Non‐invasive Neuromodulation Using Ultrasound

The discovery of light sensitive proteins led to the development of optogenetics and allowed the precise manipulation of neuronal and non‐neuronal cells. This technique uses particular wavelengths of light to manipulate both neuronal and non‐neuronal cells [2, 5]. It has enabled the study of information processing in the brain and recent studies are looking into clinical translational applications of the technique [1]. Despite the advantages offered by optegenetics, it has the drawback of being invasive as light does not penetrate skin past a few millimeters. It is not possible to target deep tissue within the body using this technique and this limits the application in the context of diseases such as Parkinson’s [3] or heart malfunction [4]. We are developing devices that can non‐invasively manipulate cells using a technique termed “sonogenetics”. This technique uses a combination of engineering cells to be more sensitive to mechanical stimuli as well as developing ultrasound transducers capable of stimulating cells in freely moving, awake mice. We demonstrate the development of miniature transducers made from non‐hysteretic single crystal lithium niobate to be used for the development of sonogenetics. In addition, we o er mathematical insights to the mechanism of action of ultrasound on neurons. Our analysis of membrane deflection enables us to predict cellular activity based on the applied ultrasound stimulus. By extension, we use this analytical framework to inform the development of transducers and stimulation parameters for achieving non‐invasive stimulation of cells. Support or Funding Information WM Keck Foundation National Institute of HealthMembrane Deflection and Capacitance Change due to Ultrasound a–d) Membrane deflection due to an ultrasound stimulus, with parameters 7 MHz and 1 MPa pressure. The stimulus is provided for 10 ms, the resulting area change(e) and the capacitance (f) are then calculated from the input parameters. The value of capacitance generated in this model is then used in a Hodgkin‐Huxley neuron model to determine action potential generation.a) LN transducer housed in a MMCX coaxial connector designed for long term behavioral studies in awake, freely‐moving mice. b) Device mounted on a mouse skull to be used for characterization using an automated hydrophone setup (c). d)Pressure profile over the transducer face with a 450 mV input results in up to 2 MPa pressures. e) Transducer attached to mouse skull for long term behavioral studies.References [1] Patrick M Boyle , Thomas V Karathanos , and Natalia A Trayanova . “Beauty is a light in the heart”: the transformative potential of optogenetics for clinical applications in cardiovascular medicine ”. In: Trends in cardiovascular medicine 25 . 2 ( 2015 ), pp. 73 – 81 . [2] Karl Deisseroth . “ Optogenetics: 10 years of microbial opsins in neuroscience ”. In: Nature neuro-science 18 . 9 ( 2015 ), p. 1213 . [3] Paul S Larson . “ Deep brain stimulation for movement disorders ”. In: Neurotherapeutics 11 . 3 ( 2014 ), pp. 465 – 474 . [4] Brian D McCauley and Antony F Chu . “ Leadless cardiac pacemakers: the next evolution in pacemaker technology ”. In: Rhode Island Medical Journal 100 . 11 ( 2017 ), pp. 31 – 34 . [5] Wignand WD Muhlhauser et al. “ Optogenetics-Bringing light into the darkness of mammalian signal transduction ”. In: Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1864 . 2 ( 2017 ), pp. 280 – 292 .