Sleep disorders linked to faulty brain chemistry, study finds

First evidence of neurochemical basis for obstructive sleep apnea and REM behavior disorder found

The first tantalizing clues that chemical imbalances in the brain may be partly to blame for certain life-disrupting sleep disorders are being reported in two new studies by University of Michigan Health System researchers.

In two papers in the July 8 issue of the journal Neurology, the team reports apparent links between deficits in brain chemistry and obstructive sleep apnea (OSA) and REM sleep behavior disorder (RBD). Both are relatively common sleep problems that disturb the slumber — and daytime behavior — of millions of Americans.

The new findings were made using two types of neurochemical brain scans and detailed sleep studies in 13 patients with multiple system atrophy (MSA), a rare and fatal degenerative neurological disease almost always accompanied by severe sleep disorders. Their results from the MSA patients, who all had both sleep apnea and REM behavior disorder, were very different from those of 27 healthy control subjects.

Specifically, the researchers found that MSA patients had a far lower density of certain brain cells, or neurons, that produce the key chemicals dopamine and acetylcholine. The greater their lack, the worse their sleep problems were.

The patients with the fewest dopamine-producing neurons in the striatum of their brains had the worst RBD symptoms of thrashing, talking and violent flailing while they slept. And patients with the lowest levels of acetylcholine-producing neurons in the brainstem had the most interruptions in their breathing during sleep.

And while the researchers are careful to note that their findings to date can only show a correlation, not causation, between brain chemistry and sleep disorders, they plan further research to explore the relationship.

“It’s exciting to be able to show this major neurochemical deficit for the first time, and confirm what others have suspected,” says lead author Sid Gilman, M.D., F.R.C.P., the William J. Herdman Professor and chair of the Department of Neurology at the U-M Medical School. “We don’t yet know if we will find this same effect in patients with other neurological diseases or in people who are otherwise neurologically well, but these findings are already suggesting further research opportunities.”

For instance, the U-M team is recruiting patients with Parkinson’s disease for a similar study, to see if brain chemistry disruptions from their disorder may also be linked to sleep problems. Gilman says he and other specialists suspect that sleep disorders may be an early symptom in many cases of Parkinson’s disease.

Gilman and his colleagues chose MSA patients as their first subjects for studying sleep disorders and brain chemistry because of their extremely high incidence of OSA, RBD and other sleep problems; their disease’s tendency to cause degeneration of certain nerve cells in their brains and spinal cords; and clinical evidence that some of their sleep problems can be successfully treated with medications that replace lost dopamine.

MSA is a complex, debilitating and life-shortening disease that affects only about 75,000 people nationwide, though many others are thought to be misdiagnosed. Also known as Shy-Drager Syndrome, MSA usually strikes people in their 40s, 50s or 60s, and affects blood pressure, muscle tone and movement, balance, bladder control and sleep. Patients experience debilitating and rapidly progressing symptoms, usually dying within seven to 10 years of diagnosis.

In addition to plaguing MSA patients, sleep disorders are also a fact of life for millions of others.

Obstructive sleep apnea, in which breathing temporarily stops or diminishes dozens or even hundreds of times during a person’s sleep, may affect 3 percent of adults but goes undiagnosed in most of them. Its most notable symptoms are snoring and excessive daytime sleepiness, though it can also affect blood pressure, memory and even reaction time while driving.

REM sleep behavior disorder, meanwhile, occurs less often but is outwardly more dramatic. Patients literally act out their dreams during the rapid-eye movement, or REM, phase of sleep, moving their arms and legs, getting out of bed, talking and shouting, and even hitting or punching. RBD can endanger the sleeping person, or his or her bed partner,

“Usually, while we sleep, our brains keep our hearts and lungs going automatically — while disabling the muscles that might otherwise let us unconsciously act out our dreams,” Gilman explains. “But many people, including most MSA patients, have sleep disorders that close off their airway and interrupt their nighttime breathing, as in obstructive sleep apnea, or cause them to thrash, talk and walk about, as in REM sleep behavior disorder.”

The precise causes of these problems are unknown, although obesity is known to be involved in OSA. None of the participants in the newly published studies were obese, and the control subjects were matched with the MSA patients by age and gender.

UMHS researchers have been studying sleep disorders for years at the Michael S. Aldrich Sleep Disorders Laboratory. The newly published studies, funded by the National Institute of Neurological Diseases and Stroke, were possible because of the unique blend of clinical and research resources available at UMHS.

Gilman and his colleagues run one of the nation’s most comprehensive and busiest clinics for patients with MSA, receiving patients via referrals from physicians around the country. In 1998, Gilman chaired a national panel that established diagnostic criteria for MSA.

In addition to having a ready source of MSA patients willing to take part in research studies, UMHS has a dedicated facility and staff for inpatient sleep research in its General Clinical Research Center, and the expertise and facilities needed to study brain chemistry through the imaging techniques known as positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

The new studies used radioactive PET and SPECT tracers that attach specifically to proteins on cells that release dopamine and acetylcholine, thereby revealing the density of such cells in various brain areas. Gilman and his colleagues matched each MSA patient’s PET and SPECT results with his or her results from two successive nights of polysomnography, a detailed sleep study that records everything from brain activity and breathing to muscle movement and pulse.

In addition to correlating brain chemistry with the overall severity of sleep disorder symptoms, the new studies even give hints as to how the brain chemistry changes may affect the specific muscles involved in those symptoms.

For instance, the specific brainstem areas where the largest deficits in acetylcholine neurons were seen — know as the PPT/LDT nuclei — are connected to the part of the brain that controls the muscles of the upper airway and tongue. Those muscles are crucial to maintaining uninterrupted breathing during sleep.

Gilman notes that the correlation between brain chemistry and sleep symptom severity suggested by the new results is bolstered by recent evidence showing the MSA patients experience nerve loss in some of the same specific brain areas pinpointed in the current study.

In addition to Gilman, the research team included Robert Koeppe, Ph.D., who directs the PET Physics program in the Division of Nuclear Medicine of the U-M Department of Radiology; Ronald Chervin, M.D., an associate professor of neurology who directs the U-M’s Michael S. Aldrich Sleep Disorders Laboratory; Flavia Consens, M.D., a clinical assistant professor of neurology and sleep disorder specialist; Roderick Little, Ph.D., a professor in the Department of Biostatistics at the U-M School of Public Health; Hyonggin An, M.S., a graduate student in biostatistics; Larry Junck, M.D., a professor of neurology; and Mary Heumann, a research associate in the Department of Neurology.

For information on MSA, Parkinson’s disease and sleep disorder treatment and research at the University of Michigan Health System, call 734-936-9020.

Reference: Neurology 61, July 2003, pp. 29 – 34 (RBD) and 35-39 (OSA)