Washington, D.C. - Nir Grossman is the 2018 grand prize winner of the Science & PINS Prize for Neuromodulation, for his research on a new strategy to stimulate deep and specific regions of the brain without surgery. His approach, described in his essay "Modulation without surgical intervention," may someday benefit patients with brain disorders for whom first- and second-line interventions, such as talk therapy or drugs, are ineffective.
"By pioneering new tools and principles, we hope to potentially thwart disease pathology via direct and non-invasive modulation of the underlying neural activity," said Grossman.
Brain disorders like dementia, Parkinson's disease, obsessive-compulsive disorder (OCD), and depression, to name a few, comprise an epidemic, accounting for approximately 30% of the global burden of disease. The majority of patients with brain disorders do not respond to treatment by first- and second-line interventions, highlighting the urgent need for alternate therapies that approach these disorders differently than common interventions like drugs.
Recent technological advances have given rise to therapies of brain disorders that utilize neural stimulation, whereby specific neurological sites are activated with electrical stimulation or chemical agents. Deep brain stimulation (DBS) has proven highly effective in treating Parkinson's disease and OCD and shows potential for treating conditions like depression.
However, DBS requires surgery to implant the neuron-stimulating electrodes, raising the risk of complications and limiting the potential for its use. "Other brain regions that are viable targets for brain disorders have not been tested using implantable electrodes due to the risk of the procedure," said Grossman.
To address the challenge of deep neurological stimulation without surgery, Grossman and colleagues at Massachusetts Institute of Technology developed a strategy that only requires electrodes be placed on - not in - the scalp. Temporal interference (TI), as the method is called, involves applying multiple electric fields of different frequencies at once - the overlapping of which "sculpts" a combined field so that it can be targeted to specific brain regions at depth.
"Realizing, as musicians do, that the sum of two unequal waves produces a third signal, Grossman leveraged electromagnetism to enable focused targeting of a brain region without having to physically reach that spot in the brain," said senior science editor Dr. Pamela Hines.
"We apply two (or more) high-frequency electrical currents to the brain using these electrodes," explained Grossman. "By themselves, the changing electrical currents are too rapid to recruit neural activity, but at the small regions where the currents intersect, the amplitude [or wave height], of their combined currents changes at a low frequency that is capable of stimulating neural activity."
Other non-surgical brain stimulation methods are already in human clinical trials, but what's different about Grossman's TI approach is the capacity to stimulate deep neurons at selected areas without simultaneously activating neighboring or overlying regions. This can be done because, in contrast to traditional electrical stimulation, the location of activation depends on the relative amplitude and orientation - rather than the total amplitude - of the applied currents.
"By tuning the location of the electrodes and the relative amplitude of the applied currents, the size and location of the brain tissue that receives the low-frequency stimulation can be controlled," said Grossman. "This allows us to target the activation to deep locations within the brain remotely from the electrodes without affecting any of the surrounding brain structures."
In his award-winning essay, which will be published in the 3 August issue of Science, Grossman and his colleagues describe testing their TI method on mouse models. They applied TI on the hippocampi of anesthetized mice and measured their brain activation by staining for the expression of c-fos, a marker of neuronal activity that is often expressed when neurons fire. They found that TI resulted in elevated c-fos expression in the targeted structure - the hippocampus, which is located in the deep inner recesses of the brain. In comparison, transcranial stimulation without TI activated both the hippocampus and the surrounding cortex.
To literally "see" the effects of TI specificity, Grossman and his team demonstrated how TI stimulation of the forelimb-controlling region of the mouse's motor cortex evoked movement of the limb. Importantly, the researchers did not have to move the electrodes for this stimulation experiment. "The location of stimulation can be steered, by altering the ratio between the overlapping currents, without physically moving the electrodes," said Grossman.
"This approach opens the door to regulating disordered brain activity in diverse regions of the brain," said Dr. Hines. "Grossman's innovative and noninvasive technology holds tremendous promise for treating brain disorders."
However, TI is still, in some ways, a phenomenon. For the future, Grossman and his team hope to better clarify the concepts behind TI. He also seeks to investigate whether TI stimulation can work for higher frequencies and stronger electric fields, and whether it's possible to pinpoint smaller regions of the brain using a larger number of interfering fields.
Currently, TI does not have the spatial resolution of implantable DBS. That said, noted Grossman, some brain regions not targeted by DBS - due to the high risk of implanting electrodes at those locations - can potentially be targeted using the specificity of TI. As well, by placing the electrodes on the surface of the brain, not within it, the resolution and strength of the TI stimulation at depth can be improved significantly. Such a minimally invasive method is critical for diseases like Parkinson's that require continuous brain stimulation.
"Our aim is to further develop TI stimulation to achieve better focality at depth, while working with expert labs around the world to translate it to clinical research which can eventually lead to new treatments for brain disorders," said Grossman. "It is clear that this is only the beginning of a potential long journey that requires a close collaboration between the world's best engineers and clinicians to succeed."
Established in 2016, the Science & PINS Prize for Neuromodulation is a highly competitive prize which honors scientists for their excellent contributions to neuromodulation research - awarded annually for outstanding research as described in a 1,500 word essay based on research performed in the past three years. The winner is awarded $25,000 and publication of his or her essay in Science. The award will be announced and presented at a ceremony in September 2018. PINS will provide financial support to allow the grand prize winner and finalist to attend the ceremony.
Grossman and finalist Aryn Gittis will be recognized at a prize ceremony at the Huabei Hotel in Beijing on 8 September, during the 9th Annual Meeting of the Chinese Neuromodulation Society, where they will each present their prize-winning research.
2018 Grand Prize Winner
Nir Grossman, for his essay "Modulation without surgical intervention." Grossman received a B.Sc. in physics from the Israeli Institute of Technology (Technion), an M.Sc. in electromagnetic engineering from the Technical University of Hamburg-Harburg, and a Ph.D. in neuroscience from Imperial College London. He then completed a postdoc training at the Massachusetts Institute of Technology (MIT) and Harvard University. Grossman is now an assistant professor at Imperial College London and a fellow of the UK Dementia Research Institute. The long-term goal of his research is to develop neuromodulatory interventions for brain disorders by direct control of the aberrant neural activity.
Finalist Aryn Gittis, for her essay " Genetic road maps pave the way to repair basal ganglia function in Parkinson's disease." Gittis received undergraduate degrees from Brandeis University and a Ph.D. from the University of California, San Diego. After completing her postdoctoral fellowship at the Gladstone Institute of Neurological Disease-University of California, San Franciso, Gittis started her lab in the Department of Biological Sciences at Carnegie Mellon University in 2012. Her research uses mouse models of Parkinson's disease combined with electrophysiology and optogenetics to understand the cellular basis of motor dysfunction and to develop novel strategies for intervention.
For the full text of finalist essays and for information about applying for next year's awards, see the Science Web site at http://www.
Beijing PINS Medical Equipment Co. Ltd. was established in 2008 and is located in Changpin Garden, Zhongguancun Science and Technology Park, Beijing, China. As an innovative high-tech enterprise with focus on neuromodulation, a variety of clinical products have been developed to date, which include stimulators for deep brain, vagus nerve, spinal cord and sacral nerve stimulation therapies. PINS Medical devotes itself to providing cutting edge treatments for patients who suffer from neurological disorders such as Parkinson's disease, epilepsy, chronic pain and uroclepsia.
As part of the "National Engineering Laboratory for neuromodulation", PINS Medical works in close cooperation with Tsinghua University and the numerous affiliated clinical centers, becoming a center of attraction for a wide range of professional talents in areas of clinical research, innovative R&D and business management. Since 2008, PINS Medical has developed rapidly in becoming a leading brand in neuromodulation within the Chinese market, due to the success of its creative research platform that efficiency links basic research, R&D of novel products, clinical testing and market entry. With an outstanding reputation as a high-tech healthcare corporation, PINS Medical has a primary mission for providing innovative, high-quality products and services for patients to improve quality of life.
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