Schematic illustration of electrical field interactions designed to increase the focus of prefrontal cortex entrainment in the mouse brain.
Image Credit: © Iurii Savvateev
Scientific Frontline: Extended "At a Glance" Summary: Deep Brain Stimulation Without Surgery
The Core Concept: Temporal interference stimulation (TIS) is an advanced, non-invasive neurotechnology that selectively modulates deep neural networks without requiring surgical implants.
Key Distinction/Mechanism: Unlike transcranial magnetic stimulation (TMS), which cannot reach deep structures, and deep brain stimulation (DBS), which requires invasive surgery, TIS applies two high-frequency electrical fields to the scalp with a slight frequency offset. When these fields intersect deep in the brain, the frequency difference generates a slow signal that neurons detect, while a newly developed cancellation field suppresses unwanted activation in peripheral tissues.
Major Frameworks/Components:
- Temporal interference stimulation (TIS): The fundamental mechanism of intersecting high-frequency electric fields to achieve deep neural entrainment.
- Functional magnetic resonance imaging (fMRI): Utilized to map and quantify whole-brain off-target effects safely.
- Calcium imaging and electrophysiology: Deployed in murine models to measure localized cellular responses within the targeted medial prefrontal cortex.
- Suppression field modeling: An engineered electrical field introduced specifically to inhibit unintended neuronal firing along the signal path.
Branch of Science: Neurobiology, neuro-engineering, and clinical neuroscience.
Future Application: The development of non-invasive therapeutic interventions for severe neurological and psychiatric disorders, specifically conditions like Parkinson's disease and treatment-resistant depression that originate in deep-brain circuitry.
Why It Matters: This advancement bridges a critical gap in neurotherapeutics, successfully isolating deep-brain neuromodulation from the surgical risks of traditional DBS while vastly improving the depth limitations of conventional transcranial methods.
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| Valerio Zerbi, Assistant professor, Department of Psychiatry, Department of Basic Neurosciences, UNIGE. Photo Credit: © Valerio Zerbi |
A study by UNIGE, in collaboration with ETH Zurich, has significantly improved the accuracy of a non-invasive brain stimulation technique, paving the way for its use in the treatment of neurological and psychiatric disorders.
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 the surgical implantation of electrodes. A team from the Synapsy Center 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 for 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 synchronized. 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 Center. “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.”
“We have introduced a field designed to suppress interference where it is unwanted.”
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 visualize 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 they also reveal unwanted activations in other circuits.
Toward 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 neutralizes 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, while 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 provide 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.
Published in journal: Cell Systems
Title: Multipair phase-modulated temporal interference electrical stimulation combined with fMRI
Authors: Iurii Savvateev, Florian Missey, Valeriia Beliaeva, Sofia Peressotti, Marija Markicevic, Diana Kindler, Fabrice Chaudun, Giulia Casarotto, Camilla Bellone, Christian Lüscher, Daniel Razansky, Viktor Jirsa, Adam Williamson, Rafael Polania, and Valerio Zerbi
Source/Credit: Université de Genève
Edited by: Scientific Frontline
Reference Number: ns060826_01
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