Summary: Researchers discovered a shared brain circuit that may link diverse lesion locations that cause epilepsy.
The study, which analyzed data from over 1,500 patients with brain lesions, utilized a technique called lesion network mapping. This discovery suggests that the connections disrupted by lesions, rather than the lesion locations, are crucial.
These findings could lead to new strategies for predicting epilepsy risk after brain damage and improved brain stimulation treatments.
The common brain circuit identified is not located on the brain’s surface, but deep within regions known as the basal ganglia and cerebellum. For decades, these structures have been known to control seizures in animal models of epilepsy.
Using the identified brain circuit, the researchers evaluated the outcomes of 30 patients who underwent deep brain stimulation (DBS) for drug-resistant epilepsy. The patients showed significant improvements when the DBS site was connected to this identified network.
This study was a retrospective analysis using existing datasets and a wiring diagram of healthy individuals. Future investigations could utilize individual patient wiring diagrams and prospectively test this circuit as a clinical tool, leading to personalized epilepsy management.
Source: Brigham and Women’s Hospital
Focal epilepsy affects over 30 million patients worldwide and is commonly caused by brain lesions, such as stroke. However, it is unclear why some lesion locations cause epilepsy while others do not.
A new study by investigators from the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, found that a common brain circuit may link different lesion locations causing epilepsy.
In a paper published in JAMA Neurology, the researchers used a technique called lesion network mapping to identify this brain circuit with findings that point to potential targets for brain stimulation.
“We’re learning more and more about where in the brain epilepsy comes from and what brain circuits we need to modulate to treat patients with epilepsy,” said lead author Frederic Schaper, MD, PhD, an Instructor of Neurology at Harvard Medical School and scientist at the Brigham and Women’s Center for Brain Circuit Therapeutics.
“Using a wiring diagram of the human brain, lesion network mapping allows us to look beyond the individual lesion location and map its connected brain circuit.”
Schaper and the team studied 5 datasets of over 1,500 patients with brain lesions. Participating centers across the US and Europe included the Brigham and Women’s Hospital, Massachusetts General Hospital, Boston Children’s Hospital, Northwestern University, and University Hospitals of Turku in Finland, Maastricht in the Netherlands, and Barcelona in Spain.
They studied a variety of brain lesions such as stroke, trauma, and tumors, which allowed them to search for common network connections associated with epilepsy across different regions and types of brain damage.
One of the datasets included combat veterans from the Vietnam Head Injury Study, which was originally designed in the 1960s because brain damage from combat shrapnel wounds resulted in a significant increase in the occurrence of epilepsy.
“In our studies, up to 50 percent of Vietnam combat veterans suffered at least one seizure post-injury, sometimes many years after the injury,” said co-author Jordan Grafman, Ph.D. of the Shirley Ryan AbilityLab in Chicago. “However, it has remained unclear why lesions to some locations cause epilepsy and others don’t.”
The Brigham researchers compared the locations of brain damage in patients that developed epilepsy to patients that did not, and found that lesions associated with epilepsy were distributed throughout the brain.
However, these same lesion locations were connected to a common brain network, suggesting the brain connections disrupted by the lesions, rather than the locations of the lesions itself, were the key.
These findings may have clinical implications for predicting the risk of epilepsy after brain damage.
“If we can map a lesion to the brain network we identified, we may be able to estimate how likely someone is to get epilepsy after a stroke,” Schaper said. “This is not a clinical tool yet, but we lay the groundwork for future studies investigating the use of human brain networks to predict epilepsy risk.”
The key brain connections they identified were not on the brain’s surface but were located deep within the brain in regions called the basal ganglia and cerebellum. The authors state that for decades, these deep brain structures have shown to modulate and control seizures in animal models of epilepsy and are hypothesized to act like a brain “brake”.
Based on these findings, the researchers analyzed outcome data of 30 patients with drug resistant epilepsy who underwent deep brain stimulation (DBS) to treat seizures. They found that patients did a lot better if the DBS site was connected to the same brain network, they identified using brain lesions.
“When programming a DBS electrode to improve seizures, it’s hard to know which spot to stimulate because it can take months before the patient’s seizures improve” said senior author Michael Fox, MD, PhD, an Associate Professor of Neurology at Harvard Medical School and founding director of the Brigham and Women’s Center for Brain Circuit Therapeutics.
“Identifying this brain circuit for epilepsy may help us target the right spot to improve patient outcomes.”
The authors note that the current study was a retrospective analysis using existing datasets and a wiring diagram of healthy individuals. When available, future studies could use a patients’ wiring diagram and prospectively test the utility of this circuit as a clinical tool.
“Now we know more about what brain circuits may play a role in both the cause and control of epilepsy, this opens up promising opportunities to guide our therapies” said Schaper. “Future clinical trials are needed to determine if this circuit can effectively guide brain stimulation treatment for epilepsy and benefit patients”.
Funding: The present analysis was funded by grants from the American Epilepsy Society (grant no. 846534) and NIH (grant no. R01NS127892). FLWVJS was supported by grants from the Royal Netherlands Academy of Arts and Sciences, Dr. Jan Meerwaldt Stichting, and Stichting De Drie Lichten. MDF was supported by the NIH (grant nos. R01NS127892, R01MH113929, R21MH126271, R56AG069086, R21NS123813), Sidney R. Baer Jr Foundation, the Nancy Lurie Marks Foundation, the Kaye Family Research Fund, the Ellison / Baszucki Foundation, and the Mather’s Foundation.
Disclosures: MDF and SHS are scientific consultants for Magnus Medical and independently own patents on using brain connectivity to guide brain stimulation. The full list of disclosures is available in the paper.
Mapping Lesion-Related Epilepsy to a Human Brain Network
It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions.
To assess whether lesion locations associated with epilepsy map to specific brain regions and networks.
Design, Setting, and Participants
This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets.
The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded.
Main Outcomes and Measures Epilepsy or no epilepsy.
Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories.
However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001).
Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months).
Conclusions and Relevance
The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.