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Illuminating Parkinson’s Disease

New technique suggests how deep brain stimulation ameliorates symptoms.
March 20, 2009

Parkinson’s disease is often treated with deep brain stimulation (DBS), which delivers electrical pulses to a deep-seated cluster of neurons called the subthalamic nucleus. But while the technique is successful in many patients, scientists have struggled to understand its mechanism.

Let there be light: By seeding neurons with light-activated proteins and piping light through a fiber-optic cable into the brains of mice with Parkinson’s disease (above), researchers reversed the mice’s symptoms. The line on the left traces an untreated animal’s path, which is restricted by the disorder’s characteristic dysfunctional movement. The line on the right shows that when light was applied, the animal was able to move much more freely. Credit: Deisseroth lab, Stanford University

“What’s been mysterious is we don’t know how those stimulation treatments really work,” says Karl Deisseroth, a bioengineer and psychiatrist at Stanford University and senior researcher on a new project that sheds light–literally–on how DBS affects the Parkinsonian brain.

Deisseroth and his colleagues engineered cells in the subthalamic nucleus of mice with Parkinson’s to express proteins derived from light-sensing bacteria. One protein triggers cells to fire in response to blue light, while another quiets cells’ electrical activity in response to yellow light. The researchers systematically marched through the circuit targeted by DBS, piping in light through a fiber-optic cable to probe each cell type in turn.

“What we found was quite surprising,” says Deisseroth. None of the cell types in the subthalamic nucleus, when stimulated or calmed by light, had any effect on the mice’s symptoms. But when light was used to activate the wire-like axons projecting to the subthalamic nucleus from other parts of the brain, the mice’s symptoms were completely reversed. The results appeared online yesterday in the advance online edition of Science.

“That showed that a big feature of disease pathology may not always be misfiring of cells within a structure,” says Deisseroth, “but more the flow of information between structures.”

The researchers hope that by tracing the axons back to their source–nearer to the surface of the brain–they will uncover potential targets for less invasive treatment of the disease. Deisseroth also believes that a newer incarnation of his team’s light-based approach, which activates cells biochemically rather than electrically, could reveal why some patients respond better than others to the electrical activation DBS produces. “For some symptoms or some disease states, biochemical modulation may be what should be the primary target,” he says.

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