Moving Toward Precision Neuromodulation in Functional Neurosurgery

For appropriately selected patients with drug-resistant focal epilepsy, resective surgery remains the only treatment capable of eliminating seizures entirely. While epilepsy surgery remains an underutilized treatment approach for multiple reasons, many patients are not candidates for resection because their seizures arise from eloquent cortex, involve multiple regions or are of a more generalized nature, or target areas cannot be safely localized. For these individuals, neuromodulation approaches have become an increasingly important therapeutic option to control and reduce seizure burden.

Within the Neurological Surgery Department at UPMC, Jorge A. González-Martínez, MD, PhD, and colleagues are working to make those therapies more precise. Dr. González-Martínez is the Stuart Niles Rowe Professor; vice-chair, Department of Neurological Surgery; director, Epilepsy and Movement Disorders Program; co-director, UPMC Epilepsy Center; and director, Cortical Systems Laboratory. Dr. González-Martínez is one of the world’s foremost experts in the use of stereotactic electroencephalography (SEEG) and robotic-assisted neurological surgery techniques.

One area of research for Dr. González-Martínez and colleagues is focused on better understanding the brain networks involved in epilepsy and using that information to individualize neuromodulation for patients who are not candidates for resective surgery.

"Our work focuses on translating what we are learning about the brain's networks into practical surgical decision making," Dr. González-Martínez says. "As we better understand how seizures propagate through those networks, we can begin to personalize where and how we deliver neuromodulation."

Recent work published in Nature Communications by Dr. González-Martínez and colleagues, titled “Thalamocortical Hodology to Personalize Electrical Stimulation for Focal Epilepsy,” illustrates this ongoing effort. By combining advanced neuroimaging, intracranial electrophysiology, and clinical outcomes, they examined whether stimulation targets could be selected based on the organization of an individual patient's seizure network rather than relying on a one-size-fits-all approach to thalamic stimulation.

Rather than approaching the thalamus as a single therapeutic target, Dr. González-Martínez and colleagues asked if different seizure networks might respond more effectively when stimulation is directed to the thalamic nucleus most closely connected to the cortical region where an individual's seizures originate.

Matching the Target to the Seizure Network

For this study, the team combined intracranial recordings, advanced neuroimaging, and clinical outcome data from patients with drug-resistant focal epilepsy. The goal was to determine whether different seizure onset zones consistently corresponded to different thalamic nuclei and whether matching stimulation targets to those networks could improve outcomes.

Dr. González-Martínez and colleagues found that distinct seizure networks demonstrated predictable anatomical and functional relationships with specific thalamic nuclei. Those relationships remained consistent across multiple imaging and electrophysiologic analyses, allowing the team to identify stimulation targets that were anatomically matched to an individual patient's seizure network.

"The study demonstrates that different seizure networks are associated with different thalamic connections," Dr. González-Martínez says. "If we can identify those relationships before treatment, we may be able to select stimulation targets that are better suited to each patient's epilepsy."

The study also found that stimulation of matched targets more effectively suppressed epileptiform activity than stimulation of unmatched targets. Patients who underwent chronic stimulation of anatomically matched targets had greater seizure reduction than patients whose stimulation sites were not aligned with their seizure networks.

"The goal is not simply to develop new technology," Dr. González-Martínez says. "It's to understand which patients are most likely to benefit from a particular neuromodulation strategy and which stimulation target best matches their disease."

Translating Brain Network Science Into Clinical Care

More validation and refinement are still needed, but this work is an important step toward more individualized functional neurosurgery. Treatment for drug-resistant epilepsy has often been chosen by matching a patient to a standard target or procedure. Network-based approaches start from the other direction: They map how a particular patient’s seizures begin, spread and recruit other brain regions, and then design treatment around that map.

“Studies like this help bridge the gap between what we observe in research and what we do in the operating room,” Dr. González-Martínez says. “Ultimately, the objective is to make better treatment decisions for individual patients.”

That shift is already changing practice. Stereo-EEG lets the team record from deep structures such as the thalamus during evaluation. Responsive and deep brain stimulation systems can then deliver therapy that is tailored and, more and more frequently, adaptive.

“We are moving away from asking only where seizures start and toward asking how they spread and which nodes we can influence to stop them,” Dr. González-Martínez says. “The thalamus is a good example. It isn’t one target. Different thalamic nuclei connect to different networks, and choosing the right one for the right patient may matter as much as the decision to stimulate at all.”

Where Neuromodulation Is Headed

Dr. González-Martínez sees the field of neuromodulation heading in a few clear directions:

• From fixed to adaptive therapy. Most neurostimulation approaches used to run on a preset schedule. Newer systems can sense an individual’s brain activity and respond to it in real time. They can also record data that helps clinicians adjust treatment over months and years.
• From one-size-fits-all targets to personalized networks. Recordings and imaging from each patient increasingly guide which brain region to treat and how.
• From open surgery to minimally invasive and noninvasive options. Laser ablation, small-footprint stimulation systems, and, eventually, focused ultrasound aim to change abnormal networks while sparing healthy tissue.

Focused ultrasound shows where this could lead. It is already used clinically for some movement disorders, including essential tremor and certain symptoms of Parkinson’s disease, where it can create a precise, incision-free lesion deep in the brain. For epilepsy it is still investigational. Researchers are studying both whether it can safely treat deep targets and if low-intensity ultrasound can modulate brain activity reversibly, without making a lesion.

“What excites me is the idea of reaching deep brain circuits with less and less disruption to the patient,” Dr. González-Martínez says. “If we understand the network well enough, the tools can become more precise, and potentially less invasive. That principle applies to epilepsy, to Parkinson’s disease and movement disorders, and likely to other conditions where abnormal neural circuits drive the symptoms.”

He adds that technology alone is not enough.

“The advances that last will come from combining better tools with a better understanding of each patient’s brain. That is why research like this matters. It tells us where and how to intervene.”

References and Further Reading

Damiani A, Nouduri S, Ho JC, Salazar S, Jegou A, Chen JJ, Reedy E, Ikegaya N, Sarma S, Aung T, Pirondini E, Gonzalez-Martinez JA. Thalamocortical Hodology to Personalize Electrical Stimulation for Focal Epilepsy. Nat Commun. 2025 Oct 20; 16(1): 9209.