Electrocardiogram-Based Sleep Spectrogram
—using sleep as a window into fibromyalgia
Principal Investigator: Robert J. Thomas, M.D.
Harvard & Beth Israel Deaconess Medical Center
Award: $60,000 (September 2009)
Impaired quality of sleep is a dominant clinical feature of fibromyalgia syndrome (FMS) that is not well understood. The standard approach to measure sleep uses the electroencephalogram (EEG) to depict brain wave activity. In general, this approach has not been useful in identifying characteristics specific to people with FMS, nor can it help explain why patients are so unrefreshed following a night of apparently “good” sleep. Even with additional techniques to evaluate breathing (which is helpful for the accurate diagnosis of sleep apnea), an overnight sleep study doesn’t readily explain any abnormal physiology that may be occurring during the night.
Sleep processes taking place in the brain strongly influence the autonomic nervous system, which in turn, regulates heart rate and breathing. Robert J. Thomas, M.D., will use new technology that evaluates the interactions (or coupling) of the cardiac rhythm and respiratory pattern during sleep using information taken from the electrocardiogram (ECG).
“This technique can easily differentiate stable or effective sleep, which allows normal nighttime functions, and unstable or ineffective sleep, which may not allow normal sleep functions to occur,” says Thomas. “Sleep disrupting conditions reliably decrease stable sleep, while sleep enhancers increase it. This information is obtained without requiring a technician to place numerous electrodes on the skull for an EEG that measures brain wave activity. Instead, the ECG equipment involves a monitor that patients strap around their chest, making it easy to use as often as needed.”
A 3D-looking chart generated by the ECG technique is called a sleep spectrogram and provides information about how well the heart, lungs, and nervous system are coordinating efforts during sleep. When these three systems are coupled at the frequency of respiration (8 to 20 times a minute), a person’s sleep is very stable (e.g., good, restorative sleep). When these systems are coupled at a lower frequency, about 2 times a minute, sleep is unstable (e.g., fragmented with lots of arousals and unrefreshing). During sleep, there seems to be little if any overlap between the higher and lower frequencies, making it relatively easy to distinguish between potentially restorative and non-restorative sleep states.
The ECG may be useful for detecting sleep disturbances in FMS patients that are not apparent by looking at the brain waves. In one small study, FMS patients showed a significant reduction in the stable and restorative interactions between heart rate and respirations (in press, Sleep Medicine 2009). At the same time, carefully done conventional sleep studies using an EEG to measure REM and non-REM brain stages did not provide useful information.
Thomas proposes to use “sleep as a window into FMS” and hypothesizes that the sleep spectrogram can be a useful marker of disease for this condition. “It does not matter what causes FMS,” says Thomas, adding the analogy that “a thermometer can show fever regardless of cause. The ECG technique can be used as a ‘sleep thermometer.’ It has been applied to more than 10,000 sleep studies in people of all ages. The patterns of undisturbed sleep are consistent and predictable.”
Blood pressure (BP) normally drops during restful sleep (called blood pressure “dipping”). Brief awakenings and persistent disruptions from sleep reliably cause BP increases, and the profile is referred to as “non-dipping.” Until recently, it was not possible to readily measure BP continuously during sleep because a tight-fitting finger cuff could disturb the natural flow of the nighttime processes. However, recent research in primary insomnia patients shows BP non-dipping.
“A new approach to measuring BP throughout the night makes use of a simple finger probe that is currently in standard clinical use for measuring blood oxygenation levels,” says Thomas. “We propose to show that FMS patients are non-dippers—their BP will remain increased during sleep because sleep itself is disturbed. The combination of the ECG-based sleep spectrogram and simultaneously measured continuous BP could provide a useful marker of FMS.”
The ECG and BP will be recorded for seven consecutive nights from10 healthy subjects and 20 patients with FMS who are free of medications and without any other painful or psychiatric diseases. “Recording many nights at a time will reduce the impact of changes that can be seen on different nights,” says Thomas. “It also allows us to determine if next-day pain and discomfort are related to poor sleep.” In addition, Thomas will simultaneously evaluate each participant’s sleep with the standard EEG-type of equipment to allow comparisons between the various measures.
Although the small, comfortable devices for measuring the ECG and BP are designed for patients to use at home, all evaluations for this study will take place in the clinical research facilities at Beth Israel Deaconess Medical Center. Performance measures on cognitive tasks, vigilance, and function will be assessed in a consistent, controlled, and quiet environment. As a result, Thomas will be able to explore the relationship between sleep and performance in people with FMS.
“The ECG and BP devices are simple enough to use by patients for monitoring treatment effects, but first we must show that this method provides important information,” says Thomas. “Development of disease severity markers will greatly assist with monitoring progress in drug trials and the use of other novel therapies. The absence of reliable markers of abnormal physiology in FMS has presented a major challenge that we hope to overcome. Sleep then becomes a window that allows clinicians and researchers to look into and track the disease state of FMS.”
Genetic Influences on Pain Modulation Systems in Fibromyalgia
Principal Investigator: Serge Marchand, Ph.D.
University of Sherbrooke, Quebec, Canada
Award: $55,000 (October 2009)
“There is a genetic predisposition to developing fibromyalgia syndrome (FMS), so why not look at the main neurotransmitters that play a role in pain modulation?” asks Serge Marchand, Ph.D. Both dopamine and serotonin are involved in providing pain relief through the diffuse noxious inhibitory control (DNIC) system, while glutamate is known for its role in turning up the volume on the pain amplification system. Various genetic abnormalities that alter the function of dopamine, serotonin, and glutamate in the central nervous system will be evaluated in this study.
The DNIC operates on the basis that pain inhibits more pain. When a person is first subjected to a noxious stimulus, the DNIC system releases pain-relieving substances into the spinal cord to reduce the impact of additional discomfort. Marchand has already shown that this system is not working well in FMS patients, but he stresses that there is a lot of variability.1 “Some healthy subjects have a very strong DNIC and others have such a weak DNIC that if we did not know better, we would think that they were FMS patients,” says Marchand. “There are likely certain genetic predispositions that determine the strength of a person’s DNIC system.”
The DNIC uses serotonin, norepinephrine, and dopamine transmitters that cause the release of opioid-like pain relievers. Given that FMS patients have double the normal concentration of opioids in their spinal fluid, their faulty DNIC is probably not due to a genetic inability to produce opioids. However, genetic abnormalities pertaining to serotonin, norepinephrine, and dopamine have been identified in FMS and will be examined.
Sleep disruption is another factor that can interfere with DNIC function. Yet, it is not known what role this sleep disorder in FMS plays in the lack of DNIC response. As a result, all study subjects (70 FMS patients and 70 healthy controls) will wear a watch-like actigraphy device that monitors movement during the entire week before the DNIC and other pain sensory testing. Not only will this provide a measure for how disturbed a person’s sleep is, it will also produce an estimate of physical function.
The role of dopamine in FMS has garnered more attention in recent years, partly due to the efforts of Patrick Wood, M.D., and Andrew Holman, M.D., both in Renton, WA. Wood showed that dopamine activity in the brain was greatly increased in healthy subjects given a painful stimulus, but not in FMS patients.2 Testing a dopamine-like drug, Mirapex (pramipexole), Holman documented significant FMS symptom relief in a small group of patients.3 And Marchand has already collected preliminary data that will be expanded upon in this AFSA-funded study to evaluate the influence of the dopamine 3 receptor (D3) in FMS.4
A genetic mutation, called the Ser9Gly polymorphism, can alter the sensitivity of the D3 receptor. A less sensitive receptor would require more dopamine to produce the same results, such as the release of opioid-like pain relievers. The preliminary data indicates that the less sensitive (poorer functioning) D3 receptor lowers the heat pain threshold in FMS patients but not healthy control subjects. Why the differing effect? FMS patients already have signs of abnormal pain processing in their spinal cord (e.g., elevated pain transmitters like substance P and glutamate), so having genes that make things worse will have more of an impact on pain thresholds.
“The role of DNIC across the natural menstrual cycle is a good example,” says Marchand, who just published a study on this topic.5 “In healthy women we found that the DNIC was really strong in the mid-phase of the cycle and then drops off. If you have chronic pain, then during your pre-menstrual phase when your DNIC is so weak, it is not blocking pain and could make a significant difference to your pain threshold.”
In addition to evaluating the neurotransmitters involved in DNIC, Marchand will look at the pain amplifying system. Increased glutamate levels are believed to play an important role in magnifying FMS pain, and he will measure two enzymes that could help explain glutamate’s role in pain.
“With regards to patient relevance, it would be important to show different genetic markers exist between people with FMS and healthy subjects, as well as other diseases like Parkinson’s, for example,” says Marchand. “If we can show that one neurotransmitter plays a larger role in generating the symptoms of FMS, this can alter our therapeutic strategies.” More than likely, he expects to identify different subgroups of patients, some that would respond favorably to dopamine-like drugs, while others that might need a boost in serotonin or could benefit from drugs that reduce glutamate.
1. Julien N, et al. PAIN 114:295-302, 2005. www.afsafund.org/research_2000.html
2. Wood PB, et al. Eur J Neurosci 25:3576-82, 2007.
3. Holman AJ, Myers RR. Arthritis Rheum 52(8):2495-505, 2005.
4. Potvin S, et al. J Pain 10(9):969-75, 2009.
5. Tousignant-Laflamme Y, Marchand S. PAIN 146:47-55, 2009.
Gene Expression Biomarkers for Fibromyalgia
Principal Investigator: Alan Light, Ph.D.
University of Utah in Salt Lake City
Award: $50,000 (September 2009)
“One of the critical needs in FMS research is to develop truly objective biomarkers for the disorder,” says Alan Light, Ph.D. “Blood-based biomarkers are especially valuable because they are consistent with traditional medical models, they are viewed as unbiased, and they are relatively low risk for patients (compared to cerebrospinal fluid or tissue sampling markers).”
Light has teamed up with his wife Kathleen Light, Ph.D., and together they have overcome the obstacle of the blasé blood work in which everything comes back “normal.” A preliminary study shows dramatic differences in many test markers between patients with both chronic fatigue syndrome (CFS) and FMS, compared to healthy controls.1 All of the subjects were required to perform moderate exercise on a stationary bicycle for 25 minutes.
What does exercise have to do with blood markers and your symptoms? “Muscle pain and both physical and mental fatigue are sensations that a healthy body uses for protection or as a warning signal to prevent overuse of muscles and important areas of the brain,” says Light. “However, in FMS and CFS patients these sensations are overwhelming and unrelenting, and interfere with normal life activities.”
Based on research in mice, Light identified the specific receptors that are located on the nerve fibers traveling through the muscle, which allow the sensory nerves to detect the chemicals produced by muscle activity.2 For example, they sense how much energy the muscle has consumed or the amount of lactic acid accumulated. Once a muscle’s activity produces a certain level of chemicals, these sensory fibers send a signal to the brain that is interpreted as muscle fatigue. Continued use of the muscle will eventually signal the brain with a message that is perceived as pain.
The sensory nerves in the muscles are alongside the blood vessels. Light found that the white blood cells (or leukocytes) are like magnets picking up information from the sensory fibers, sympathetic nervous system, and the immune system (see below). By measuring the leukocyte messenger RNA (mRNA), which contains the genetic blueprints for making what the cells need, the Lights can look for gene expression test markers.
“The amounts of mRNA did not change in healthy control subjects following moderate exercise, nor did they experience any post-exertional fatigue or pain,” says Light. “The picture was different for the patients with CFS, of which 70 percent also had FMS. The mRNA that create receptors increased rapidly and remained high for at least 48 hours after the same exercise task.” Certain receptor increases tended to correlate with symptoms of mental and physical fatigue. Other receptors tended to increase in conjunction with the symptom of pain.
What might it be like when the number of receptors on sensory nerve endings increase? Light has a hypothesis: “The small amounts of muscle activity involved in sitting or walking will more readily activate the receptors, causing them to send signals of fatigue and muscle pain to the brain as if the body was always overworking.”
Light’s work has shown that exercise triggers a substantial increase in mRNA in CFS-FMS patients. Now it’s time to look at specific conditions and symptoms. In this AFSA-funded project, 15 people with FMS only and 15 people with regional low back pain will be evaluated by the same exercise protocol that was used in Light’s preliminary study. In a separate study funded by the CFIDS Association of America, Light is already testing CFS-only patients and additional healthy controls. All four groups will provide valuable comparisons.
“We want to determine if patients with focal or low back pain show a regulation of the sensory receptor pathways that is different than patients with the widespread muscle pain of FMS,” says Light. “Our long-term goal is to create a blood test that can be used to objectively diagnose FMS and CFS, as well as distinguish these disorders from other painful or fatiguing conditions. The biomarkers could also be used for early interventions, new therapies, and could shed light on the causes of the primary symptoms of FMS and CFS.”
1. Light AR, et al. J Pain 10:1099-112, 2009.
2. Light AR, et al. J Neurophysiol 100:1184-201, 2008.
Role of Myofascial Trigger Points in FMS - Part 2
Principal Investigator: Hong-You Ge, M.D., Ph.D.
Aalborg University, Denmark
Award: $20,000 (October 2009)
Now that Hong-You Ge, M.D., Ph.D., and his colleagues have demonstrated that myofascial trigger points (MTPs) are an important contributor to the painful symptoms of FMS, Part 2 of this project focuses on treatment. Ge will recruit 60 FMS patients who will be divided into two therapy groups: active and placebo. The active treatment will consist of using acupuncture needles to inactivate the MTPs during twice weekly sessions for four to five consecutive weeks. The insertion of tiny acupuncture needles into the heart of the MTP forces the area of sustained contraction to relax. This treatment approach, called dry needling, releases the nasty chemicals that are held within the muscle knot and allows for improved circulation.
The placebo group will meet for the same number of therapy sessions as those in the active group, except instead of inserting the needle into the MTP to release it, the needles will only penetrate the top skin layer. All patients will be evaluated before and after treatments by a skilled examiner. Neither the patients nor the examiner will know who has been assigned to the active therapy group. To assess how robust the treatment protocol is for the inactivation of the MTPs, the examiner will assess patients in the “active” group at three, six and twelve months after the end of the therapy sessions.
In previous studies involving healthy subjects, Ge has shown that painful stimulation of latent MTPs (injecting them with a chemical irritant) causes an increase in sympathetic nervous system activity that leads to constriction of nearby blood vessels.* Latent MTPs do not produce spontaneous pain so people are not aware of them unless they are pressed, or in the case of Ge’s experiments, injected with a chemical irritant. Based on these studies, one might ask if the sympathetic nervous system’s hyperactivity that is well-documented in people with FMS might be reduced upon inactivation of MTPs.
“Sympathetic activation is one of the perpetuating factors that leads to the formation of MTPs,” says Ge. An important question to answer is: Which came first, the MTPs or the sympathetic hyperactivity in people with FMS? Ge will be evaluating the level of sympathetic nervous system activity in all subjects. “If deactivating trigger points leads to decreased sympathetic activity, then it will prove that MTPs are one of the causes of sympathetic hyperactivity in FMS.”
* Zhang Y, Ge HY, et al. Arch Phys Med Rehabil 90:325-32, 2009.