Romulo fuentesBrain activity oscillation in rat before (left) and after spinal cord stimulationRomulo fuentes
When drugs that stimulate the production of dopamine, a neurotransmitter, stop being effective, those who suffer from Parkinson’s disease currently have one last therapeutic resource to diminish their persistent shaking and motor dysfunction: expensive and delicate surgery to implant a neurostimulator in their brain. Physicians drill a hole in the skull and install electrodes in the part of the brain associated with movement. Wires that come out of the electrodes are attached to the actual neurostimulator, a device that functions as the system’s “battery” and that is normally implanted near the shoulder bone, in the chest or even in the abdomen. All of this small apparatus is hidden under the patient’s skin. It is estimated that 55 thousand people with Parkinson’s or other motor conditions worldwide have resorted to surgery to introduce this sort of brain pace-maker, or DBS – deep brain stimulation device, in medical jargon.
Though DBS is a medical advance, its application may become even more selective in the near future if neurological research shows that one can achieve similar results without opening the skull and attaching electrodes in people’s brains. Last month, research coordinated by a Brazilian neuroscientist, Miguel Nicolelis, from Duke University (USA), and also founder of IINN-ELS (the International Institute of Neurosciences of Natal – Edmond and Lily Safra) took a large step toward this, with major international repercussions. Through small electrodes placed at a specific point in the spinal cord of rats and mice with movement disturbances akin to those of Parkinson’s patients, the scientists electrically stimulated the dorsal part of the animals’ spinal cord and restored their normal locomotion capabilities. “The rodents responded to the electrical stimulation almost immediately”, says Nicolelis. This surgery takes only 20 minutes and is safe. One need only open the skin and place the electrodes on the spinal cord’s surface.
This is the first potential therapy for Parkinson’s that does not act on the brain – where the disease originates, due to the death or poor functioning of the neurons that produce dopamine, an indispensable neurotransmitter for full control of movement – but at another point of the nervous system. The promising results of the study with rodents were reported in an article that made the cover of the March 20 issue of Science, one of the most prestigious international scientific journals. Nicolelis believes that the new approach may be a good alternative for deep brain stimulation. “DBS is a form of surgery that involves a certain amount of risk and that only helps some patients, the most serious cases”, comment the neuroscientist. “Our procedure is far simpler and might help people at any stage of the disease.”
ScienceMarch 20 Science: Brazilian’s study on the coverScience
The research must go through several stages before the new procedure can be tested in Parkinson’s patients. This year, studies with two types of primates (marmosets at the Natal institute and rhesus monkeys at Duke University) should begin. If these tests also confirm the almost immediate benefits of the new approach, Nicolelis’s team expects to turn to clinical studies on humans in one year’s time.
There is no cure for Parkinson’s, a progressive neurological disease whose most frequent victims are people over the age of 65. Estimates indicate that one percent of the world population in this age group, or some 200 thousand people in Brazil, suffer from this condition, clinically characterized by tremors, muscular rigidity, slowness of movement, and speech and writing impediments. The disease may also compromise intellectual capacity at different levels, from a slight cognitive decline to dementia. The current treatments are designed to diminish Parkinson’s symptoms and to improve patient’s quality of life. “The cause of most Parkinson’s cases is still unknown”, comments neuroscientist Koichi Sameshima, from the Medical School of the University of São Paulo (FMUSP). “Nicolelis’s chief contribution is not only to introduce therapy that provides an alternative to DBS, but eventually to produce knowledge that may help us understand Parkinson’s. The study takes the body as a whole into account and indicates that Parkinson’s may be a systemic problem.”
Parkinson and epilepsy
The heterodox approach proposed by Nicolelis’s team suggests that one can explore the multiple connections between the central nervous system and the peripheral nervous system in the search for safer and more efficient treatments for certain neurological conditions. In other words, one can electrically stimulate one element of the nervous circuitry (in this case, the spinal cord) and produce results in the brain, another part of the system. According to this rationale, it would be unnecessary to forcibly interfere in the system area where the neuronal problem originates . Perhaps one can fight a condition such as Parkinson’s, whose origin lies in the brain, by gaining access to other nervous circuitry pathways, as the experiment with the rodents would seem to indicate.
The idea of testing electrical stimulation of the spinal cord to treat Parkinson’s disease arose after Nicolelis noticed, a few years ago, that the procedure alleviated epilepsy crises. To some degree, the situation of a patient with advanced Parkinson’s is comparable to that of a permanent epileptic, says the neuroscientist. In both cases, the motor neurons emit signals in a synchronized manner, creating an electrical dysfunction that impairs movement control. In epilepsy, the synchronicity of the emissions is occasional, happening only during crises. In advanced Parkinson’s, it is permanent and its severity tends to increase over time. Electrical stimulation of the nervous fibers in the spinal cord seems to break down the rhythm of the signal emissions, reestablishing a healthy lack of synchronicity in the neurons’ electrical activity. Thus, the brain once again becomes the ruler of motor capabilities. “We surmised there was a connection between the two fields of study, epilepsy and Parkinson’s, which nobody had considered before”, says the Chilean neuroscientist Romulo Fuentes, another one of the authors of the Science article.
The experiments with mice and rats were carried out by Fuentes, who is now completing his post-doctoral studies at Duke University and who is to move to Natal by the end of the year, where he will teach at the Federal University of Rio Grande do Norte (UFRN) and continue his research at the neurosciences institute in that city. After he induced in the animals a state akin to advanced Parkinson’s, characterized by muscular rigidity and difficulties of movement due to diminished dopamine production, Fuentes observed the effects of the low electrical stimulation upon the animals’ spinal cords. The device with electrodes is the size of a finger nail and is as thin as a sheet of paper, although it is made out of metal. In the tests, electrical stimulation using a 300 hertz frequency combined with small doses of drugs that induce dopamine production is what yielded the best results, “The procedure involving the spinal cord would allow patients to use far lower doses of medication to diminish the disease’s symptoms”, comments Nicolelis. “Thus, the person will take far longer to acquire resistance to the medication”. The therapy’s effects are virtually immediate. As soon as electrical stimulation is switched on, the rodents resume their mobility.
There are many questions yet to be answered about this new therapeutic approach, although these obscure points are not exclusive to spinal cord stimulation. To date, the mechanisms underlying the beneficial effects of DBS itself are not entirely understood, although this surgical procedure has been used for years. “Our method works”, comments Fuentes. “And when I get to Natal, I’ll focus on understanding why it works.” However, some researchers are still reticent about the human application prospects of the treatment tested on rodents. They argue that mice and rats are not a good clinical model of what Parkinson’s is and are saving their optimism for if and when the alternative therapy achieves the same results with monkeys. Like man, primates have a more sophisticated nervous system and suffer naturally from neuro-degenerative conditions, whereas in rodents Parkinson’s symptoms are artificially triggered.
nih/Edwin Hartley Pratt and Frederick WilliamsNeurosurgeon Manoel Jacobsen Teixeira, from FMUSP, is one of the researchers that regards with caution the use of electrical stimulation on the spinal cord to treat Parkinson’s. “Let’s wait for the early results of the study with primates first”, he says. “The animal model using rodents has little to do with humans”. The neurosurgeon’s skepticism is also based on another finding. According to him, electrical stimulation of the spinal cord has already been tested in connection with other types of movement disturbance, called dystonias (a group of illnesses characterized by involuntary muscle spasms), with poor results. “Since the 1970’s, we have used electrical stimulation of the spinal cord only to treat pain of neuropathic origin and to diminish the discomfort brought on by the amputation of limbs”, says the neurosurgeon. The electrical stimulation current used for pain is around the 100 hertz (in the Parkinson’s rodents, 300 hertz produced the best results).
Jacobsen’s critical posture is strictly technical. He has nothing against the Duke team. To the contrary, the neurosurgeon, who also works at the Sírio-Libanês Hospital, in São Paulo, has partnered Nicolelis in several studies. Although he questions the potential use of this new therapeutic approach against Parkinson’s for the time being, Jacobsen is prepared to test it on patients if the experiment with primates is successful. In Brazil, the efficacy of electrical stimulation of the spinal cord may be submitted to a trial on ten people with the neurodegenerative disease.
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