Dopamine Imbalances Cause Sleep Disorders In Animal Models Of Parkinson's Disease And Schizophrenia
13 Oct 2006

http://forums.braintalk2.org/newthre...newthread&f=34

Neuroscientists at Duke University Medical Center working with genetically engineered mice have found that the brain chemical dopamine plays a critical role in regulating sleep and brain activity associated with dreaming.

When dopamine levels were dramatically reduced, the mice could no longer sleep, the scientists said. When dopamine levels were increased, the mice exhibited brain activity associated with dreaming during wakefulness.

The same processes likely occur in humans, according to the researchers. They said the findings give insight into the sleep problems common among patients suffering from Parkinson's disease, a neurodegenerative disorder in which brain cells containing dopamine die or become impaired.

"Our study may lead to development of new diagnostic tools for the early detection of Parkinson's disease based on the sleep disturbances that are often associated with motor symptoms of the disease," said senior study investigator Miguel Nicolelis, M.D., Ph.D., Anne W. Deane professor of neuroscience.

The findings may also provide a mechanism to explain some of the symptoms, such as hallucinations, experienced by psychotic and schizophrenic patients, he said.

The researchers published their findings in the Oct. 11, 2006, issue of the Journal of Neuroscience. The work was supported by the National Institutes of Health, the Hereditary Disease Foundation and the Anne W. Deane professorship to Nicolelis.

Parkinson's disease occurs when the brain cells, or neurons, that normally produce dopamine die or become impaired. Once 60 percent to 70 percent of the neurons are knocked out of commission, the jerky movements and fixed facial expressions characteristic of Parkinson's appear.

The new study suggests that destruction of significantly fewer dopamine-producing cells could result in sleep problems long before the motor problems become apparent, the researchers said.

Dopamine is a "neurotransmitter" that carries signals from one neuron to another. It is known to control movement, balance, emotion and the sense of pleasure.

Normally, when a signal needs to travel through the brain, neurons release dopamine to transport the signal across the gap, or synapse, between neurons. A kind of protein pump, called a transporter, recycles dopamine back to the neurons to prepare for the next burst of signal.

In studies 10 years ago, Marc Caron, Ph.D., James B. Duke professor of cell biology and a co-investigator in the current study, used the techniques of genetic engineering to produce a strain of mice that lacked this protein transporter. In such transgenic mice, dopamine lingers outside brain cells, stimulating surrounding neurons hundreds of times longer than normal. Caron and colleagues found that when they placed the mice in an unfamiliar environment, such as a new cage, the animals groomed themselves excessively and ran around the cage, mirroring the bizarre behaviors experienced by people with schizophrenia.

The researchers used this same strain of transgenic mice in the current study. They reasoned that both schizophrenia and Parkinson's disease are characterized by imbalances of dopamine in the brain, and that patients with both diseases experience sleep disturbances. So the researchers sought to further manipulate the mice to study the role of dopamine in the sleep cycle.

First, the researchers treated the mice with a chemical that stops the production of dopamine entirely. In fairly short order, the mice had used up their initial supply of dopamine and were running on empty.

The mice became rigid, immobile, and unable to sleep or dream, displaying symptoms similar to those experienced by patients with Parkinson's disease, the researchers said.

The researchers then measured the electrical activity in each animal's hippocampus, the region of the brain known to be involved in emotion and memory, during three major brain states: wakefulness, quiet sleep and dreaming (also known as rapid eye movement sleep). Using electrodes finer than a human hair implanted into individual neurons, the researchers could monitor signals passed among hundreds of neurons in the treated mice. They found a lack of dopamine completely suppressed brain activity and behaviors associated with quiet sleep and dreaming.

To verify that the sleep disturbances were caused by a lack of dopamine, the researchers gave the mice L-dopa, a drug used to increase the levels of dopamine in Parkinson's disease patients. The treated animals regained the brain patterns and behaviors associated with sleep and dreaming, demonstrating the critical role dopamine plays in the sleep-wake cycle, according to the researchers. Further pharmacological testing revealed that L-dopa exerted its effects by docking at a specific site, called the D2 receptor, on the surface of the neurons.

"Sleep disorders may be the first sign of Parkinson's disease," said lead study investigator Kafui Dzirasa, an M.D.-Ph.D. student working in Nicolelis's laboratory.

"By further studying the sleep patterns in animal models of Parkinson's disease, we hope to come up with a sleep diagnosis test that could detect the early signs of the disease years before the major symptoms appear," he said.

The study also provided insights into the biology underlying schizophrenia, the researchers said. They found that the excess dopamine in the brains of the mice generated patterns of brain activity that made it look as though the animals were experiencing brain activity associated with dreaming when they were actually awake.

"One of the preeminent ideas of classical psychiatry is that people who had hallucinations, such as schizophrenics, were actually dreaming while they are awake," Nicolelis said. "Our results give some initial biological evidence for this theory."

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Other researchers who participated in the study were Sidarta Ribeiro, Rui Costa, Lucas Santos, Shih-Chieh Lin, Andres Grosmark, Tatyana Sotnikova and Raul Gainetdinov.

Contact: Marla Vacek Broadfoot
Duke University Medical Center

Sleep Disorder Channel
RBD and Parkinson's Disease
http://www.sleepdisorderchannel.com/...html#parkinson

There is some evidence to suggest that RBD precipitates Parkinson's disease. Parkinson's disease is caused by the continual death of dopamine-producing brain cells. Dopamine inhibits and regulates muscle control.

Parkinson's disease and RBD have been known to happen concurrently, but the relationship has not been proven. In one study, nearly 40% of men in their late 60s, who demonstrated RBD, later developed Parkinson's disease. Parkinson's disease affects as many women as it does men, but this isn't true of RBD.

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Sleep Disorder Channel
http://www.sleepdisorderchannel.com/rem/

Overview

Patients with rapid eye movement behavior disorder (RBD) act out dramatic and/or violent dreams during rapid eye movement (REM) stage sleep. Another feature of RBD is shouting and grunting. RBD seems similar to other sleep disorders that involve motor activity, like sleepwalking or periodic limb movement disorder. Unlike these conditions, RBD movements occur during REM sleep, which is usually characterized by a state of atonia, or sleep paralysis. Diagnosis and treatment involves polysomnography, drug therapy, and the exclusion of potentially serious neurological disorders.

RBD is usually seen in men 60 years old or older, but also occurs in younger people and in women. Incidents of REM behavior disorder are often described anecdotally to family members and not to physicians, so statistics of incidence are inexact.

Physiology and Causes

Rapid eye movement behavior disorder is an uncommon sleep disorder first described in 1986. There is no known cause for RBD. It is, however, known to occur during rapid eye movement sleep, which is characterized by brain activity patterns that resemble wakefulness and which has been documented with polysomnography and other sleep tests. Most dreaming occurs during REM sleep. Another characteristic of REM sleep is a general state of atonia, or muscle paralysis. So, while the brain is very active during REM sleep, the body is usually still.

Sleep Paralysis

The basic mechanism for REM sleep paralysis is found in the brainstem, the part of the brain that connects the spinal chord to the cerebral hemispheres and that consists of the pons, midbrain, and the medulla oblongata. Though physicians do not thoroughly understand the complex processes, it is known that the brainstem undergoes changes in REM sleep that result in paralysis of the body’s voluntary muscles. Certain neurotransmitters, like acetylcholine (Ach), become dormant and do not communicate motor activity. The absence of muscular contraction during REM can be seen with polysomnography. The electroencephalogram (EEG) shows elevated brain activity during REM.

Physicians and sleep technicians hypothesize that the brain naturally and purposely prevents motor activity during REM sleep to ensure restful, inactive sleep during the most electrically active stage of sleep. In this context, sleep paralysis describes a normal state of sleep, unlike sleep paralysis experienced in narcolepsy, which affects people while they are trying to stay awake.

Motor Activity and REM Sleep

In RBD, neurotransmitters are not blocked, and the voluntary muscles become tonic, or tensely contracted, allowing a sleeping person to move his or her muscles during REM. Rapid eye movement behavior disorder is characterized by significant submental (under the chin) and limb muscle tone. The combination of heightened cerebral activity and muscular tonicity results in physically acting out dreams that involve excited and sometimes violent movement.

The body can be rigid and extremely tense during episodes of RBD. For example, a person might straighten his or her leg, flexing it intensely for several seconds or a minute. Often, sleepers curl up slightly, while flexing their limbs and chin.

People with RBD typically remember little nothing of this activity, unless they fall out of bed, bump into the furniture, or injure themselves and wake up. But they can usually remember and tell the dreams they were having during an episode.

Dreams that involve physical or violent activity—such as fighting, dancing, running, chasing, attacking, being attacked, running from an assailant—are more likely to trigger RBD activity. Sleepers with RBD sometimes injure their bed partners. Some people have been known to leave the bed, run into a wall, run through a window, or run down the stairs. But RBD activity is usually confined to the bed and the surrounding area.

eMedicine from WebMD – 7/21/2005
http://www.emedicinehealth.com/rem_s...r/page6_em.htm

REM Sleep Behavior Disorder

Neurologic examination

The neurologic examination is often normal. However, symptoms and signs of Parkinson disease, such as hand tremor at rest, slowness in movement, and muscle stiffness (rigidity) that may suggest an underlying neurologic cause of REM sleep behavior disorder (RBD), should be considered.

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eMedicine from WebMD – 7/21/2005
http://www.emedicine.com/neuro/bynam...r-disorder.htm

Excerpt from REM Sleep Behavior Disorder

Synonyms, Key Words, and Related Terms: rapid eye movement sleep behavior disorder, REM parasomnias, REM sleep parasomnia, RBD, sleep disorder, REM sleep

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is a newly described disorder, recognized as a distinct clinical entity following a series of reports in 1986 of adults with RBD. RBD is the best studied REM sleep parasomnia. Clinically, RBD is characterized by loss of normal voluntary muscle atonia during REM sleep associated with complex behavior while dreaming. According to the International Classification of Sleep Disorders, the minimal diagnostic criteria include movements of the body or limbs associated with dreaming and at least one of the following criteria: potentially harmful sleep behavior, dreams that appear to be acted out, and sleep behavior that disrupts sleep continuity (American Sleep Disorders Association, 1997). In 1965, experimental models showed that cats with bilateral pontine lesions adjacent to the locus ceruleus act out their dreams.

Pathophysiology: Normally, generalized atonia of muscles occurs during REM sleep. This atonia results from active inhibition of motor activity by pontine centers (ie, perilocus ceruleus) that exert an excitatory influence on the medulla (ie, magnocellularis neurons) via the lateral tegmentoreticular tract. These neuronal groups, in turn, hyperpolarize the spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract. In RBD, the brainstem mechanisms generating the muscle atonia normally seen in REM sleep may be interfered with.

Studies by Eisensehr et al using iodine 123 (123I) immunoperoxidase technique (IPT) single photon-emission computed tomography (SPECT) demonstrated that striatal presynaptic dopamine transporters are reduced in idiopathic RBD. Recent studies by Fantini et al demonstrated impairment of cortical activity in idiopathic RBD, particularly in the occipital region during both wakefulness and REM sleep compared with controls. Results were similar to the functional studies such as perfusion and metabolic impairment pattern observed in diffuse Lewy body (DLB) disease and to some extent in Parkinson disease. Similar cortical activity in the frontal and temporal regions was impaired only during wakefulness. The subcortical structures involved in the pathophysiology of RBD provide dopaminergic (nigrostriatal neurons), noradrenergic (locus coeruleus), and cholinergic innervation (pedunculopontine tegmental nucleus) of the cerebral cortex and play a role in cortical activation during wakefulness and REM sleep.

In essence, RBD may be the prodrome of neurodegenerative disease, such as DLB or Parkinson disease. In experimental studies in cats, bilateral pontine lesions resulted in a persistent absence of REM atonia associated with prominent motor activity during REM sleep similar to that observed in RBD in humans.

SeniorJournal.com, 6/19/2006
http://www.seniorjournal.com/NEWS/Ag...9-REMSleep.htm

REM Sleep Behavior Disorder May Lead to Dementia, Parkinson's

Acting out vivid dreams may forewarn of more serious illness

June 19, 2006 –Mayo Clinic sleep medicine specialists have found that almost two-thirds of patients with REM sleep behavior disorder (RBD) develop degenerative brain diseases, like Parkinson's and dementia, by approximately 11 years after diagnosis of RBD. It is another disturbing finding for many seniors who are the most in fear of dementia and frequently worry about their sleep. (Senior citizens often complain of sleep problems and it has become associated with natural aging. Research , however, finds sleep problems grow with the accumulation of illnesses, not years. Read more about REM sleep and senior citizens below this news report.)

"This study found RBD most frequently led to neurodegenerative diseases called the synucleinopathies: Parkinson's disease or dementia with Lewy bodies," says Maja Tippmann-Peikert, M.D., Mayo Clinic sleep medicine specialist, neurologist and the study's lead researcher. "From our findings, I would consider those with RBD at increased risk for these diseases."

RBD is a sleep disorder in which patients act out their dreams, which are often unpleasant and violent, according to Dr. Tippmann-Peikert. This acting out results from a loss of normal muscle paralysis in REM (rapid eye movement) sleep, the dream stage, which ordinarily prevents enacting one's dreams.

"The danger with RBD is that patients can hurt themselves or their spouses during the acting out behaviors -- bruises, lacerations, bone fractures and even subdural hematomas (brain hemorrhages) have been reported," says Dr. Tippmann-Peikert.

In this study, the investigators mailed questionnaires to 39 patients diagnosed with RBD at the Mayo Clinic Sleep Disorders Center between 1988 and 1995. If a patient had died, the questionnaire was mailed to surviving relatives. Of the 23 patients who agreed to participate, five had developed dementia or Parkinson's disease, and 10 reported neurological symptoms highly suggestive of dementia or Parkinson's disease. The patients in this study were an average of 11.2 years beyond their diagnoses of RBD.

This study is the second long-term follow-up study following patients with idiopathic, or inexplicable, RBD, confirming previous findings by Carlos Schenck, M.D., and Mark Mahowald, M.D., of Minnesota Regional Sleep Disorders Center at Hennepin County Medical Center in Minneapolis.

Other studies are under way to determine whether RBD is a state of pre-Parkinson's, pre-dementia or pre-multiple system atrophy (another type of synucleinopathy), according to the Mayo Clinic researchers.

Researchers have reported that as the brain-degenerating disease progresses, RBD may decrease in frequency and intensity or resolve completely, says Dr. Tippmann-Peikert.

There is no intervention to prevent those with RBD from progressing to Parkinson's disease, dementia or multiple system atrophy, says Dr. Tippmann-Peikert, as the origin of RBD is not clear enough to develop an appropriate therapy. Even though no preventive treatment exists yet, she says RBD patients can:

Use safety precautions in their bedrooms to prevent injury (e.g., move nightstands away from the bed, use extra pillows or pillows on the floor next to the bed for extra padding, remove dangerous objects such as weapons from the bedroom, lock all windows and doors to walk-out decks)

See a sleep specialist and, if prescribed, take medications to suppress RBD symptoms
Become familiar with the signs and symptoms of Parkinson's disease, dementia or multiple system atrophy
Follow up regularly with a sleep specialist to monitor for signs of brain-degenerating illnesses, and consider a referral to a neurologist if any signs appear

Dr. Tippmann-Peikert also stresses the importance of diagnosing RBD as early as possible.

"Awareness of excessive nocturnal behaviors and dream enactment and bringing it to the attention of a physician could lead to an early diagnosis of Parkinson's disease, dementia or multiple system atrophy," she says. "Hopefully, early identification of patients with idiopathic RBD will lead to close monitoring and early treatment of any developing neurological disorders."

Editor's Note: Findings will be presented today at the Associated Professional Sleep Societies' SLEEP 2006 meeting in Salt Lake City. Other investigators involved in this study include: Eric Olson, M.D.; Bradley Boeve, M.D.; and Michael Silber, M.B.Ch.B.

SeniorJournal.com, 6/19/2006
http://www.seniorjournal.com/NEWS/Ag...9-REMSleep.htm

About REM

National Institute of Neurological Disorders and Stroke of National Institutes of Health

From "Understanding Sleep"

During sleep, we usually pass through five phases of sleep: stages 1, 2, 3, 4, and REM (rapid eye movement) sleep. These stages progress in a cycle from stage 1 to REM sleep, then the cycle starts over again with stage 1 (see figure 1). We spend almost 50 percent of our total sleep time in stage 2 sleep, about 20 percent in REM sleep, and the remaining 30 percent in the other stages. Infants, by contrast, spend about half of their sleep time in REM sleep.

When we switch into REM sleep, our breathing becomes more rapid, irregular, and shallow, our eyes jerk rapidly in various directions, and our limb muscles become temporarily paralyzed. Our heart rate increases, our blood pressure rises, and males develop penile erections. When people awaken during REM sleep, they often describe bizarre and illogical tales — dreams.

The first REM sleep period usually occurs about 70 to 90 minutes after we fall asleep. A complete sleep cycle takes 90 to 110 minutes on average. The first sleep cycles each night contain relatively short REM periods and long periods of deep sleep. As the night progresses, REM sleep periods increase in length while deep sleep decreases. By morning, people spend nearly all their sleep time in stages 1, 2, and REM.

People awakened after sleeping more than a few minutes are usually unable to recall the last few minutes before they fell asleep. This sleep-related form of amnesia is the reason people often forget telephone calls or conversations they’ve had in the middle of the night. It also explains why we often do not remember our alarms ringing in the morning if we go right back to sleep after turning them off.

Since sleep and wakefulness are influenced by different neurotransmitter signals in the brain, foods and medicines that change the balance of these signals affect whether we feel alert or drowsy and how well we sleep. Caffeinated drinks such as coffee and drugs such as diet pills and decongestants stimulate some parts of the brain and can cause insomnia, or an inability to sleep.

Many antidepressants suppress REM sleep. Heavy smokers often sleep very lightly and have reduced amounts of REM sleep. They also tend to wake up after 3 or 4 hours of sleep due to nicotine withdrawal.

Many people who suffer from insomnia try to solve the problem with alcohol — the so-called night cap. While alcohol does help people fall into light sleep, it also robs them of REM and the deeper, more restorative stages of sleep. Instead, it keeps them in the lighter stages of sleep, from which they can be awakened easily.

People lose some of the ability to regulate their body temperature during REM, so abnormally hot or cold temperatures in the environment can disrupt this stage of sleep. If our REM sleep is disrupted one night, our bodies don’t follow the normal sleep cycle progression the next time we doze off. Instead, we often slip directly into REM sleep and go through extended periods of REM until we "catch up" on this stage of sleep.

People who are under anesthesia or in a coma are often said to be asleep. However, people in these conditions cannot be awakened and do not produce the complex, active brain wave patterns seen in normal sleep. Instead, their brain waves are very slow and weak, sometimes all but undetectable.

Dreaming and REM Sleep (REM sleep behavior disorder – RBD)

We typically spend more than 2 hours each night dreaming. Scientists do not know much about how or why we dream. Sigmund Freud, who greatly influenced the field of psychology, believed dreaming was a "safety valve" for unconscious desires. Only after 1953, when researchers first described REM in sleeping infants, did scientists begin to carefully study sleep and dreaming.

They soon realized that the strange, illogical experiences we call dreams almost always occur during REM sleep. While most mammals and birds show signs of REM sleep, reptiles and other cold-blooded animals do not.

REM sleep begins with signals from an area at the base of the brain called the pons. These signals travel to a brain region called the thalamus, which relays them to the cerebral cortex — the outer layer of the brain that is responsible for learning, thinking, and organizing information.

The pons also sends signals that shut off neurons in the spinal cord, causing temporary paralysis of the limb muscles. If something interferes with this paralysis, people will begin to physically "act out" their dreams — a rare, dangerous problem called REM sleep behavior disorder. A person dreaming about a ball game, for example, may run headlong into furniture or blindly strike someone sleeping nearby while trying to catch a ball in the dream.

REM sleep stimulates the brain regions used in learning. This may be important for normal brain development during infancy, which would explain why infants spend much more time in REM sleep than adults (see Sleep: A Dynamic Activity). Like deep sleep, REM sleep is associated with increased production of proteins. One study found that REM sleep affects learning of certain mental skills. People taught a skill and then deprived of non-REM sleep could recall what they had learned after sleeping, while people deprived of REM sleep could not.

Some scientists believe dreams are the cortex’s attempt to find meaning in the random signals that it receives during REM sleep. The cortex is the part of the brain that interprets and organizes information from the environment during consciousness. It may be that, given random signals from the pons during REM sleep, the cortex tries to interpret these signals as well, creating a "story" out of fragmented brain activity.

Sleep Disorders

At least 40 million Americans each year suffer from chronic, long-term sleep disorders each year, and an additional 20 million experience occasional sleeping problems. These disorders and the resulting sleep deprivation interfere with work, driving, and social activities. They also account for an estimated $16 billion in medical costs each year, while the indirect costs due to lost productivity and other factors are probably much greater. Doctors have described more than 70 sleep disorders, most of which can be managed effectively once they are correctly diagnosed. The most common sleep disorders include insomnia, sleep apnea, restless legs syndrome, and narcolepsy.