ScienceDaily (Dec. 24, 2007) — A brain chemical that makes us sleepy also 
appears to play a central role in the success of deep brain stimulation to 
ease symptoms in patients with Parkinson's disease and other brain disorders. 
The surprising finding is outlined in a paper published online Dec. 23 in 
Nature Medicine.
The work shows that adenosine, a brain chemical most widely known as the cause 
of drowsiness, is central to the effect of deep brain stimulation, or DBS. 
The technique is used to treat people affected by Parkinson's disease and who 
have severe tremor, and it's also being tested in people who have severe 
depression or obsessive-compulsive disorder.
Patients typically are equipped with a "brain pacemaker," a small implanted 
device that delivers carefully choreographed electrical signals to a very 
precise point in the patient's brain. The procedure disrupts abnormal nerve 
signals and alleviates symptoms, but doctors have long debated exactly how 
the procedure works.
The new research, by a team of neuroscientists and neurosurgeons at the 
University of Rochester Medical Center, gives an unexpected nod to a role for 
adenosine and to cells called astrocytes that were long overlooked by 
neuroscientists.
"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., 
the neuroscientist and professor in the Department of Neurosurgery who led 
the research team. "But we also found a very important role for adenosine, 
which is surprising."
Adenosine in the brain is largely a byproduct of the chemical ATP, the source 
of energy for all our cells. Adenosine levels in the brain normally build as 
the day wears on, and ultimately it plays a huge role in making us sleepy -- 
it's the brain's way of telling us that it's been a long day, we've expended 
a lot of energy, and it's time to go to bed.
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 DBS's 
effect of squelching abnormal brain signaling.
"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 neurosurgeon 
at the University of Rochester and 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."
Nedergaard's team showed that the 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 brain's neurons.
The team also showed that in mice, an infusion of adenosine itself, without 
any deep brain stimulation, reduced abnormal brain signaling. They also 
demonstrated that in mice whose adenosine receptors had been blocked, DBS did 
not work; and they showed that a drug like caffeine that blocks adenosine 
receptors (the reason why caffeine helps keep us awake) also diminishes the 
effectiveness of DBS.
"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, it's 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 latest work continues Nedergaard's line of research showing that brain 
cells other than neurons play a role in a host of human diseases. ATP in the 
brain is produced mainly by astrocytes, which are much more plentiful in the 
brain than neurons. 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 Alzheimer's disease.
The research on DBS came about as a result of a presentation Nedergaard made 
to colleagues about her research on astrocytes. Bakos linked her detailed 
description of astrocyte activity to what he sees happening in the brain when 
deep brain stimulation is applied. Based on Bakos' experience in the 
operating room and with funding from the National Institute of Neurological 
Disorders and Stroke, Nedergaard went back to the laboratory and analyzed the 
effects of deep brain stimulation in a way that no one had ever before 
considered.
"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."
The lead authors on the paper are post-doctoral research associate Lane Bekar, 
Ph.D., and neurosurgeon Witold Libionka, M.D. The Rochester team is based 
both in the Department of Neurosurgery and the Center for Translational 
Medicine. In addition to Nedergaard and Bakos, other authors from Rochester 
include research assistant professors Guo F. Tian and Takahiro Takano; 
graduate students Arnulfo Torres and Ditte Lovatt; technical associate Qiwu 
Xu; former post-doctoral research associate Xiaohai Wang; and Erika Williams, 
a Fairport native and an undergraduate student at Williams College. Jurgen 
Schnermann of the National Institutes of Health also contributed.
Adapted from materials provided by University of Rochester Medical Center.

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