Fundamentals of selective ultrasonic brain stimulation

Abstract

Ultrasonic brain stimulation is well recognized as an encouraging method for probing brain function and treating brain disorders with the advantages of non-invasiveness, fine spatial control, and deeper tissue penetration. The focal spot can be steered dynamically in brain wide with high spatiotemporal resolution. Recently, various studies have shown that ultrasound can be utilized to modulate neuronal activity and signaling in animal and human brain effectively without damaging brain tissues. However, the mechanism is unclear. In addition, the minimum focal spot of a low frequency ultrasound beam is still much larger than a single neuron or a specific small set of neurons, so it is difficult to probe the complex neural circuits entangled with interdependent different neurons. The stimulation outcome of current approach is not easy to be predicted and even controversial. Therefore, understand the mechanism of ultrasound brain stimulation and engineering the ability to stimulate a selected subset of neurons is a key issue for precise ultrasound neuro-modulation for future application and translation. Ultrasound is a mechanical wave which can insert various mechanical perturbations onto the tissue. Recently, mechanical perception of the cells has gain momentum with the discovery of various mechanosensitive ion channels with wide spectrum of mechanosensing properties. It has been hypothesized that ultrasound could activate mechanosensitive ion channels. It is emergent to test in mammalian cells. In addition, inspired by optogenetics, to achieve targeted ultrasound stimulation, one can rely on altering neuronal sensitivity by inserting artificial ultrasonic sensitive ion channels to chosen neurons. The targeting ability of such ultrasonic sensitivity could be achieved either by genetic approach or biochemical targeting technology. The discovery of the underlying mechanism will make it possible to develop a analogue strategy to optogenetics, for selective neural activation and inhibition in deep brain regions non-invasively. The selectivity of such method relies on altering neuronal ultrasound sensitivity by inserting mechanosensitive proteins which will transduce ultrasonic energy into electrochemical signaling and induce neural activity and subsequent downstream intracellular signaling to chosen neurons using genetic modification method. To achieve, it is emergent to discover the effective ion channels for initiate ultrasound neuron stimulation and obtain solid knowledge about the biophysical mechanism. In addition, toolkits should be validated in vivo and its application should be developed and well-characterized. The present thesis explored the mechanism of ultrasound brain stimulation and the way to develop toolkits for achieving selective ultrasound stimulation in in vivo rodent model. This thesis is a summary of the past three-years exploration in ultrasound brain stimulation. The output of these thesis provides a critical approach for selective brain stimulation with a non-invasive, deep brain targeted and selective stimulation technique, with or without genetic modification and invasive procedure. I also envision that the outcome of this thesis could provide an invaluable tool for screening mechanosensitive proteins as well.