The use of brain stimulation as a therapeutic option for patients with certain disorders, like Parkinsons disease and depression, has been well appreciated for some time. Today, however, those modalities have limited reach and accuracy. Noninvasive modalities are limited to stimulating brain tissue at the surface (such as TMS, tDCS, and tACS), whereas deep brain stimulation (DBS) requires surgical implantation.
A team of researchers from the University of Geneva, ETH Zurich, the Wyss Center, and EPFL has taken an intermediate step with a study they propose may overcome these limitations.
This technique, known as temporal interference stimulation (TIS), uses the interaction of two high-frequency electric fields delivered through scalp electrodes. Neurons do not directly respond to these high frequencies, but respond to the slower ‘beat’ frequency that results from the overlap in such signals. In theory, this mechanism would allow specific targeting of deeper brain regions without overstimulating overlying tissues.
The overall off-target effects of TIS on the brain had, to date, not been systematically characterized. To probe this, the team used a combination of electrophysiology, calcium imaging, functional MRI, and stimulation of the medial prefrontal cortex in mice.
White matter affects how people respond to brain stimulation therapy
Valerio Zerbi, a researcher involved in the project, explained: “Thanks to functional MRI, we were able to visualize all the activated regions and quantify the off‑target effects.”
The outcomes showed that TIS shapes functioning at the target site but also enables unauthorized activations in other areas.
For greater specificity, the scientists integrated a third electrode pair configured to block interference from areas outside 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,” Zerbi said.
This breakthrough may be a key to medications for such psychiatric and neurological disorders. Eventually, with the capability to silence nonphysiological signals, TIS may also permit clinicians to noninvasively activate small, deep sources widely regarded as critical circuitry for mood disorders, including depression and OCD; addiction; or even tremor effects in Parkinson’s disease without any surgical intervention.
However, the researchers caution that TIS is still not a substitute for deep brain stimulation but instead a supplementary technique.
“Understanding and managing to limit the off‑target effects of TIS was an essential step before considering broader clinical applications,” Zerbi concluded.
At the same time, the Geneva team’s results mark an important step towards precision noninvasive brain stimulation, a clinically interesting field that investigators have previously struggled with due to technical challenges. They believe these restrictions are about to change.
Journal Reference:
- Iurii Savvateev, Florian Missey, Valeriia Beliava, Sofia Peressotti et al. Multipair phase-modulated temporal interference electrical stimulation combined with fMRI. Cell Systems. DOI: 10.1016/j.cels.2026.101610
