Natural Drowsiness Chemical Vital to Deep Brain Stimulation Effectiveness

Scientists at the University of Rochester have found that adenosine, a brain chemical most widely known as the cause of drowsiness, also appears to play an essential role in the success of deep brain stimulation to ease symptoms in patients with Parkinson’s disease and other brain disorders.

Deep brain stimulation, or DBS, is a technique for treating people affected by Parkinsons disease and who have severe tremor, and its also being tested in people who have Tourettes syndrome, severe depression or obsessive-compulsive disorder.

“There are at least a dozen theories of what is happening in the brain when deep brain stimulation is applied, but the fact is that no one has really understood the process completely,” said Robert Bakos, M.D., a co-author of the paper, who has performed more than 100 DBS surgeries in the last decade. ““We’ve all been focused on what is happening to the nerve cells in the brain, but it may be that we’ve been looking at the wrong cell type.”

Adenosines Surprising Role

The paper, published Dec. 23 2007 in Nature Medicine (1), shows that DBS is correlated with a distinct increase in the release of adenosine triphosphate (ATP), causing an accumulation of its byproduct, adenosine.

“Certainly the electrical effect of the stimulation on neurons is central to the effect of deep brain stimulation,” said Maiken Nedergaard, M.D., Ph.D., Rochester Department of Neurosurgery who led the research team. “But we also found a very important role for adenosine, which is surprising.”

Adenosine levels in the brain usually build as the day passes, and in due course it plays an important role in making us sleepy its the brains way of telling us that its been a long day, we’ve expended a lot of energy, and its time to go to bed. (2)

The scientists say the role of adenosine in deep brain stimulation has not been realized before. Even though scientists have recognized its ability to inhibit brain cell signaling, they did not suspect any role as part of DBSs effect of squelching abnormal brain signaling.

The researchers showed that electrical pulses that are at the heart of DBS evoke those other cells astrocytes in the area immediately around the surgery to release ATP, which is then broken into adenosine. The extra adenosine reduces abnormal signaling among the brains neurons. Astrocytes are star-shaped glial cells in the brain linked by gap junctions that perform many functions.(3).

Astrocytes were long thought of as simple support cells, but in recent years, Nedergaard and colleagues have shown that they play an important role in a host of diseases, including epilepsy, spinal cord disease, migraine headaches, and Alzheimers disease.

Effectiveness Enhancing

“It may be possible to enhance the effectiveness of deep brain stimulation by taking advantage of the role of agents that modulate the pathways initiated by adenosine,” said Nedergaard. “Or, its possible that one could develop another type of procedure, perhaps using local targeting of adenosine pathways in a way that does not involve a surgical procedure.”

“The correlation between what we see in the clinic and Dr. Nedergaard has found in the laboratory is really quite startling,” said Bakos. “All the credit goes to her and her team. This has been a nice interchange of information between the clinic and the laboratory, to speed a discovery that really could have an impact on patients.”

References

1. Lane Bekar, Witold Libionka, Guo-Feng Tian, Qiwu Xu, Arnulfo Torres, Xiaohai Wang, Ditte Lovatt, Erika Williams, Takahiro Takano, Jurgen Schnermann, Robert Bakos & Maiken Nedergaard:  Adenosine is crucial for deep brain stimulation mediated attenuation of tremor Nature Medicine 23 December 2007 | doi:10.1038/nm1693

2. Basheer R, Porkka-Heiskanen T, Strecker RE, Thakkar MM, McCarley RW Adenosine as a biological signal mediating sleepiness following prolonged wakefulness Biol Signals Recept. 2000 Nov-Dec;9(6):319-27 PMID: 11025338

3. Bennett M, Contreras J, Bukauskas F, Sáez J (2003). New roles for astrocytes: gap junction hemichannels have something to communicate.. Trends Neurosci 26 (11): 610-7. PMID 14585601.

Image: Ludovic Collin, Wellcome Images