Direct Evidence for Non-Invasive Deep Brain Modulation
Neuroscientists at the University of Iowa have produced the first direct human evidence that transcranial magnetic stimulation can reliably alter activity in the hippocampus, a deep brain structure central to memory and emotion that was previously thought to be beyond the reach of non-invasive techniques.
The study, published in Nature Communications on 2 April, combined TMS with intracranial electroencephalography in eight neurosurgical patients who already had electrodes implanted in or near the hippocampus. A separate cohort of 79 neurologically healthy volunteers underwent concurrent TMS and functional magnetic resonance imaging. The dual-method approach allowed the team to measure hippocampal responses both electrically and through blood-flow changes.
Personalisation Doubled the Effect
The critical finding centred on personalisation. In four of the eight implanted patients, the researchers used resting-state fMRI to map each individual’s unique connectivity between the cortical surface and the hippocampus, then directed the TMS coil at the cortical site most strongly linked to the hippocampus in that specific brain. Those four patients showed evident hippocampal activity changes following stimulation. The remaining four, whose stimulation sites were not individually tailored, showed no robust hippocampal response.
The implication is that a one-size-fits-all targeting approach — the standard in most current TMS protocols — may simply miss the hippocampus in many patients. By contrast, connectivity-guided targeting appeared to roughly double the modulatory effect, according to the research team led by Jing Jiang, an assistant professor of pediatrics and psychiatry at Iowa.
How the Targeting Works
Standard TMS directs magnetic pulses at the scalp over a cortical region, generating electrical currents in the tissue beneath. The hippocampus sits too deep for direct stimulation, but it is densely connected to cortical areas — particularly in the parietal lobe — through white-matter pathways. The Iowa team exploited these connections by identifying, for each patient, the parietal site whose resting-state activity most closely tracked hippocampal activity. When TMS was delivered to that personalised target, the pulses propagated along the connectivity pathway and engaged the hippocampus indirectly.
The team’s first author, Zhuoran Li, worked alongside collaborators including Nicholas Trapp, Aaron Boes, Matthew Howard, and Amit Etkin of Alto Neuroscience. The combination of intracranial recording (which captures millisecond-level electrical responses) and fMRI (which captures broader regional activation) provided converging evidence that the effect was genuine and not an artefact of either technique alone.
Clinical Implications
The hippocampus is implicated in Alzheimer’s disease, major depression, post-traumatic stress disorder, and temporal lobe epilepsy. Existing treatments for these conditions — including deep brain stimulation — require neurosurgery. If TMS can reach the hippocampus non-invasively, it opens a pathway to outpatient neuromodulation therapies for conditions that currently have limited treatment options.
The findings also carry relevance for the brain-computer interface field. Non-invasive BCI systems that aim to decode or modulate memory, emotion, or spatial cognition would benefit from a reliable method of engaging the hippocampus without implanted hardware. The connectivity-guided targeting approach demonstrated here could serve as a template for personalised non-invasive neurostimulation more broadly.
Limitations and Next Steps
The sample of implanted patients was small — eight in total, with personalised targeting applied to only four. The study demonstrated that hippocampal modulation is achievable, but did not test whether it produces lasting therapeutic benefit. Larger trials with clinical endpoints will be needed to determine whether connectivity-guided TMS translates into measurable improvements for patients with memory disorders or depression.
The University of Iowa team has indicated that further work will explore whether repeated personalised TMS sessions can produce sustained changes in hippocampal function, a prerequisite for any clinical application.