dr. Osborn’s book on the topic of OCD and medication.

“The medications that are most useful for OCD are the SSRIs. These drugs which had previously been known to have anti-depressant effects, have now been discovered to have distinct, specific anti-OCD effects as well. Over a hundred well-controlled research studies involving thousands of patients have now conclusively proven that SSRIs are both safe and effective in the treatment of OCD.

In the treatment of OCD the SSRIs have their major therapeutic activity in one small area of the brain. Brain-imaging techniques, able to show the brain at work, reveal that OCD is caused by a hyperactive circuit of nerve cells running from the basal ganglia to the orbital frontal area of the brain. SSRI medications decrease the firing of nerve impulses in this circuit.

Basal Ganglia -- lizard brain type stuff all squished into the center of the brain.

From a practical standpoint, what patients report is that the SSRIs allow them to let go of obsessions more easily and to resist the urge to do compulsions more readily. They are classified as anti-depressants because even before their anti-OCD effect was discovered, all had been show to reverse the severe states of depression characterized by loss of energy, interests, appetite, and sleep. The anti-depressant effect appears to be unrelated to the anti-OCD effect.

What is clear is that these medications help 60-70% of patients with OCD – a figure remarkably similar to the percentage helped by behavior therapy. They bring the symptoms under control, but do not eliminate the underlying disorder. Typically, what SSRIs do when they work is to free a person from being disabled by obsessions and compulsions, allowing a return to a relatively normal life. Although this is a great boon to the OCD sufferer, it is not a complete cure.

An important consideration in prescribing for OCD is whether a second, distinct psychiatric disorder is present along with OCD. If so, it is imperative that this second condition be treated as well. Severe depression, panic disorder, bipolar disorder, and tics all occur with an increased frequency among OCD sufferers. OCD often will not respond to treatment until after these accompanying disorders have been addressed.

Many people think that medications are a cop-out; that taking them is to shrink from a personal challenge that should be met. This view is even promoted by some psychiatrists, notably Peter Breggin, author of Talking Back to Prozac and Toxic Psychiatry. Dr. Breggin, who rails against the use of all psychiatric medicines, including those that are used to treat very serious disorders such as schizophrenia, views all drugs that affect the mind as escapes from feeling the suffering of intense feelings, suffering that should be dealt with as a means of personal growth. What people should do, Dr. Breggin says, is try to understand the roots of their problems, not escape them through drugs.

The error in this reasoning is the assumption that OCD has deep psychological “roots.” It is now widely believed that OCD has little or nothing to do with unconscious conflicts or hidden hang-ups. Research has now proven OCD is a discrete, partially genetic, brain disorder. OCD is often brought on by life stresses, and they should be addressed in therapy. But far from being an escape, medications are used to treat the direct physiologic cause of OCD so that those afflicted can get back on their feet and begin meeting life’s real challenges.

Antiobsessional medications take more than two months to reach their full effect, a delay that has puzzled researchers, since the direct action of these medications on serotonin at the nerve synapses takes place in hours. Researchers have long concluded that secondary changes in the brain are responsible for the SSRIs’ therapeutic effects. A similar delay in therapeutic action is observed with behavioral therapy.

Behavioral therapy and medication, when effective, produce identical changes in the brains of OCD patients: specifically, decreased activity in a small part of the brain known as the orbital frontal area. Each treatment shares some sort of a final, common biochemical pathway -- changes in the concentration of neurotransmitters at the brain cell junctures. All life events affect us by causing synaptic changes (Don’s note here: e.g. Hebbian learning, and the connectome).

It is hypothesized that “secondary messengers” may subsequently carry the chemical changes to the genes. It may be by altering the information transcribed from the genes that these two therapies are able to alter many different and far-reaching aspects of brain functioning, including those generally considered to be “psychological,” such as memories, attitudes, and motivation.”

Medications, especially the SSRIs, are an indispensable part of therapy for the majority of OCD sufferers. These medications, now conclusively proven to be a specific treatment for OCD, represent a truly remarkable advance in the treatment of brain disorders. Relatively free of side effects, easy to take, and apparently safe for long-term use, these drugs can offer dramatic relief from crippling suffering, OCD patients should not hesitate to make use of them, nor should they feel guilty when they do.”

Ian Osborn, M. D.

Tormenting Thoughts and Secret Rituals: The Hidden Epidemic of Obsessive-Compulsive Disorder by Ian Osborn, M. D.

As many as six million Americans may suffer from obsessive-compulsive disorder (OCD), making it one of the most common mental diseases. Osborn had a bout with it while in medical training, and he narrates the unfolding understanding of the disease and its treatment informatively and readably. In medieval times, many felt that the disorder had a religious basis. Later, puritanism imputed it to sinning, and psychoanalysis "proved" that it had deep psychological roots. Osborn shows that OCD is caused by a chemical imbalance in the brain and that behavior therapy and drugs, preferably together, can take care of it for most patients; Osborn personalizes this part of the discussion with case histories of individuals rather than stick-figure textbook abstractions. He also mentions new research, such as that which finds a possible link between OCD and childhood streptococcal infections; brain injury and stress may also play causative roles. He concludes with a long list of OCD support groups and other helpful information.

"A truly wonderful, compassionate book."

--James W. Broatch, executive director, Obsessive-Compulsive Foundation

"A splendid book on OCD--lively, lucid, informative, and scholarly."

--Ronald Pies, M.D., clinical professor of psychiatry, Tufts University School of Medicine

"A marvelous achievement--an excellent and very practical overview of OCD and its treatment."

--Jeffrey Schwartz, M.D., associate professor, UCLA School of Medicine

Death by Desperation

I think I mentioned how roughed-up I got by my untreated chronic insomnia in 2010. Ugh! During my relentless internet research (not always a good idea for someone with OCD tendencies, but whaddya gonna do to find relief, otherwise?) I would often come across the medical meme, "except for extremely rare cases of fatal familia insomnia, chronic insomnia is not life-threatening." Right, if you can stand it. Some people can, they manage to keep working and living, despite their lousy sleep. How they do this is beyond me.

Two infamous celebrity deaths have showcased how desperate the sleep-deprived can become. Take the tragic cases of actor Heath Ledger and pop star Michael Jackson.




Heath Ledger.


According to Wikipedia, "Heath Andrew Ledger (1979-2008) was an Australian television and film actor. After performing roles in Australian television and film during the 1990s, Ledger left his homeland for the United States in 1998 to develop his film career. His work comprised nineteen films, including 10 Things I Hate About You (1999), The Patriot (2000), A Knight's Tale (2001), Brokeback Mountain (2005), and The Dark Knight (2008). In addition to acting, he produced and directed music videos and aspired to be a film director.
In a New York Times interview, published on 4 November 2007, Ledger told reporter Sarah Lyall that his recently completed roles in I'm Not There (2007) and The Dark Knight (2008) had taken a toll on his ability to sleep: "Last week I probably slept an average of two hours a night. ... I couldn't stop thinking. My body was exhausted, and my mind was still going." At that time, he told Lyall that he had taken two Ambien pills, after taking just one had not sufficed, and those left him in "a stupor, only to wake up an hour later, his mind still racing."

Prior to his return to New York from his last film assignment, in London, in January 2008, while he was apparently suffering from some kind of respiratory illness, he reportedly complained to his co-star Christopher Plummer that he was continuing to have difficulty sleeping and taking pills to help with that problem: "Confirming earlier reports that Ledger hadn't been feeling well on set, Plummer says, 'we all caught colds because we were shooting outside on horrible, damp nights. But Heath's went on and I don't think he dealt with it immediately with the antibiotics.... I think what he did have was the walking pneumonia.' [...] On top of that, 'He was saying all the time, 'dammit, I can't sleep'... and he was taking all these pills to help him.' "

In talking with Interview magazine after his death Ledger's former fiancée Michelle Williams also confirmed reports the actor had experienced trouble sleeping. "For as long as I'd known him, he had bouts with insomnia. He had too much energy. His mind was turning, turning turning -- always turning."

At about 2:45 p.m., on 22 January 2008, Ledger was found unconscious in his bed by his housekeeper, Teresa Solomon, and his masseuse, Diana Wolozin, in his fourth-floor loft apartment at 421 Broome Street in the SoHo neighborhood of Manhattan.

After two weeks of intense media speculation about possible causes of Ledger's death, on 6 February 2008, the Office of the Chief Medical Examiner of New York released its conclusions, based on an initial autopsy of 23 January 2008, and a subsequent complete toxicological analysis. The report concludes, in part, "Mr. Heath Ledger died as the result of acute intoxication by the combined effects of oxycodone, hydrocodone, diazepam, temazepam, alprazolam and doxylamine." It states definitively: "We have concluded that the manner of death is accident, resulting from the abuse of prescription medications." The medications found in the toxicological analysis are commonly prescribed in the United States for insomnia, anxiety, depression, pain, or common cold symptoms, or any combination thereof.

Yow! It sounds as though Mr. Ledger had prescriptions for the antihistamine and benzodiazopine "sleep aids" of vallium, restoril, xanax, and unisom, as well as the infamous "controlled" pain medications, oxycodone and hydrocodone.

It seems plausible from these accounts that Mr. Ledger was so desperate for sleep, he chowed down one or more of everything he had previously tried, resulting in a fatal "drug cocktail."

The later photos of Michael Jackson are so disturbing, I decided to use this portrait for my post.

Even more notorious was the death of Michael Jackson (1958-2009). Linda Deutsch reported in her Associated Press article:

"Los Angeles -- Michael Jackson was physically exhausted from a day of grueling rehearsals for his marathon 50-night comeback tour. But his nightly battle with insomnia had just begun. After showering and getting into bed, he called for his "milk," a powerful drug he had been using to escape into unconsciousness.

Jackson saw the anesthetic known as propofol as his salvation. On June 25, 2009, it became the King of Pop's death potion.

How he overdosed in his mansion on a drug intended for hospital use is at the center of the manslaughter trial this week of the doctor he hired to be his highly paid personal physician for the "This is It" tour.

Testimony about the drug is expected to dominate the trial of Dr. Conrad Murray, a Houston cardiologist who has pleaded not guilty to a charge of involuntary manslaughter in Los Angeles Superior Court.

The prosecution claims Murray was grossly negligent in giving Jackson propofol at home without proper lifesaving equipment available and then left the room long enough to find his patient not breathing when he returned.

His defense team claims the singer, desperate for sleep, swallowed an additional dose of the drug when his doctor was out of the room.
Getting to the truth of it will come down to sometimes technical testimony from an array of medical experts, pathologists and even the police officers and paramedics who inspected Murray's equipment in the bedroom where Jackson went into cardiac arrest.

The defense theory, based on evidence that a trace amount of propofol -- .13 milligrams -- was found in Jackson's stomach, may be a hard sell.

The drug is administered intravenously, usually during surgery. Scientific witnesses may be asked to explain how it could have gotten into his stomach. Some doctors say ingesting it orally is almost unheard of.

"It's an odd, on-the-edge defense theory," said Dr. Gil Tepper, chief of staff at Miracle Mile Medical Center in Los Angeles. "It would not put you to sleep and it would move through the system very rapidly, causing awful diarrhea."

There are few authoritative studies and few statistics on deaths caused by the drug. It remains uncertain if the judge will allow a Chilean doctor's study of students who voluntarily drank the drug or a study of pigs who received it rectally.

The prosecution has a key expert witness, as well as forensic experts from the Los Angeles County coroner's office who are considered at the top of the field.

The defense boasts an advantage in one of its lawyers, J. Michael Flanagan, who says he is the only California attorney ever to try a propofol death case.

Flanagan represented one of a pair of nurses charged with killing a cancer patient who died after propofol was allegedly given without proper authorization by an anesthesiologist. Flanagan's client was acquitted and the other nurse pleaded no contest to a lesser charge.

Abuse of the drug is said to occur among medical professionals but rarely among patients.
In anesthesia, propofol is known as something of a wonder drug. Tepper said it's ideal for short term procedures such as colonoscopies or cataract surgery. Patients report feeling energized when they come out of it and there is no grogginess.

"But it's absolutely not recommended as a sleep aid," said Tepper. "You would never reach restful sleep and you would have to have constant monitoring."

In a hospital setting, Tepper said the doctor would have heart and blood oxygenation monitors as well as surgical equipment to do intubation if the patient stops breathing. Witnesses have said no such equipment was in Jackson's bedroom.

"It's a very dangerous drug," said Dr. Mark Schlesinger, head of anesthesiology at Hackensack University Medical Hospital in New Jersey, who said he has administered it thousands of times in his 25-year career. "The difference between unconsciousness and no longer breathing is a very slim margin of safety."

In the hands of a trained anesthesiologist, he added: "It's a wonderful drug and a very safe drug. It's not the drug that kills somebody. It's the way it is used."

Murray was not the first doctor to give Jackson the drug as a sleep aid, although others have not been publicly named.

Jackson's reliance on propofol was first disclosed to The Associated Press days after Jackson's death. Cherilyn Lee, a nurse nutritionist who treated Jackson with vitamins, said he pleaded unsuccessfully with her to get the drug he knew as Diprivan. He said his doctor told him it was safe and he described falling asleep as soon as the drug dripped from an IV into his vein.
"I said, `Michael, the only problem with you taking this medication,' and I had a chill in my body and tears in my eyes ... , "`You're going to take it and you're not going to wake up.'"

Lee, who said she treated him from January to April 2009, is on the trial witness list. She said she never saw Jackson use other drugs.

"He wasn't looking to get high or feel good and sedated from drugs," she said. "This was a person who was not on drugs. This was a person who was seeking help, desperately, to get some sleep, to get some rest."

Murray, who had been consulted by Jackson in his Las Vegas office, was promised $150,000 a month when he signed on as Jackson's personal physician six weeks before he died. He closed the doors of his offices there and in Houston to devote himself to the singer.

An autopsy report showed that Jackson was generally healthy, indicating his key problem was insomnia. Murray has told police he administered other drugs known as benzodiazepines, which are also used as sleep aids. But when they did not work, Jackson demanded propofol.
Murray told police he was trying to wean him from the drug and gave him a minimal dosage, then left the room for five minutes to use the bathroom. However, cell phone records suggest he was making phone calls for a longer time. His actions after he found Jackson not breathing are also central to the case.

In the two years since Jackson died, doctors have been known to refer to propofol as "The Michael Jackson drug." Some fear a backlash for its use.

Dr. Lawrence Koblinksy, head of forensic science at John Jay College in New York, said the situation of a famous man demanding propofol is an anomaly and should not cast doubt on its effectiveness in hospitals.

"If you have a drug that is wonderful, just because a celebrity dies doesn't mean you take it off the market," he said."

So in conclusion to this nightmarish post, while the insomnia itself may not be life-threatening, the deadly combination of severe desperation and too much readily-available prescription medicine lying about can prove fatal over time. Even having your own in-house personal physicians to monitor your situation cannot guarentee safety from this doubly-dangerous risk. Before I suffered my own insomnia, I didn't fully appreciate how desperate the chronically sleep-deprived can become. Thankfully, my own treatment, while also desperate at first, has brough me some much-needed rest. I hope that the awareness and treatment of chronic insomnia will soon improve. As things stand now, it is sorely lacking.

Leave it to Underground Comix legend Robert Crumb to capture the appropiate mood.

Chronic Insomnia: A Primer

In the Fall of 2010, I began to suffer chronic insomnia. I had earlier in life suffered severe sleep problems due to obstructive sleep apnea, which since 2003 I have treated with a Continous Postitive Airway Pressure (CPAP) machine, but this bout of chronic insomnia proved to be something new, and might I add, horrible. 

Chronic insomnia lasts for longer than a month. It can be caused by another disorder, or it can be a primary disorder. People with high levels of stress hormones or shifts in the levels of cytokines are more likely to have chronic insomnia. Its effects can vary according to its causes. They might include muscular fatigue, hallucinations, and/or mental fatigue. Some people that live with this disorder see things as if they are happening in slow motion, wherein moving objects seem to blend together.

Symptoms of insomnia can be caused by or can be co-morbid with:

Use of psychoactive drugs (such as stimulants), including certain medications, herbs, caffeine, nicotine, cocaine, amphetamines, methylphenidate, aripiprazole, MDMA, modafinil, or excessive alcohol intake.

Withdrawal from depressant drugs such as opioids and benzodiazepines.Use of fluoroquinolone antibiotic drugs,

Restless Legs Syndrome, which can cause sleep onset insomnia due to the discomforting sensations felt and the need to move the legs or other body parts to relieve these sensations.

Periodic limb movement disorder (PLMD), which occurs during sleep and can cause arousals that the sleeper is unaware of.

Pain

An injury or condition that causes pain can preclude an individual from finding a comfortable position in which to fall asleep, and can in addition cause awakening.

Hormone shifts such as those that precede menstruation and those during menopause

Life events such as fear, stress, anxiety, emotional or mental tension, work problems, financial stress, birth of a child and bereavement.

Mental disorders such as bipolar disorder, clinical depression, generalized anxiety disorder, post traumatic stress disorder, schizophrenia, obsessive compulsive disorder, or dementia.

Disturbances of the circadian rhythm, such as shift work and jet lag, can cause an inability to sleep at some times of the day and excessive sleepiness at other times of the day. Chronic circadian rhythm disorders are characterized by similar symptoms.

Certain neurological disorders, brain lesions, or a history of traumatic brain injury

Medical conditions such as hyperthyroidism and rheumatoid arthritis

Abuse of over-the counter or prescription sleep aids (sedative or depressant drugs) can produce rebound insomnia

Poor sleep hygiene, e.g., noise

Parasomnias, which include such disruptive sleep events as nightmares, sleepwalking, night terrors, violent behavior while sleeping, and REM behavior disorder, in which the physical body moves in response to events within dreams

A rare genetic condition can cause a prion-based, permanent and eventually fatal form of insomnia called fatal familial insomnia.

Physical exercise. Exercise-induced insomnia is common in athletes, causing prolonged sleep onset latency.

Sleep studies using polysomnography have suggested that people who have sleep disruption have elevated nighttime levels of circulating cortisol and adrenocorticotropic hormone They also have an elevated metabolic rate, which does not occur in people who do not have insomnia but whose sleep is intentionally disrupted during a sleep study. Studies of brain metabolism using positron emission tomography (PET) scans indicate that people with insomnia have higher metabolic rates by night and by day. The question remains whether these changes are the causes or consequences of long-term insomnia.

A common misperception is that the amount of sleep required decreases as a person ages. The ability to sleep for long periods, rather than the need for sleep, appears to be lost as people get older. Some elderly insomniacs toss and turn in bed and occasionally fall off the bed at night, diminishing the amount of sleep they receive.

In many cases, insomnia is co-morbid with another disease, side-effects from medications, or a psychological problem. Approximately half of all diagnosed insomnia is related to psychiatric disorders. In depression in many cases "insomnia should be regarded as a co-morbid condition, rather than as a secondary one;" insomnia typically predates psychiatric symptoms."In fact, it is possible that insomnia represents a significant risk for the development of a subsequent psychiatric disorder."

Knowledge of causation is not necessary for a diagnosis, but it might be nice to know.