Modulation of Neurotransmission by Therapeutic Ultrasound – MONTUS

The field of neurostimulation by low-energy ultrasound (LEUS) is an exciting and fast-growing field for the treatment of neurodegenerative and psychiatric disorders such as epilepsy, Parkinson’s disease, depression, among many others. LEUS is an attractive technology offering the ability to non-invasively target different regions of the brain: a feature that can elevate this technology to rival other competing, clinically-approved technologies for neuromodulation/neurostimulation such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS). However, the biological mechanisms underlying neurostimulation and neurotransmission by LEUS at the cellular and neuronal network level remain poorly understood thus limiting the development and transfer of this technology into the clinic; in addition to preventing proper identification of potential clinical applications.
The general objective of the MONTUS project is to demonstrate and describe the capability of modulating neurotransmitter release by LEUS stimulation in a safe, efficient and controllable manner. For this purpose, I have designed a series of experiments for spatio-temporal characterization of LEUS-induced neurotransmitter secretion in neuronal models of increasing anatomical and physiological complexity. These experiments seek to demonstrate that preferential secretion of specific neurotransmitters can be achieved by targeting focused LEUS to brain regions known to predominantly contain neurons that produce a specific neurotransmitter (i.e. dopamine, glutamate, acetylcholine). The studies included in the MONTUS project will include a variety of in vitro and ex vivo experimentation on neuronal cell cultures and rat hippocampal brain slices, as well as in vivo studies on rat models. Experimental setups for in vitro and ex vivo studies will consist of integrating custom designed LEUS stimulation devices with several techniques and platforms commonly used in neurosciences such as carbon fiber amperometry, calcium fluorescence imaging and microelectrode arrays. Hence, particular attention will be given to studies of calcium transport across cell membranes and neuronal networks resulting from exposure to LEUS since neurotransmitter secretion is a process highly regulated by intracellular calcium dynamics. Likewise, in vivo studies aimed at characterizing the efficacy and immediate tolerance of a LEUS-based treatment for enhancing neurotransmitter release will include microdialysis quantification, amperometry techniques and microPET/CT functional imaging.
The proposed research is interdisciplinary, transversal and translational; and is expected to integrate multiple disciplines and expertise in ultrasound physics, biology, electrophysiology, and neurosciences. The project will involve integration of findings from different experimental setups and perspectives in order to produce a unified model of neurostimulation and signal transmission by LEUS that fits models from individual neurons to complex neuronal networks. To this day, there has been very little research into the signal transmission characteristics of neurostimulation and neuromodulation by LEUS, thus making it a largely unexplored yet crucial area of study. In addition to complementing current knowledge on the biological and biophysical mechanisms regulation neurostimulation by LEUS, the work described in this proposal would reveal potential new targets for the treatment of various psychiatric and neurological diseases. The results and conclusions of the MONTUS project will have a significant impact on the field of energy-based neurostimulation technology while introducing LEUS as a viable strategy for treating disorders characterized by imbalances in neurotransmitter release such as Parkinson’s disease and depression.