In response to the BRAIN initiative RFA-NS-17-003 ?New Technologies and Novel Approaches for Large-Scale Recording and Modulation in the Nervous System (U01)?, in this project we aim at accomplishing selective stimulation and recordings at ultra-high cellular level spatial resolution of distinct axonal bundles with different orientations during deep brain stimulation (DBS). This goal will be accomplished by utilizing high density multielectrode arrays with 1250 independent electrodes/mm2 for large scale stimulation and electrophysiological recording of neuronal populations. The fundamentally novel stimulation paradigms will revolutionize neuromodulation strategies by implementing amplitude modulated waveforms delivered to each channel independently and with different phases among channels. Our novel DBS system can be configured not only to generate unidirectional fields for orientation-selective stimulation, but also to produce rotating electrical field gradients for modulation of neuronal activity regardless of axon orientations. The latter concept is entitled here rotating field phase steering (RFPS). Our main objective is to establish proof-of- concept of our new electrode design combined with our novel paradigms of stimulation in the rat brain. Our strategy is to manufacture high density microelectrode array and conduct extensive modeling/simulations (Aim 1). Experimental testing will be conducted in both anaesthetized (Aim 2) and awake (Aim 3) rats. We will specifically focus on the rat brain area that is homologous to the human subgenual cingulate cortex (sgACC), a key nucleus associated with depression. Since the sgACC is characterized by a crossroad of several fiber tracts, its stimulation by our novel orientation-selective and rotating DBS paradigms will allow us to test the efficacy of our new DBS concept to activate distinct neuronal pathways. Animal experiments will utilize the new DBS technology in combination with electrophysiological recording, functional MRI (fMRI) and resting state- fMRI (rs-fMRI) for measuring neuronal networks during the novel DBS paradigms. Since MRI is particularly challenging during DBS because of electrode-induced field distortions on the MRI images, another critical innovation of our project relies on the utilization of multi-band sweeping frequency with Fourier transformation (MB-SWIFT) MRI technique which has minimal sensitivity to magnetic susceptibility artifacts originating from implanted electrode even at ultra-high magnetic fields. Because MB-SWIFT is a silent technique, it is optimal for fMRI of awake behaving animals. Using MB-SWIFT, we will conduct rs-fMRI studies of head-fixed behaving animals with implanted stimulation/recording electrodes and chronically implanted RF coils. The immediate impact of this proposal is to form a strong program at the University of Minnesota, Columbia University and A.I. Virtanen Institute (Finland) for investigating our innovative DBS approaches using MRI on animals. The knowledge gained will be critical for addressing the current shortcomings in current DBS technology and advance understanding of DBS mechanisms in humans.

Public Health Relevance

This project aims at developing a completely new concept and technology for deep brain stimulation which relies on orientation-selective and rotating field manipulation of neuronal activity. The system is based on amplitude modulated waveforms with different phases and it operates in conjunction with a high density - cellular resolution multielectrode arrays for generating either unidirectional or rotating electrical fields. The novel neuromodulation system will allow maximal stimulation of selected neuronal populations in tissue based on spatially oriented electric fields. This research will ultimately have large impact and will revolutionize deep brain stimulation as a biomedical research tool as well as a treatment modality.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1)
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Langhals, Nick B
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Slopsema, Julia P; Peña, Edgar; Patriat, Remi et al. (2018) Clinical deep brain stimulation strategies for orientation-selective pathway activation. J Neural Eng 15:056029