Brain stimulation techniques can correct abnormal activity in the neural circuits involved in conditions such as Parkinson's disease and depression. However, current transcranial stimulation methods delivered through the scalp reach only the brain’s surface, limiting their effectiveness. Deep brain stimulation, on the other hand, can target deeper structures but requires surgical implantation of electrodes. A team from the Synapsy Centre for Neuroscience and Mental Health Research at the University of Geneva (UNIGE), in collaboration with ETH Zurich, the Wyss Center Geneva and EPFL, has succeeded in improving a promising intermediate technology called "temporal interference stimulation". This method could allow deeper and more targeted non-invasive brain stimulation. The study can be found in Cell Systems.
The brain functions thanks to electrochemical signals circulating through vast neural networks. In certain conditions, these rhythms become too weak, too strong or poorly synchronised. Delivering electrical stimulation to specific brain circuits can help restore activity to healthy, functional patterns.
“The principle is not to stimulate the entire brain, but to target a specific network whose activity is disrupted,” explains Valerio Zerbi, assistant professor in the departments of psychiatry and basic neuroscience at the UNIGE Faculty of Medicine, and a member of the Synapsy Centre. “However, some regions essential for movement, memory or emotional regulation are deeply buried in the brain, making them difficult to reach in a non-invasive and precise way.”
A promising but imperfect technique
Current non-invasive techniques, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) or transcranial alternating current stimulation (tACS), mainly affect the superficial layers of the brain. Conversely, deep brain stimulation (DBS) effectively targets deep-seated structures, but at the cost of invasive surgery. Temporal interference stimulation (TIS) represents an emerging alternative capable of reaching deep regions without surgery.
Its principle is based on the interference between two high-frequency electric fields applied from the scalp with a slight frequency offset. When these fields meet in the brain, their frequency difference creates a slower signal to which neurons can respond. “Neurons are not very sensitive to very high frequencies, yet they can detect the interference frequency produced when two such signals interact,” explains Valerio Zerbi. “This interference theoretically allows us to target a deep region without strongly stimulating the tissues through which the signal passes, but the extent of peripheral effects has never really been measured across the entire brain until now.”
Observing effects throughout the brain
To assess off-target effects, the team stimulated a brain region known as the ''medial prefrontal cortex'' in mice. The researchers drew on a combination of electrophysiology, calcium imaging, and functional MRI to capture the effects of TIS at the target site and across the brain as a whole.
“Previous studies showed that a deep region could be stimulated with this technology, but without knowing precisely what was happening elsewhere, we can’t safely apply it to humans,” says Valerio Zerbi. “Thanks to functional MRI, we were able to visualise all the activated regions and quantify the off-target effects.” The results confirm that TIS does indeed modulate neuronal activity in the target region, but also reveal unwanted activations in other circuits.
Towards safer stimulation
To improve the technique’s precision, the researchers decided to add a third pair of electrodes to generate a cancellation electric field. This actively neutralises the electric fields in non-targeted regions, without reducing the effect in the area of interest. “We have introduced a field designed to suppress interference where it is unwanted, whilst maintaining the effectiveness of the desired stimulation,” explains the researcher. This breakthrough addresses one of the main obstacles to TIS and could become essential for targeting small, deep-seated structures involved in psychiatric and neurological disorders such as depression, OCD, addictions or even Parkinson’s disease.
These results do not yet make TIS a direct substitute for deep brain stimulation, but they significantly strengthen its clinical potential. Ultimately, this approach could complement existing therapies, as the aim is not necessarily to replace them, but to have a more precise and complementary non-invasive tool. “Understanding and managing to limit the off-target effects of TIS was an essential step before considering broader clinical applications,” concludes Valerio Zerbi.