Neuronal UltraSound Stimulation – Understanding and control of the biophysical mechanisms toward applications to sensory handicaps – NeUStim

The only way to artificially induce brain activity has long been electrical stimulation. This technique is well-established for the management of various diseases (Parkinson's disease, pain, epilepsy, treatment of deafness). Electrical stimulation techniques require the placement of subdural electrodes or deep brain electrodes, which involves a certain degree of invasiveness. In the past few years, the emergence of mini- or non-invasive technics has shown encouraging results, with excitations of various origins: electric (tDCS) and magnetic (TMS). These promising techniques opening a new field of investigation on neural dysfunctions are however constrained by various limitations, such as treatment targeting / selectivity, or the access to deep tissues.

Recent experiments have shown the ability of Low Energy UltraSound (LEUS) to affect the activity of neurons from distance without the need for needle insertion. Since 2011, several teams from the University of Arizona, Harvard Medical School, the University of Stanford and Langevin Institute have demonstrated the ability to induce deep stimulation in vivo in the cerebral cortex, diffusely and with low frequency LEUS (0.3-0.6 MHz), despite extended focal zone. In 2013, another team of Stanford University was able to obtain in vitro stimulation of the retina with high-frequency LEUS (40 MHz), which is associated with extremely thin focal spot and high spatial resolution. Biophysical mechanisms involved in these types of neurostimulation remain however unknown. In the 70s and 80s, numerous studies have been conducted, particularly at the University of Moscow, on superficial ultrasound stimulation of the external structures (mechanoreceptors, auditory nerves). These studies have highlighted some ultrasound parameters conducive to the induction of tactile, thermal (hot, cold), or sound sensations. However, no complete description of biophysical mechanisms and their interactions could have been yet validated for understanding these experimental observations.

The use of ultrasound for minimally-invasive deep neurostimulation may represent a revolution is this domain. However, the current knowledge on the biophysical mechanisms involved in LEUS neurostimulation is very limited and block potential transfer to the patient.The NeUStim project (Neuronal UltraSound Stimulation) is a multidisciplinary programme which will be conducted at the Laboratory of Therapeutic Applications of Ultrasound (LabTAU, INSERM U1032), in order to accelerate the emergence of ultrasound neurostimulation, in 2 main phases: 1) improve of our current knowledge on the biophysical mechanisms and validate our hypotheses, 2) highlight ad hoc LEUS parameters for inducing controlled, selective, reproducible and safe neuronal stimulation. Ultimately, the objective is to develop an original extra-dura mater LEUS strategy involving a small cranial LEUS prosthesis (intact dura-mater, no probe insertion in the brain) capable of modulating deep-seated sensory areas from distance, and to consider future clinical applications. The development of LEUS prostheses for brain stimulation could provide an excellent and innovative approach for improving the portability of the systems, freezing the planning of long-term chronical treatments, with extensive consequences expected for the autonomy of a patient (no systemic MRI sessions required for planning of repetitive treatments), and identified applications in the management of chronical neurological disorders (e.g. motor, pain, audition, visual).

For achieving these challenges, a new team (the NeUSteam) will be created and dedicated to this programme: it will mainly involve LabTAU’s members with internationally recognized expertise in biomedical ultrasound research and will also beneficiate from clinical external expertise in neurophysiology.