Acoustic stimulation device for treatment of depression – DEPAC

Our approach is based on the hypothesis that the repeated application of transcranial ultrasound stimulation (rTUS) could reduce the depressive-like behaviours in animals. Therefore, we propose here to optimize and validate the proof of concept of the rTUS approach in MD by using different animal models of depression. More specifically, DEPAC project proposes the following tasks:
• Development and evaluation of an ultrasound applicator device for brain stimulation for awake and freely behaving animals.
• Optimization and validation of rTUS protocol using 2 different animal models of depression.
• Investigation of underlying mechanisms of rTUS in depression.

In this first part of the project, we determined the ultrasound parameters to achieve optimal brain stimulation in mice. Hence, we were able to define the ultrasound frequency and the acoustic pressure to obtain significant cerebral activation of targeted brain regions.
Also, and with the industrial partner, 2 prototype ultrasound matrix probes have been developed. These probes will stimulate various brain regions (depth, location).

The ultrasound probes developed are currently being characterized. The results will allow us to select the best configuration corresponding to the application before the miniaturization phase of the device for the pre-clinical trials of the following work packages.

The results obtained within WP1 have been selected for an oral presentation during the International Ultrasonics Symposium IEEE IUS last Sept in Las Vegas.

Many neuropsychiatric (e.g., major depression, autism) and neurodegenerative (e.g., Parkinson's disease) disorders are characterized by structural and functional alterations of the brain. In many situations, these cerebral alterations are associated with high drug resistance (e.g., depression) where 50% of patients do not show improvement after treatment: they are non-responders or resistant. In addition, these pathologies do not all have effective and safe treatments. In this context, neurostimulation approaches using electric fields (deep brain stimulation) or magnetic fields (transcranial magnetic stimulation) have been suggested as a therapeutic tool. While pilot studies have shown very promising results, these two methods of neurostimulation have severe limitations. Indeed, deep brain stimulation is an invasive method that requires intrusive procedures such as surgical implantation of electrodes thus limiting its application in humans. On the other hand, magnetic stimulation does not allow the stimulation of deep brain structures since it has a limited focusing capability and lacks brain penetration power and hence it is limited to superficial areas only.
Recent studies carried out within the research unit Inserm Tours have shown that transcranial ultrasound application on the brain can induce noninvasive modifications of cerebral electrical activity in small animals. Indeed, a prototype allowing transcranial ultrasound stimulation in anesthetized mice has been developed. Specific ultrasound sequences were generated by a single element transducer and allowed the application of the waves to different brain regions. Acute ultrasound application of the motor cortex induced neuronal activation resulting in the contraction of skeletal muscles located in various parts of the rodent's body (e.g., tail, paws, whiskers). More interestingly, the repeated application of these stimulations on the medial prefrontal cortex of the mouse has made it possible to counteract the anxious behavior triggered by chronic stress. Although the stimulations are not focused and not optimized, these preliminary results are very encouraging and allow to consider new therapeutic opportunities of psychiatric or neurodegenerative diseases using ultrasound stimulation.
This project, which brings together two public partners and one industrial partner, aims to optimize and validate the proof of concept of the ultrasound neurostimulation approach in different animal models of depression. More specifically, the objectives of the DEPAC project are: (i) development and evaluation of an ultrasound probe and device for brain stimulation of awake behaving small animals; (ii) optimizing and validating the effects of the repeated neurostimulation protocol using different animal models of depression and (iii) finally exploring the mechanisms underlying the therapeutic effects of repeated ultrasound neurostimulation in the animal model of depression.