Bioelectronic medicine: Preclinical insights and clinical advances

The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies. 

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Strategies for precision vagus neuromodulation

Mechanosensitive channels (MSCs) play an important role in how cells transduce mechanical stimuli into electrical or chemical signals, which provides an interventional possibility through the manipulation of ion channel activation using different mechanical stimulation conditions. With good spatial resolution and depth of penetration, ultrasound is often proposed as the tool of choice for such therapeutic applications. Despite the identification of many ion channels as mechanosensitive in recent years, only a limited number of MSCs have been reported to be activated by ultrasound with substantial evidence. Furthermore, although many therapeutic implications using ultrasound have been explored, few offered insights into the molecular basis and the biological effects induced by ultrasound in relieving pain and accelerate tissue healing. In this review, we examined the literature, in particular studies that provided evidence of cellular responses to ultrasound, with and without the target ion channels. The ultrasound activation conditions were then summarized for these ion channels, and these conditions were related to their mode of activation based on the current biological concepts. The overall goal is to bridge the results relating to the activation of MSCs that is specific for ultrasound with the current knowledge in molecular structure and the available physiological evidence that may have facilitated such phenomena. We discussed how collating the information revealed by available scientific investigations helps in the design of a more effective stimulus device for the proposed translational purposes. Traditionally, studies on the effects of ultrasound have focused largely on its mechanical and physical interaction with the targeted tissue through thermal-based therapies as well as non-thermal mechanisms including ultrasonic cavitation; gas body activation; the direct action of the compressional, tensile and shear stresses; radiation force; and acoustic streaming. However, the current review explores and attempts to establish whether the application of low-intensity ultrasound may be associated with the activation of specific MSCs, which in turn triggers relevant cell signaling as its molecular mechanism in achieving the desired therapeutic effects. Non-invasive brain stimulation has recently become an area of intense research interest for rehabilitation, and the implication of low-intensity ultrasound is particularly critical given the need to minimize heat generation to preserve tissue integrity for such applications. 

Activation of Mechanosensitive Ion Channels by Ultrasound.

Hybrid Ultrasound-Activated Nanoparticles Based on Graphene Quantum Dots for Cancer Treatment.

Precise and on‐demand release of sufficient hydrogen (H2) to tumor sites remains a key challenge for emerging H2‐oncotherapy, and little is known about the physiological effects of “abundant” H2 on complex tumor microenvironments (TME). Here, a highly efficient and cost‐effective imaging‐guided/‐assessed H2‐therapy of tumors based on a joint electrochemo‐sonodynamic treatment (H2‐EC/SD co‐therapy) with strong “domino effect” triggered by endogenous H2 generation at tumor sites is reported to speedily eliminate tumor tissue (≤80 mm3) within 1 day. Adequate H2 is controllably generated in tumor sites through mild electrochemistry in vivo due to acidic TME by using clinical acupuncture Fe needles as electrodes. Besides starvation damage due to gas blockage/destruction of vessels, nano‐/micro‐bubbles of H2 formed in situ can elevate the tumor's internal temperature and burst vessels to further destroy the tumor under ultrasound irradiation. Remarkably, vulnerable homeostasis of TME is disturbed as H2 also participates in the physiological activity of tumor cells, leading to tumor dysfunction. Last but not least, the body's inflammatory response to cancer is reduced after the treatment, which is beneficial for the body's immune system during post‐treatment recovery. Based on all of these merits, the H2‐EC/SD co‐therapy provides a potentially safe and viable therapeutic strategy for future clinical applications.

Imaging Guided Endogenic H2‐Augmented Electrochemo‐Sonodynamic Domino Co‐therapy of Tumor in Vivo

Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine

Multiple types of memory guide attention: Both long-term memory (LTM) and working memory (WM) effectively guide visual search. Furthermore, both types of memories can capture attention automatically, even when detrimental to performance. It is less clear, however, how LTM and WM cooperate or compete to guide attention in the same task. In a series of behavioral experiments, we show that LTM and WM reliably cooperate to guide attention: Visual search is faster when both memories cue attention to the same spatial location (relative to when only one memory can guide attention). LTM and WM competed to guide attention in more limited circumstances: Competition only occurred when these memories were in different dimensions - particularly when participants searched for a shape and held an accessory color in mind. Finally, we found no evidence for asymmetry in either cooperation or competition: There was no evidence that WM helped (or hindered) LTM-guided search more than the other way around. This lack of asymmetry was found despite differences in LTM-guided and WM-guided search overall, and differences in how two LTMs and two WMs compete or cooperate with each other to guide attention. This work suggests that, even if only one memory is currently task-relevant, WM and LTM can cooperate to guide attention; they can also compete when distracting features are salient enough. This work elucidates interactions between WM and LTM during attentional guidance, adding to the literature on costs and benefits to attention from multiple active memories. 

Long-term memory and working memory compete and cooperate to guide attention.

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Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine

Long-term memory and working memory compete and cooperate to guide attention.