In a groundbreaking advance in neuroscience, researchers at the University of Iowa Health Care have unveiled compelling evidence that noninvasive brain stimulation can directly influence the activity of the hippocampus—a deep brain structure integral to memory formation and emotional regulation. This revelation marks a crucial milestone in neuromodulation science, as it demonstrates, for the very first time, that targeted transcranial magnetic stimulation (TMS) can modulate hippocampal function in humans without the need for invasive procedures.
The hippocampus, nestled deep within the medial temporal lobe, plays a pivotal role in encoding new memories and shaping emotional responses. Aberrations in hippocampal circuitry underpin a host of debilitating neurological and psychiatric disorders, including Alzheimer’s disease, major depressive disorder, anxiety syndromes, and post-traumatic stress disorder (PTSD). Historically, direct manipulation of hippocampal activity has been limited to invasive methods such as deep brain stimulation or pharmacological interventions with broad systemic effects, posing significant risks and limited precision.
This novel study employed cutting-edge technology to surmount these challenges by coupling noninvasive TMS with real-time intracranial recordings and neuroimaging. The research team capitalized on a rare clinical opportunity afforded by eight neurosurgical patients who had intracranial electrodes implanted in their hippocampi for medical reasons. Through this unique setup, they could administer single-pulse and repetitive TMS to cortical regions while simultaneously measuring immediate electrophysiological responses deep within the hippocampus via intracranial electroencephalography (iEEG).
A defining feature of this investigation was the emphasis on personalized neuromodulation. Rather than relying on conventional, one-size-fits-all stimulation targets, the researchers harnessed resting-state functional magnetic resonance imaging (fMRI) to map each individual’s unique functional connectivity profile between the hippocampus and accessible cortical sites. This stratagem allowed precise identification of parietal cortex locations most strongly coupled to the hippocampus, enabling a tailored stimulation approach designed to maximize engagement of hippocampal networks.
Findings revealed a remarkable enhancement in hippocampal activation when TMS pulses were delivered to these individualized cortical hotspots. Patients with connectivity-informed stimulation sites exhibited robust hippocampal electrophysiological responses, whereas those receiving stimulation at generic cortical sites did not show significant modulation. Importantly, this disparity underscores the critical role of functional connectivity as a biomarker for effective and targeted neuromodulation.
To extend these insights beyond the clinical population, the researchers conducted a parallel noninvasive experiment involving 79 neurologically healthy volunteers undergoing simultaneous TMS and fMRI. Although individual connectivity-guided targeting was not applied in this cohort, analyses demonstrated a compelling correlation: stronger intrinsic functional connectivity between the stimulation sites and the hippocampus predicted more pronounced TMS-evoked hippocampal responses. Furthermore, proximity of the stimulation site to the personalized target map also positively influenced the neuromodulatory efficacy.
These comprehensive multimodal data collectively illustrate that harnessing an individual’s unique brain connectivity can improve the precision, magnitude, and reliability of hippocampal neuromodulation. This representa a critical leap forward in circuit-based brain stimulation therapies, enabling interventions that may be tailored to the specific neuroanatomical and functional architecture of each patient’s brain.
Dr. Jing Jiang, the senior author and an assistant professor at the UI College of Pediatrics and Psychiatry, highlights the transformative potential of this approach: “The hippocampus has always been a challenging target due to its deep location and complex circuitry. Our findings provide a proof-of-concept that noninvasive, personalized stimulation can modulate hippocampal function safely and effectively, potentially opening new avenues for treating a range of neurological and psychiatric conditions.”
The methodological innovation underpinning this research—simultaneous TMS combined with intracranial electrophysiological and fMRI monitoring—allowed unprecedented temporal and spatial resolution in assessing the immediate effects of brain stimulation. This integrative paradigm enables researchers to dissect the causal pathways through which cortical stimulation propagates to deeper subcortical structures.
Moreover, the ability to tailor stimulation sites according to an individual’s resting-state brain connectivity map moves beyond traditional trial-and-error approaches, positioning functional connectivity as an essential biomarker for therapeutic targeting. This sets the stage for personalized neuromodulation therapies that could be optimized to enhance efficacy and predict patient-specific responses.
The implications of this work are far-reaching. By demonstrating the feasibility of noninvasive hippocampal modulation, it paves the way for the development of novel therapeutic modalities to combat memory impairments in Alzheimer’s disease, alleviate symptoms of depression and anxiety, and potentially ameliorate trauma-related disorders. Furthermore, this approach alleviates the risks associated with invasive implantation of electrodes, such as infection or tissue damage.
The research team included a multidisciplinary ensemble of experts, with contributions from neuroscientists, clinicians, and engineers, underscoring the collaborative nature of modern brain research. Funding support came from prominent institutions including the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, emphasizing the significance of this research trajectory for public health.
Looking ahead, this pioneering demonstration invites further clinical trials to evaluate the long-term efficacy and therapeutic potential of personalized TMS protocols targeting the hippocampus. Such work will refine stimulation parameters, optimize patient selection based on individual connectivity profiles, and expand understanding of the mechanistic underpinnings governing brain network modulation in health and disease.
In summary, the University of Iowa Health Care team’s research inaugurates a new era in noninvasive brain stimulation, where personalized functional neuroimaging guides the precise engagement of deep brain structures like the hippocampus. This innovation holds promise for revolutionizing treatments for a variety of disorders rooted in hippocampal dysfunction, translating neuroscience breakthroughs into tangible clinical benefits.
Subject of Research: People
Article Title: Multimodal evidence for hippocampal engagement and modulation by functional connectivity-guided parietal TMS
News Publication Date: 8-Mar-2026
Web References: https://www.nature.com/articles/s41467-026-70346-x
Image Credits: Jing Jiang Lab, University of Iowa Health Care
Keywords: Transcranial magnetic stimulation, Hippocampus, Electroencephalography, Psychiatric disorders, Neuroimaging
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