Indirect brain treatment may relieve Parkinson's symptoms
External magnetic fields or spine implants could provide alternatives to invasive brain surgery.
The symptoms of Parkinson's disease could one day be relieved by indirect electrical stimulation of the brain, via the spinal cord or even through the surface of the skull, according to two studies on rodents.
Parkinson's disease is a severe neurological disorder characterized by tremors, rigid limbs and difficulty in moving. Some patients who do not respond to drug treatment undergo deep brain stimulation (DBS), in which tiny electrodes are placed within the basal ganglia deep inside their brain. The operation can help to alleviate symptoms, but it is risky because it is highly invasive.
Miguel Nicolelis, a neuroscientist at Duke University in Durham, North Carolina, and his colleagues have now shown that, in animal models of Parkinson's disease, the DBS effect can be achieved by stimulating fibres in the spinal cord1.
The team's finding "opens the door for trials of less-invasive spinal-cord stimulation in other animal models of Parkinson's disease and in parkinsonian patients", says Bart Nuttin, a neurosurgeon at the Catholic University of Leuven in Belgium who has performed many DBS operations.
Meanwhile, at Stanford University in California, neuroscientist Karl Deisseroth and his colleagues have found that the neurons activated by DBS might lie not at the site of the electrode, but much closer to the surface of the brain2.
This means that doctors might be able to reach the neurons by using non-surgical techniques such as transcranial magnetic stimulation, where magnetic fields induce weak electric currents in the brain. Both studies are published in this week's Science.
Parkinson's disease is caused by degeneration of neurons in parts of the basal ganglia that make up the neural circuitry involved in movement. The neurons use dopamine as a neurotransmitter, but drugs that simply replace the lost dopamine become less effective with time.
In DBS, electrodes are usually implanted into a tiny structure in the basal ganglia called the subthalamic nucleus (STN), or nearby parts of the brain. The electrodes correct aberrant electrical signals in the parkinsonian brain, although no-one is really sure how.
Nicolelis says that the faulty electrical signals are similar to those seen during brain seizures, which can sometimes be controlled by stimulating nerves outside the brain. "So we thought we should try something similar," he says.
His team used two animal models of Parkinson's disease. In the first model, the researchers used mice that had been genetically altered so that they could no longer efficiently re-use dopamine previously released from the neurons. In a series of experiments, Nicolelis and his colleagues temporarily depleted dopamine levels using the chemical AMPT (a-methyl-P-tyrosine), and recorded activity in neurons in different parts of the brain. The mice had difficulty moving and showed neuronal activity typical of Parkinson's disease.
The researchers then implanted tiny electrodes onto the dorsal column of the spinal cord close to the neck, which has connections with many parts of the brain, including the motor cortex. When they stimulated the electrodes at high-frequency, the mice began walking normally again (see video). Low-frequency stimulation had a smaller effect.
In the second model, the team permanently destroyed dopamine-secreting neurons in rats by injecting the chemical 6-hydroxydopamine into both hemispheres of the brain. The resulting movement difficulties were also improved by spinal-cord stimulation.
Nicolelis is now repeating the experiments in marmosets, which model the human disease better than rodents.
Deisseroth says that Nicolelis' results "fit beautifully" with their own experiments, supporting the idea that the motor cortex is key to the DBS effect.
Deisseroth's team genetically engineered specific neurons in and around the STN in rats' brains so that the neurons could be selectively switched on or off with light fed through a thin, implanted fibre-optic cable. Then they injected 6-hydroxydopamine into one hemisphere of the rats' brains to induce abnormal movement, mimicking the symptoms of Parkinson's disease.
The researchers were surprised to find no effect on movement when they manipulated the STN neurons, but dramatic improvements when they targeted a layer of the motor cortex known as the V region. Deisseroth speculates that since the neurons there can be reached by transcranial magnetic stimulation, "these findings could help more precisely design and target a sort of DBS effect in Parkinson's patients without any kind of surgical intervention."
The role of the STN in brain stimulation has always been poorly understood, says neurologist William Langston, director of the Parkinson's Institute and Clinical Center in Sunnyvale, California. "If all this turns out to be the next-generation story, it is revolutionary, paradigm-breaking," he says.
But it is early days, he cautions, as rodent models are very artificial. "Primates are the only species to get Parkinson's disease naturally, so everything has to be first confirmed in monkeys."
- Fuentes, R., Petersson, P., Siesser, W. B., Caron, M. G. & Nicolelis, M. A. L. Science 323, 1578–1582 (2009).
- Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Science Advanced online publication doi:10.1126/science.1167093 (2009).