Multitarget neurostimulation of the deep brain: clinical opportunities, challenges, and emerging technologies.

Recent computational, pre-clinical, and clinical studies have demonstrated the potential for using neuromodulation through simultaneous targeting of multiple deep brain regions. This approach has already been used by therapeutic and systems neuroscience applications. However, the broad clinical adoption of invasive distributed deep brain interfaces remains in its early stages. This review explores the barriers to implementation by addressing three key questions: Do the benefits of implanting multiple electrodes justify the associated risks for specific applications? What is the risk-benefit ratio, and what technological advancements will be necessary to encourage clinical adoption? We also examine next-generation technologies that could enable distributed brain interfaces, including system-on-chip micro-stimulators as well as nanoparticles. We highlight the role of novel machine learning algorithms in the optimization of stimulation parameters and for the guidance of device placement. Emerging hardware accelerators equipped with on-chip AI have demonstrated functionality that can be used to decode and to classify distributed neuronal data. This advance in hardware accelerators has also contributed to the potential for enhanced closed-loop stimulation control of devices. Despite these advances, significant technological and translational barriers persist, limiting the widespread clinical application of distributed brain interfaces. This review provides a critical analysis of recent prototypes and novel hardware for use in distributed systems. We will discuss both clinical and research applications. We will focus and highlight the utilization of multi-site technologies to meet the needs of neurological diseases. We conclude that there exists a critical need for further innovation and integration of multi-site technologies into clinical practice.