New Insights Into Parkinson's Disease And Possible Treatments
ScienceDaily (Mar. 21, 2009) - About the only thing doctors have understood
about deep-brain stimulation, which is widely used to treat Parkinson's
disease symptoms, is that somehow it works for many patients.
In a new study that will be published March 20 in the journal Science,
Stanford University researchers used light to illuminate how the treatment
works, generating surprising insights into the diseased circuitry and also
suggesting new ideas to improve Parkinson's therapy.
Parkinson's disease is a brain disorder that affects an estimated 1.5
million Americans, causing tremors, stiffness and difficulty balancing. In
those who undergo deep-brain stimulation, pulses of electricity are applied
to the circuitry of a tiny brain region called the subthalamic nucleus.
Naturally, researchers suspected that cells within that region are somehow
stimulated, or calmed, by the shocks, leading to reduced Parkinson's
symptoms.
In the new study, which will also appear in an upcoming print issue of
Science, the medical and engineering researchers found that by far the
biggest effect in "Parkinsonian" rodents occurs not by stimulating cells in
the subthalamic nucleus, but by stimulating the neural wires, called axons,
that connect directly to it from areas closer to the surface of the brain.
"Pointing to these axons that converge on the region opens the door to
targeting the source of those axons. This insight leads to deeper
understanding of the circuit and could even lead to new kinds of
treatments," said senior author Karl Deisseroth, MD, PhD, associate
professor of bioengineering and of psychiatry and behavioral sciences.
"Because these axons are coming from areas closer to the brain's surface,
new treatments could perhaps be less invasive than deep-brain stimulation."
A spotlight on brain circuits
To perform the research, Deisseroth's team, which included students and
faculty from bioengineering, neuroscience and neurosurgery, used a technique
his lab has pioneered called "optogenetics." They genetically engineered
specific types of cells, or neurons, in the subthalamic nucleus regions of
different rodents to become controllable with light. A blue-colored laser
pulse makes the neurons more active, while a yellow laser light suppresses
activity.
[In a separate paper to be published in the journal Nature on March 18,
Deisseroth and another cadre from within his research group show that the
optogenetic technique can be applied not only to the electrical behavior of
neurons, but also to the much broader biochemical activity of other cell
types in the body.]
"Using the technology allowed us to separate the different circuit elements
by placing them under optical control," Deisseroth said. "It allowed us to
systematically move through the circuit, turning on or off different
elements and finding out which modifications of the circuit corrected the
symptoms."
This result also required a complementary method invented in the Deisseroth
lab, namely delivering light via a thin, flexible fiber-optic cable deep
into the brain of the animals, so that they can move and behave freely
during the experiment.
The team tried every kind of neuron they could think of within the brain
region itself, and found no effect. Out of persistence and desperation, like
a person who has searched the whole house for the keys and finally finds
them in the doorknob, the team decided to investigate the incoming axons. In
rodents with cells that had been made light-sensitive, the researchers found
dramatic results both with high-frequency and low-frequency pulses.
"The [high-frequency stimulation] effects were not subtle," the researchers
wrote in the Science Express paper. "In nearly every case these severely
Parkinsonian animals were restored to behavior indistinguishable from
normal, and in every case the therapeutic effect immediately and fully
reversed.upon discontinuation of the light pulse."
Low-frequency stimulation, meanwhile, caused the Parkinson's symptoms to
become worse.
Deisseroth said the work raises even more interesting questions than it
answers, such as what types of cells the axons target.
In addition, he asked, "In what way can we team up with other clinicians to
help guide therapies capitalizing on this insight?"
Deisseroth said the most important outcome of the work, primarily carried
out by graduate students Viviana Gradinaru and Murtaza Mogri, who are the
first authors of the paper, is the new information about the role of the
axons. He cautioned that, while the optogenetic technique had a therapeutic
effect on the rodents and has worked well in every species tried so far, it
still might not be the best therapy for people.
"There may be better or simpler ways to get that therapeutic value now that
we have this key insight," he said.
This study is the first showing that optogenetics can be applied to brain
disease. Deisseroth said another of this group's hopes is to extend the
understanding of deep-brain stimulation to how it affects different
diseases, such as depression and obsessive-compulsive disorder.
"Our goal is to better understand this disease and its treatment, and to
help refine and generalize therapies by elucidating basic mechanisms," he
said.
Other Stanford co-authors include bioengineering postdoctoral scholar
Kimberly Thompson, PhD, and Jaimie Henderson, MD, associate professor of
neurosurgery. The study was funded by the National Institutes of Health, the
National Science Foundation and several private organizations including the
Keck, Coulter, Snyder, Yu and Kinetics foundations.
Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
rbrown@xxxxxxxxx
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