Summary: For years, the hippocampus—the brain’s engine for memory and emotion—was considered “out of reach” for noninvasive treatments because it sits so deep in the skull. To influence it, doctors usually needed surgery or drugs. However, neuroscientists have achieved a world-first: using Transcranial Magnetic Stimulation (TMS) on the brain’s surface to precisely modulate the deep hippocampus.
The study proves that by mapping a patient’s unique brain “highways” (connectivity) via fMRI, doctors can find a specific spot on the cortex that acts as a remote control for the deep brain.
Key Facts
- The “Remote Control” Effect: TMS uses magnetic pulses on the scalp. The researchers found that stimulating specific areas of the outer cortex can “send” a signal deep into the hippocampus if those two areas are functionally connected.
- Personalization is Power: The study found that stimulation only worked robustly when the site was tailored to the individual’s unique brain map. When a “one-size-fits-all” spot was used, the deep brain barely responded.
- Rare Clinical Proof: The team verified their results using eight neurosurgical patients who already had internal electrodes. This allowed them to “zap” from the outside and immediately “listen” from the inside.
- Large-Scale Validation: They confirmed the theory in 79 healthy participants, showing that the stronger the “highway” (connectivity) between the surface spot and the deep spot, the better the treatment worked.
- Clinical Future: This paves the way for non-surgical treatments for Alzheimer’s, depression, PTSD, and anxiety by repairing deep-brain circuits without a single incision.
Source: University of Iowa
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.
Funding: 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.
Key Questions Answered:
A: It doesn’t reach it directly. Think of it like a subway system. You can’t reach the deepest station from the street, but if you find the right entrance (a connected spot on the cortex), the signal travels down the “tracks” (neural pathways) right to the platform (the hippocampus).
A: Everyone’s “brain map” is as unique as a fingerprint. In the study, when they used a generic spot, the “signal” got lost. It was only when they used fMRI to find each person’s specific “entrance” that the deep brain actually responded.
A: Not quite. This is a tool for neuromodulation, which means “tuning” the brain’s activity. For someone with PTSD or depression, the hippocampus might be hyperactive or sluggish. This tech allows doctors to “re-tune” those circuits back to a healthy frequency without surgery.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurotech research news
Author: Jennifer Brown
Source: University of Iowa
Contact: Jennifer Brown – University of Iowa
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Multimodal evidence for hippocampal engagement and modulation by functional connectivity-guided parietal TMS” by Zhuoran Li, Nicholas T. Trapp, Joel Bruss, Xianqing Liu, Kang Wu, Ziyan Chen, Amit Etkin, Matthew A. Howard, Aaron D. Boes & Jing Jiang. Nature Communications
DOI:10.1038/s41467-026-70346-x
Abstract
Multimodal evidence for hippocampal engagement and modulation by functional connectivity-guided parietal TMS
Hippocampal activity supports memory and many other brain functions. Transcranial magnetic stimulation (TMS) guided by hippocampal functional connectivity (FC) shows promise in improving memory, but direct neural evidence of its capacity to engage and modulate hippocampal activity is lacking.
Here we combined TMS with intracranial electroencephalography (iEEG) in 8 neurosurgical patients and with functional magnetic resonance imaging (fMRI) in 79 neurologically healthy participants.
We identified that (1) single-pulse TMS to individualized parietal cortex guided by hippocampal-FC preferentially evoked distinct temporal and spectral activity patterns in the hippocampus, (2) variability in TMS-evoked hippocampal responses related to individual differences in parietal-hippocampus FC strength, and (3) repetitive TMS to hippocampal-FC-guided parietal cortex selectively suppressed hippocampal theta oscillations.
These findings provide multimodal causal neural evidence and important mechanistic insights supporting the development of personalized neuromodulation strategies aimed at improving hippocampus-dependent functions.
