Parkinson's disease destroys neurons in the basal ganglia, which means that the dopamine signals those neurons normally send to the primary motor cortex disappear. Restore that dopamine, the story goes, and you will alleviate the motor symptoms of the disease: tremor, rigidity and an inability to carry out voluntary movements.

But research in the Oct. 19, 2006, issue of Neuron shows that the dopamine level itself may be a red herring. Using a combination of gene knockout, electrophysiological and behavioral techniques, scientists from Duke University in Durham, N.C., and the NIH's National Institute of Alcohol Abuse and Alcoholism in Bethesda, Md., showed that when dopamine signals to the motor cortex stop, neurons in the motor cortex still are just as active. What changes is their level of synchronicity - whether they fire in a coordinated or an uncoordinated way.

"I wasn't surprised that we found the changes in synchrony. But I was surprised that they were so severe, and that there was no change in the overall activity level in the motor cortex," lead author Rui Costa, section chief of the section on in vivo neural function at the NIAAA, told BioWorld Today.

Costa and his colleagues created mice lacking the gene for the dopamine transporter, which normally brings dopamine back into cells after it has been released for signaling, essentially reloading the neuron for its next round. By default, mice without this transporter gene have high dopamine levels in the motor cortex, because the dopamine does not return back into neurons after firing, hanging out in the extracellular space and stimulating receptors there until it is broken down.

But because mice without the transporter must newly synthesize all the dopamine they use, it also is possible to deplete dopamine extremely quickly, but reversibly, in these animals, by inhibiting such synthesis pharmacologically. Researchers also could restore dopamine levels quickly by giving animals a dopamine precursor.

The researchers then implanted the genetically engineered mice with multiple electrodes to measure the activity of many neurons simultaneously in the motor-control regions of the brain and relate it to the animals' movement levels.

What the researchers found was that during both dopamine overabundance, which caused increased movement under some circumstances, and dopamine depletion, which caused decreased movement, the overall activity level of the cortex did not change. Many individual neurons did change their activity level, but on balance the changes evened out.

What did change was the degree of coordination of different neurons. "In the state of excessive dopamine, we saw a decrease in synchrony," Costa said, adding that this was also somewhat of a surprise because "these circuits are already not very synchronous" under standard operating conditions. In contrast, dopamine depletion led to increased synchrony in striatal firing. He added that such synchronicity is seen in normal animals when they are not moving as well, but that it is a transient state lasting only a few milliseconds, whereas in dopamine-depleted animals such synchronicity continues for much longer. "It seems like they are locked into" a synchronous firing state, Costa said.

The relationship of different motor control areas to one another and, ultimately, to movement, is little understood, and how the degree of coordination ultimately affects movement still is unclear. But Costa said one possibility, albeit an unproven one, is that the striatum could act as an "action selection filter." Too much dopamine could make the filter ineffective by letting every movement through, while a lack of dopamine could render such a filter unable to actually let any commands to move through.

Asked about the potential therapeutic implications of his findings, Costa said, "I think it's already been done inadvertently" in deep brain stimulation, where what is more or less a brain pacemaker is implanted into patients to send electrical impulses to neurons. The procedure currently is used for severe Parkinson's disease, as well for a few patients with depression and obsessive-compulsive behaviors.

"People thought they were restoring the amount of activity the cortex needs. But it turns out what they were doing is desynchronizing the circuits," Costa said. Because the primary motor cortex lies at the brain surface of the brain, it could perhaps also be stimulated by less invasive means than the deep implantation of electrode arrays, such as Tran cranial magnetic stimulation, which would make it more widely usable.

At the pharmacological level, "anything that could control the excitability [of the motor cortex] would be very helpful," Costa said. He believes a pharmacological approach would likely find even wider use than noninvasive stimulation. "Electrical stimulation is nice, but we're still not prepared to deal with that as well as something we could take as a pill."

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