Healing neurological disorders with ultrasound

When therapeutic drugs are inefficient, modulating the neural activity is one of the main alternative for treating neurological disorders. While existing techniques are invasive and inaccurate, researchers of the laboratory Physics for Medicine Paris (Inserm, ESPCI Paris, PSL University, CNRS), in collaboration with teams of the University of Oxford and the Institute of the Brain and the Spinal Cord (Inserm, CNRS), propose a non-invasive solution based on ultrasound waves. They demonstrate the potential of using ultrasound through the skull bone for modulating the neural activity in a series of three articles, recently published in prestigious journals in neurosciences (eLife, Neuron and Nature Neurosciences).

Neuromodulation (modulation of the neural activity) is a major tool in neurosciences and medicine for treating neurological disorders such as Parkinson disease, essential tremors or drug-resistant depressions. The standard method, although extremely invasive, consists in implanting an electrode to electrically stimulate the targeted region, usually located at depth in the brain. Non-invasive alternative use external magnetic coils (transcranial magnetic stimulation) or external electrodes (transcranial electric stimulation), but these two methods are limited to the treatment of superficial brain regions and have a low spatial resolution.

In this respect, ultrasound are an ideal solution: focused ultrasound are capable of neuromodulating both superficial and deep brain regions, with a millimeter resolution and in a totally non-invasive manner. Research teams of the University of Oxford, the laboratory Physics for Medicine Paris, and the Institute of the Brain and the Spinal Cord, have obtained key results establishing the feasibility of using transcranial focused ultrasound for neuromodulation.

First, the researchers have applied repeated transcranial ultrasonic stimulation (rTUS) during 40 seconds in a primate, and monitored its brain activity using magnetic resonance imaging (MRI). The brain activity remain modified for several hours after the ultrasonic stimulation (Verhagen et al., eLife, Feb 2019).

Besides, the three same research teams have demonstrated that modification of the activity was feasible not only in superficial layers of the brain but also in deep regions (Folloni et al., Neuron, March 2019), extending the potential use of ultrasound neuromodulation to the whole brain.

Finally, they went a step further by modifying over a long period of time the decision making ability of monkeys trained to perform complex tasks (Fouragnan et al., Nature Neuroscience, April 2019). More precisely, ultrasound targeted to the cingular cortex altered the animals ability to make counterfactual choices, i.e. choices that are not based on facts but rather on hypothetical situations. Imagining what you would do if you won the lottery is an example of counterfactual thinking: you are making choices between different possible used of a money that you haven’t earn yet.

These non-invasively prolonged modifications of the brain activity open new possibilities for the management of neurological disorders. Although this harmless neuromodulation is temporary, with , effects disappearing after a few hours, it would eventually facilitate the brain plasticity, i.e. the ability of the brain to remodel its connections adequately to the environment, individual experiences or in response to a disease.

• Verhagen L, Gallea C, Folloni D, Constans C, Jensen DEA, Ahnine H, Roumazeilles L, Santin M, Ahmed B, Lehericy S, Klein-Flügge MC, Krug K, Mars RB, Rushworth MFS, Pouget P, Aubry JF, Sallet J. Offline impact of transcranial focused ultrasound on cortical activation in primates. Elife (2019) 8:e40541. https://doi.org/10.7554/eLife.40541
• Folloni D, Verhagen L, Mars RB, Fouragnan E, Constans C, Aubry JF, Rushworth MFS, Sallet J. Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation. Neuron (2019) https://doi.org/10.1016/j.neuron.2019.01.019
• Fouragnan E, Chau BKH, Folloni D, Kolling N, Verhagen L, Klein-Függe M, Tankelevitch L, Papageorgiou GK, Aubry JF, Sallet J, Rushworth MFS. The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change. Nature Neuroscience (2019) https://doi.org/10.1038/s41593-019-0375-6