Neuroscientists at University of Iowa Health Care have demonstrated for the first time that noninvasive brain stimulation can alter the activity of a critical deep brain region involved in emotion and memory. Moreover, the study shows that personalizing the stimulation site using a patient’s unique brain connectivity pathway can increase the neuromodulation effect.
The study, published recently online in Nature Communications , used innovative, concurrent brain stimulation and recording techniques in people to provide direct human evidence that noninvasive transcranial magnetic stimulation (TMS) can reliably engage and modulate activity in the hippocampus.
The hippocampus is a deep brain region that plays a critical role in multiple brain functions, such as memory and emotion. Problems with hippocampal function have been implicated in several neurological and neuropsychiatric conditions including Alzheimer’s disease, depression, anxiety, and post-traumatic stress disorder (PTSD).
“The idea of manipulating neural activity in the hippocampus to help treat these types of conditions is appealing, but because the hippocampus lies so deep inside the brain, the challenge is how to engage these brain cells without using invasive implants or drugs that are not precisely targeted,” says senior study author Jing Jiang, PhD, UI assistant professor of pediatrics. “These first-of-their-kind findings establish a foundation for a safer, noninvasive, and personalized neuromodulation approach to target hippocampus-dependent functions and could potentially lead to new understanding of and new ways to treat these conditions.”
Personalizing noninvasive brain stimulation
Jiang and her colleagues studied eight neurosurgical patients who had electrodes implants in their hippocampus. This rare clinical situation allowed the researchers to combine noninvasive brain stimulation using TMS with concurrent measurement of immediate activity changes in the hippocampus using the intracranial electroencephalography (iEEG) electrodes.
Rather than stimulating the same brain location in every individual, the researchers were able to tailor the stimulation site based on each person’s unique brain connectivity in four patients. Resting-state functional magnetic resonance imaging (fMRI) was used to trace the unique hippocampal connectivity map in each person’s brain. This information helped identify individualized TMS-accessible sites in the cortex that were most strongly connected to the hippocampus.
The researchers found that stimulating these individualized cortical sites, with either single-pulse TMS, or with repetitive TMS that is widely used in clinical treatment, preferentially elicited evident activity changes in the hippocampus. In the other four patients whose stimulation sites were not personalized with patients’ unique brain connectivity, no robust activity changes were observed in the hippocampus.
These findings were complemented with evidence from a noninvasive experiment that used TMS concurrently with fMRI to measure activity changes in the hippocampus in 79 neurologically healthy participants.
Although personalized sites were not stimulated in these individuals, the researchers still found compelling evidence to support this strategy: variations in the strength of TMS-evoked hippocampal responses related to differences in functional connectivity pattern between the stimulation site and hippocampus. Specifically, the stronger the connectivity between the actual stimulation site and the hippocampus, or the closer the actual stimulation site to the individualized site, the stronger the TMS-evoked hippocampal responses were.
“This connectivity-informed strategy provides more precise targeting and modulation, which improves the effectiveness of stimulation effect, and may even help predict individual responses,” says Jiang who is also an assistant professor of psychiatry and a member of the Iowa Neuroscience Institute. “Personalizing brain stimulation site in this way represents a critical step toward more effective and reliable circuit-based neuromodulation treatments.”
In addition to Jiang, the team included first author Zhuoran Li, and UI researchers Nicholas Trapp, Joel Bruss, Xianqing Li, Kang Wu, Ziyan Chen, Matthew Howard, and Aaron Boes. Amit Etkin at Alto Neuroscience was also part of the team.
The research was funded in part by grants from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, both part of the National Institutes of Health; the Brain and Behavior Research Foundation; Magnus Medical, Inc.; and the Roy J. Carver Charitable Trust.
Nature Communications
Experimental study
People
Multimodal evidence for hippocampal engagement and modulation by functional connectivity-guided parietal TMS
8-Mar-2026
A.E. reports salary and equity from Alto Neuroscience. The remaining authors declare no competing interests.