Moran, Mark

doi: 10.1097/01.NT.0000521712.72776.d2

Features

An international group of researchers delivered high frequencies of electrical stimulation through electrodes placed outside the brain of a mouse, to selectively target neurons in the hippocampus without an incision and without affecting the overlying cortex. The method has potential for translation to humans, but as the authors and independent experts report, much more work is needed.

An innovative method of delivering noninvasive deep brain stimulation appears to activate brain areas resulting in motor changes in a mouse model that could, potentially, prove relevant to treatment of Parkinson's disease and other movement and psychiatric disorders in humans, according to a report published in the June 1 issue of Cell.

Using a novel method known as temporal interference, an international group of researchers delivered high frequencies of electrical stimulation through electrodes placed outside the brain, to selectively target neurons in the hippocampus without an incision and without affecting the overlying cortex.

Human application is unlikely very soon, but the report has stirred interest among experts in movement disorders as a possible answer to a problem: how to deliver deep brain stimulation known to be effective in neuropsychiatric disorders without the risks associated with the traditionally invasive procedure.

Traditional deep brain stimulation requires opening the skull and implanting an electrode, which can have complications, and only a small number of people can do this kind of neurosurgery, the senior study author Edward Boyden, PhD, associate professor of biological engineering and brain and cognitive sciences at MIT, told Neurology Today. Our technology could be useful, should human trials prove effective, as a wearable device that could be worn by patients with severe conditions. Conceivably it could help with conditions where occasional stimulationfor instance, for half an hourresults in plasticity that helps relieve symptoms. The strategy could also be useful to researchers in mapping parts of the brain involved with neurological disorders so that better DBS positioning may become possible.

Dr. Boyden is quick to point out the hurdles that must be overcome before the strategy could be employed in humans. We haven't yet done any peer-reviewed studies on the human brain, although we have begun studies, he said. Our technology is not as focal as traditional DBS, and for conditions where stimulation must be constant, a standard implant might be more secure and easier to maintain.

The temporal interference strategy he and colleagues used involves the manipulation of high-frequency electrical currents delivered via electrodes placed outside the mouse scalp. The currents are too fast to drive neurons, but they interfere with one another in such a way that where they intersect, deep in the brain, a small region of low-frequency current is generated inside neurons. This low-frequency current can be used to drive neurons' electrical activity, while the high-frequency current passes through surrounding tissue with no effect.

By tuning the frequency of these currents and changing the location of the electrodes, the researchers can control the location of the brain tissue that receives the low-frequency stimulation. You can go for deep targets and spare the overlying neurons, although the spatial resolution is not yet as good as that of deep brain stimulation, Dr. Boyden said.

Moreover, by shifting the site of stimulation, Dr. Boyden and colleagues could activate different parts of the motor cortex and prompt the mice to move their limbs, ears, or whiskers.

The strategy appears to be safe, based on this study. We found that TI [temporal interference] stimulation at amplitudes sufficient to recruit deep brain structures, such as the hippocampus, did not alter the neuronal and synaptic integrity of the underlying tissue 24 hours after stimulation, Dr. Boyden and colleagues wrote. Additional time points other than 24-hours post stimulation may provide in the future a more detailed picture of the safety of TI stimulation.

Commenting on the report, Michele Tagliati, MD, FAAN, director of the Movement Disorders Program at Cedars Sinai, Los Angeles, said: This is extremely exciting. The practice of brain stimulation is limited by one fundamental problem you have to stick a wire electrode in the brain. That is a limitation to the willingness of physicians to recommend the surgery and of patients to undergo it.

Finding a noninvasive way to stimulate the brain has been a holy grail in this field, Dr. Tagliati said. In my opinion, this is a credible strategy that can really advance the field by providing something that we have been trying to do for a long time noninvasive stimulation of key parts of the brain that can benefit patients with movement disorders. There is an enormous amount of work yet to do refining this strategy, and I would not expect to see this in the clinic anytime soon. However, I would not be surprised if it advances to phase 2 safety trials very soon.

Joseph Jankovic, MD FAAN, professor of neurology, Distinguished Chair in Movement Disorders, and director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, was somewhat more circumspect. The study provides a proof of principle that relatively non-invasive electrical stimulation of deep brain structures is feasible, he told Neurology Today. This should be added to a growing list of techniques, such as optogenetic manipulation of neuronal networks, that require a great deal of animal work before it can be applied clinically. While I agree with the authors that the prospects for noninvasive DBS using electricity are potentially exciting, I am very skeptical that it might be rapidly deployable in human clinical trials.

There are many unanswered questions before this technique can be applied for movement disorders, epilepsy or psychiatric disorders, Dr. Jankovic said. One question is whether the electrical stimulation can be delivered continuously in the target nucleus without untoward effects. Another question is related to the method of delivery. Would the patients require wearing a helmet device that would deliver electricity in a way to make the treatment portable?

Finally, I think there are serious safety concerns about the effect of chronic electricity on various brain structures, he said.

Nevertheless, he said, the strategy is a breakthrough. This is an important study conducted by a highly-regarded group of researchers, Dr. Jankovic said. It addresses a hugely unmet need, namely the ability to normalize abnormal brain circuitry in patients with dysfunction in the cortico-striatal-thalamic pathway in patients with Parkinson's disease, dystonia, Tourette syndrome and other hyperkinetic movement disorders, without invading the brain by either implanting stimulating electrodes or creating a lesion via focused ultrasound.

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A Noninvasive Novel Method of Deep Brain Stimulation in Animal Model - LWW Journals