Prize-Winning Research Stimulates Deep Brain Without Surgery

Temporal interference stimulating a specific region of the hippocampus (light green) in the mouse brain. | N. GROSSMAN ET. AL., CELL 169 (1 JUNE 2017) © 2017 ELSEVIER INC.

Nir Grossman is the 2018 winner of the Science & PINS Prize for Neuromodulation, for preclinical 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 interventions such as talk therapy or drugs are ineffective.

The Science & PINS Prize for Neuromodulation is bestowed annually for outstanding contributions to neuromodulation research, as described in a 1,500-word essay based upon work performed within the past three years. The winner is awarded $25,000 and publication of his or her essay in Science.

"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, currently an assistant professor at Imperial College London and a fellow of the UK Dementia Research Institute.

Brain disorders like dementia, Parkinson's disease, obsessive-compulsive disorder and depression comprise an epidemic, accounting for approximately 30% of the global burden of disease. The majority of patients with neurological disorders do not respond to traditional treatment, highlighting the urgent need for alternate therapies that approach these disorders differently than common interventions like drugs.

Deep brain stimulation — whereby embedded electrodes deliver electrical pulses to specific neurological sites — has emerged as one such strategy for targeting brain disorders at their source.

Already it has proven highly effective in treating Parkinson's disease, obsessive-compulsive disorder and shows potential for conditions like depression. The surgical requirement to implant the neuron-stimulating electrodes, however, raises the risk of complications and limits the potential of deep brain stimulation.

"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 the scalp. Temporal interference or TI, as the method is called, involves applying multiple electric fields of different frequencies at once — the overlapping of which "sculpts" a combined field that 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 Pamela Hines.

Grossman explained, "By themselves, the changing electrical currents are too rapid to recruit neural activity, but at the small regions where the multiple 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 of the brain without simultaneously activating neighboring or overlying regions.

Nir Grossman | Christina Schröder

"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 mouse models, the researchers were able to target the brain's hippocampus with TI, elevating neuronal activity in the targeted structure located in the deep inner recesses of the brain. In comparison, non-surgical transcranial stimulation using only one current activated the hippocampus as well as the surrounding cortex, Grossman found.

Visually demonstrating the precision of TI stimulation, Grossman's team applied currents on the forelimb-controlling region of the mouse's motor cortex to evoke movement of the corresponding 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 Hines. "Grossman's innovative and noninvasive technology holds tremendous promise for treating brain disorders."

Grossman and his team hope to clarify the concepts behind TI, and to investigate whether TI stimulation can work for higher frequencies and stronger electric fields. He would also like to find out whether it's possible to pinpoint smaller regions of the brain using a larger number of interfering fields.

"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."

The 2018 Finalist for the prize is Carnegie Mellon researcher Aryn Gittis, for her essay "Genetic road maps pave the way to repair basal ganglia function in Parkinson's disease." Gittis' research uses mouse models of Parkinson's disease combined with electrophysiology and optogenetics to understand the cellular basis of motor dysfunction and develop novel strategies for intervention.

Grossman and Gittis will be recognized at a prize ceremony dinner at the Huabei Hotel in Beijing September 8, before the 9th Annual Meeting of the Chinese Neuromodulation Society where they will each present their prize-winning research.

Beijing PINS Medical Equipment Co. Ltd., the prize co-sponsor, was established in 2008 and is located in Beijing. As an innovative high-tech enterprise with focus on neuromodulation, a variety of clinical devices have been developed, including stimulators for deep brain, vagus nerve, spinal cord and sacral nerve stimulation therapies. PINS Medical is dedicated to providing cutting edge treatments for patients who suffer from neurological disorders such as Parkinson's disease, epilepsy, chronic pain and uroclepsia.