Summary: For decades the hippocampus — a deep brain region essential for memory and emotion — was regarded as inaccessible to noninvasive treatments because of its depth beneath the skull. Influencing it typically required surgery or systemic drugs. For the first time, researchers have shown that Transcranial Magnetic Stimulation (TMS) applied to the brain’s surface can reliably modulate hippocampal activity when the stimulation site is selected using individualized brain connectivity maps.
The study demonstrates that mapping each patient’s unique functional connections with fMRI reveals cortical “control points” that act like remote controls for the deep hippocampus. Stimulating these personalized cortical locations produces measurable and consistent changes in hippocampal activity.
Key Facts
- Remote-control mechanism: TMS delivers magnetic pulses at the scalp. When those pulses target a cortical area that is functionally connected to the hippocampus, the induced signal travels along that network and engages the deep structure.
- Personalization is essential: The effect was strong only when the stimulation site was chosen based on each person’s hippocampal connectivity. A generic, one-size-fits-all cortical target produced little hippocampal response.
- Rare clinical validation: The team confirmed the effect in eight neurosurgical patients who already had intracranial electrodes, enabling simultaneous external stimulation and internal recording of hippocampal activity.
- Population-level support: In 79 neurologically healthy participants, TMS combined with fMRI showed that the stronger the functional connectivity between the surface site and the hippocampus — or the closer the site was to the individualized target — the greater the hippocampal response.
- Clinical potential: These results support the development of noninvasive, personalized neuromodulation therapies aimed at conditions linked to hippocampal dysfunction, such as Alzheimer’s disease, depression, PTSD, and anxiety.
Source: University of Iowa
Overview
Neuroscientists at University of Iowa Health Care provide the first direct human evidence that noninvasive TMS can engage and modify activity in the hippocampus when stimulation is guided by individual connectivity maps. The research shows that tailoring stimulation sites to each person’s brain network strengthens the neuromodulation effect and supports more precise, circuit-targeted interventions.
The study, published online in Nature Communications, combined novel methods that allow concurrent stimulation and measurement of the brain in humans. By pairing TMS with intracranial electroencephalography (iEEG) in neurosurgical patients and with functional MRI in healthy volunteers, the authors produced convergent multimodal evidence that connectivity-guided cortical TMS engages hippocampal activity.
The hippocampus supports memory formation, navigation, and emotional regulation. Dysfunction in hippocampal circuits is linked to disorders such as Alzheimer’s disease, depression, anxiety, and post-traumatic stress disorder. Reaching and modulating these circuits noninvasively has been a major challenge.
“Because the hippocampus lies deep inside the brain, the primary question has been how to influence those neurons without implants or broadly acting drugs,” said Jing Jiang, PhD, the study’s senior author and an assistant professor at the University of Iowa. “These findings lay the groundwork for a safer, personalized approach to modulate hippocampus-dependent functions.”
Personalizing noninvasive brain stimulation
The investigators studied eight neurosurgical patients with implanted hippocampal electrodes, a rare clinical opportunity that allowed simultaneous external stimulation and internal recording. Instead of stimulating the same cortical point in every patient, the team used each person’s resting-state fMRI to map the hippocampus’s functional connections and identify individualized cortical targets that were most strongly connected to the hippocampus.
When researchers applied single-pulse or repetitive TMS at these personalized cortical sites, they observed clear temporal and spectral changes in hippocampal activity. In the four patients whose cortical targets were not individualized, hippocampal responses were negligible or absent. These direct recordings demonstrate that stimulation must respect each person’s network architecture to reliably reach the hippocampus.
Complementary experiments in 79 healthy participants used TMS with fMRI to measure hippocampal responses. Although those participants did not receive fully individualized stimulation, the results supported the connectivity-guided strategy: stronger intrinsic connectivity between the stimulated cortex and hippocampus — or closer proximity to the individualized site — predicted larger TMS-evoked hippocampal responses.
“A connectivity-informed targeting strategy delivers more precise modulation and may improve treatment predictability,” Jiang said. “Personalized stimulation sites are a key step toward effective, circuit-based neuromodulation.”
The research team includes first author Zhuoran Li and coauthors Nicholas Trapp, Joel Bruss, Xianqing Liu, Kang Wu, Ziyan Chen, Matthew Howard, Aaron Boes, and Amit Etkin, among others.
Funding: This work received support from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the Brain and Behavior Research Foundation, Magnus Medical, Inc., and the Roy J. Carver Charitable Trust.
Key Questions Answered
Q: If the hippocampus is “deep,” how does a magnet on the outside reach it?
A: TMS does not reach the hippocampus directly. A useful analogy is a subway system: stimulating a cortical area that is strongly connected to the hippocampus opens a pathway so the signal travels along those neural “tracks” to reach the deep structure.
Q: Why must stimulation be personalized?
A: Each person’s brain connectivity is unique. The study found that a generic cortical target often fails to produce hippocampal engagement. Using fMRI to find an individual’s connected cortical site reliably directs the stimulation to the hippocampus.
Q: Does this enable instant erasure of memories or a quick cure for depression?
A: Not at present. The technology is a neuromodulation tool — it tunes neural circuits rather than erasing memories. For disorders like PTSD or depression, the approach offers a way to adjust hippocampal activity toward healthier patterns without surgery, but clinical translation will require further trials.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full for accuracy.
- Additional context was added by the reporting staff.
About this neurotech research news
Author: Jennifer Brown, University of Iowa
Source: University of Iowa
Contact: Jennifer Brown – University of Iowa
Image: Image 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. Published in Nature Communications. DOI: 10.1038/s41467-026-70346-x
Abstract
Multimodal evidence for hippocampal engagement and modulation by functional connectivity-guided parietal TMS
The hippocampus supports memory and several other brain functions. TMS guided by hippocampal functional connectivity has shown promise for improving memory, but direct neural evidence of its capacity to engage and modulate hippocampal activity in humans has been limited. This study combined TMS with intracranial EEG in eight neurosurgical patients and with fMRI in 79 healthy participants. Findings indicate that single-pulse TMS to individualized parietal cortex sites preferentially evoked distinct temporal and spectral hippocampal activity; variability in TMS-evoked responses was related to individual differences in parietal–hippocampal functional connectivity strength; and repetitive TMS to connectivity-guided parietal cortex selectively suppressed hippocampal theta oscillations. These results provide multimodal causal evidence and mechanistic insight supporting the development of personalized neuromodulation strategies for hippocampus-dependent functions.