You know you’re in for a different type of study when the lead author hails from the Department of Mathematics and Statistics at his University. This isn’t your usual kind of biology. No human subjects immediately needed – just studies and studies and computations and computational. It’s called computational biology and if, Gordon Brokerick and Travis Craddock at Dr. Klimas’s Institute of Neuroimmune Medicine are correct, it’s going to revolutionize our understanding of the human body. Thalamic Mechanisms Underlying Alpha-Delta Sleep with Implications for Fibromyalgia Sujith Vijayan, Elizabeth B. Klerman, Gail K. Adler, Nancy J. Kopell. J Neurophysiol (August 5, 2015). doi:10.1152/jn.00280.2015
This is the first time, that I am aware of, that these techniques have been used in fibromyalgia. They picked a good symptom to try them out in – sleep. Numerous studies have shown that depriving a person of good, deep sleep doesn’t just make them tired – it ramps up their sensitivity to pain as well.
This group focused on alpha-delta sleep wave problems. These sleep wave problems were identified in FM over forty years ago. Alpha waves are higher frequency waves that are associated, interestingly enough, with states of relaxation during wakefulness. When they occur during sleep they’re believed to produce mini arousals that pop people experiencing them out of deeper sleep stages. Alpha waves are not unusual; they are present during sleep in healthy people, but the extent of alpha wave “intrusions” found in fibromyalgia appears to be unusual.
These waves originate in the thalamus, a section of the midbrain that is a relay center for sensory signals making their way into the upper brain. Among other things, the thalamus regulates sleep and wakefulness. Several nonsleep studies suggested this is involved in fibromyalgia. A 2014 study, for instance, finding decreased connectivity between the thalamus and premotor areas, could help explain the fatigue present in FM. Increased connectivity between the thalamus and insula, on the other hand, could help explain the pain problems.
Because delta waves are responsible for “down-scaling” the activity of pain pathways during sleep, alpha wave intrusions are believed to create two problems; they’re preventing the brain from turning off the activity of pain pathways and they’re putting the brain more into wake mode – thus preventing people with FM to experience restorative sleep. It’s no wonder people with FM (and people with ME/CFS with similar sleep problems) tend to wake up exhausted.
Since the early study little research has been done on alpha wave intrusions in FM. A 2010 study by Moldovsky, however, found that Xyrem blocked alpha wave intrusions, improved sleep physiology and improved fatigue and pain in FM.
(Alpha wave problems are also found in ME/CFS. Alpha intrusions were associated with increased anxiety in a 2007 chronic fatigue syndrome (ME/CFS) study and excessive daytime sleepiness in major depressive disorder in 2011. In 2014 at the Stanford Symposium Michael Zinn reported finding large areas of the brain with reduced alpha waves during wakefulness. The reduced alpha waves were highly correlated with fatigue in ME/CFS.)
In this study these researchers, each from a different University in Boston, took what they know about how Xyrem affects the brain, how alpha waves are produced, and how the brain in FM is functioning during sleep, and piled all that data into a mathematical model.
The model suggested that the alpha intrusions could arise in two ways: through depolarization of thalamocortical cells or through the cortex depolarizing the entire somatosensory thalamus. Depolarization occurs when the electrical charge of a cell rapidly shifts from negative to positive – allowing an electrical impulse to flow through the cell. When this happens they send a burst of alpha waves into the brain. A similar situation called thalamocortex dysrhythmia is believed to disrupt brain functions such as sensory perception, cognition and movement control in disorders such as tinnitus, neuropathic pain and Parkinson’s disease.
Xyrem was able to reduce the alpha wave intrusions in fibromyalgia and improve sleep. It’s able to affect three electrical currents – in the thalamus GABA currents, potassium leak currents and hyperpolarization-activated thalamic currents. It wasn’t clear, though, which one or one’s were the key to Xyrem’s success.
GABA was a likely candidate. It is the ying to glutamate’s yang in the brain. This feel good neurotransmitter turns the brains state of arousal down. The model, in fact, suggested that increasing the rate of a “GABA current” in the thalamus – in conjunction with other changes – would help stop the alpha wave intrusions.
More surprising, though was the finding that simply reducing the activity of a calcium channel (Ih) or increasing the activity of a potassium channel (Ikl) in these thalamocortical cells was enough to stop them from producing alpha waves.
That’s an encouraging finding since it suggests that a drug need only target these cells to be effective. Since the more portions of the brain a drug targets, the greater chances it will cause side effects, the smaller the target the better.
Another way to get at depolarization problems is to determine what’s causing it in the first place. The researchers believe this depolarization is being driven by over active pain pathways that are overstimulating these thalamocortical cells. Animal studies indicate that pro-inflammatory cytokines Il-8 and IL-1b can cause these thalamic cells to depolarize. The vasoactive intestinal peptide (VIP) – a subject of interest in ME/CFS – can also induce these cells to depolarize as well.
These findings suggest that reducing neuroinflammation, if present, in the brains of FM and/or ME/CFS patients could return the thalamus to normal functioning and give FM and ME/CFS patients bodies the rest they need to heal.
We should know more about neuroinflammation in FM and ME/CFS patients over the next year or two as studies using new techniques to measure it roll out.