Epilepsy is a chronic neurological condition characterized by recurring seizures, or abnormal bursts of electrical activity in the brain that can trigger jerky movements, strange sensations or emotions, unusual behavior, and/or loss of consciousness. Although available anti-seizure medications help the majority of people with epilepsy, a third or more receive little or no relief from medical treatment. Some people with medically refractory epilepsy experience excellent outcomes with surgery to remove or disconnect brain tissue that initiates or propagates seizures, but for others, a clear seizure focus may be difficult to identify or target safely without causing new neurological deficits. In these cases, neurostimulation devices can offer another alternative.
Research supported by NINDS and conducted by NINDS scientists figured prominently in the development of two FDA-approved devices that deliver electrical stimulation to the brain in different ways to reduce seizure frequency in people who do not achieve good seizure control with medication alone. Deep brain stimulation (DBS) for epilepsy, approved in 2018, delivers chronic stimulation to the anterior nucleus of the thalamus (ANT), a small brain structure involved in the spread of an initially localized seizure. In contrast, responsive neurostimulation (RNS®), approved in 2013, delivers stimulation directly to the source of an individual’s seizures, but only when continuously monitored brain activity suggests a seizure may be beginning.
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During recordings of brain activity in people with epilepsy undergoing surgery, Wilder Penfield and Herbert Jasper observe that seizure-like activity could be halted with brief counter stimulation1.
Low frequency stimulation in the anterior nucleus of the thalamus (ANT) is reported to synchronize brain activity, while high frequency stimulation had the opposite effect9.
The first systems emerge for automated seizure detection based on EEG recordings of brain activity.30
High frequency stimulation in the ANT is shown to protect against generalized seizures in an animal model.14
The pivotal clinical trial of the NeuroPace responsive neurostimulation system (RNS®) shows that seizure frequency decreased in individuals receiving stimulation39.
The NeuroPace RNS® receives approval from the FDA for use in adults with medically refractory focal epilepsy40.
Medtronic’s DBS System for Epilepsy receives approval from the FDA for use in adults with medically refractory focal epilepsy24.
History of Development
Research supported by NINDS and conducted by NINDS scientists proved critical to the development of the first brain stimulation therapies for epilepsy, including studies to rigorously test early approaches, find new stimulation targets by understanding seizure mechanisms, and develop algorithms for automated seizure detection.
Pioneering neurosurgeons set the stage
Neurostimulation therapies for epilepsy follow a longer history of attempts to quiet seizures through surgical interventions. In the 1930s, Canadian neurosurgeon Wilder Penfield pioneered modern methods for surgery to treat epilepsy. He used electroencephalography (EEG) to identify where seizures originated in the brain of individuals with epilepsy and then more finely mapped targets for surgical resection with direct electrical stimulation through electrodes inserted into the brain. This basic approach to surgical evaluation in epilepsy remains in practice today, with ongoing improvements as brain imaging and recording technologies have advanced.
Beyond improving the success of surgery for people with epilepsy, intraoperative recording also provided new insights about how seizures originate and propagate in the brain and laid the foundation for therapeutic stimulation. Indeed, Penfield and colleague Herbert Jasper were among the first to observe that electrical stimulation to the cortex could silence seizure discharges1. By the 1960s, with the advent of the cardiac pacemaker and the exploration of deep brain stimulation (DBS) therapies to treat pain and motor disorders, researchers began to pursue similar treatments for epilepsy. The choice of targets for stimulation were based in part on research using electrical stimulation to understand seizure mechanisms in animal models. For example, in the 1970s, neurosurgeon Irving Cooper hypothesized that stimulation in the cerebellum could reduce seizures in people with epilepsy, a suggestion supported by NIH-funded studies in cats2,3. Although Cooper’s initial trials were promising4,5, placebo-controlled trials and animal studies conducted by NINDS intramural scientists and others failed to confirm the benefit of treatment6,7,8. Nevertheless, these early efforts were important for demonstrating the feasibility and safety of brain stimulation for epilepsy, and for establishing the need to control for a strong placebo effect and for changes related to surgery alone.
Identifying the anterior nucleus of the thalamus as a target for seizure control
In the search for other targets, several lines of evidence pointed to a small brain region called the anterior nucleus of the thalamus (ANT). Low frequency stimulation in this region was reported to synchronize brain activity, while high frequency stimulation had the opposite effect, suggesting it may also disrupt seizures9. NIH-supported investigators found that surgical lesions of the ANT decreased the occurrence and duration of seizures in a small clinical study10 and in an animal model11. A series of NINDS-funded studies on the mechanisms of experimentally induced seizures placed the ANT within a brain circuit that mediates seizure generalization, in which seizure activity initiated in a small focused area (focal seizure) spreads to larger areas of the brain12,13. A subsequent study prompted by these findings showed that high-frequency stimulation in the ANT could protect against generalized seizures14. Altogether, the ANT’s anatomically defined position and its role in seizure spread from other locations made it an appealing therapeutic target, potentially for a wide range of individuals with seizures initially originating in different areas.
In the 1980s, Cooper reported that chronic ANT stimulation improved seizure control in small numbers of people with medically refractory epilepsy15,16,17. While promising, these studies were unblinded and uncontrolled, and the use of an external stimulator was impractical. A decade later, the FDA had approved two implantable neurostimulation devices, Medtronic’s deep brain stimulation (DBS) system as a treatment for tremor18 and Cyberonics’ vagal nerve stimulator for medically refractory epilepsy19. These approvals helped renew interest in further development of DBS for epilepsy, and in the early 2000s, preliminary studies assessed the use of Medtronic’s DBS system for bilateral ANT stimulation20,21, including one study conducted by investigators with NINDS and NIMH support19. Medtronic subsequently sponsored a randomized, controlled clinical trial 110 patients. The SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) trial and a seven-year follow up period23 showed lasting benefits of treatment in terms of reduced seizure frequency and meaningful improvements in quality of life. These results led the FDA to approve Medtronic’s DBS System for Epilepsy in 2018, for use along with medical treatment in adults with focal epilepsy who have not achieved seizure control after trying three or more epilepsy medications24.
Responsive neurostimulation to halt seizures at their source
The DBS system for epilepsy delivers ongoing, or open loop, stimulation intended to alter brain activity just enough to prevent or limit the initiation or spread of a seizure. In contrast, closed loop or responsive stimulation, delivers stimulation only when brain activity patterns suggest a seizure is beginning or very likely to occur. Beyond Jasper and Penfield’s original observations1 in 1954, later studies–in people undergoing surgery for epilepsy and in animal models with experimentally induced seizures–provided a rationale for this approach. This research supported by NINDS and others showed that brief bursts of stimulation could terminate seizures or seizure-like activity when delivered soon after onset, either to brain structures remote from seizure activity25,26, or directly to the onset site27,28,29. For example, brain stimulation used to map an individual’s seizure focus for surgery sometimes elicits rhythmic activity called afterdischarges that resemble spontaneous seizure activity. In 1999, NINDS-supported investigators reported that brief counter stimulation at the same site could terminate such afterdischarges28.
In parallel, an expanding area of research sought to develop algorithms for automated seizure detection. By analyzing brain activity data from people with epilepsy, investigators worked to identify features that reliably indicated a seizure was beginning or very likely to occur. Early seizure detection systems emerged30 around the 1980s, and by the late 1990s, academic and industry investigators supported by NINDS, NIMH, and private sources were developing more refined algorithms that would ultimately be adapted for use in the first responsive stimulation devices31,32,33,34. Initial tests for safety and feasibility used prototypes with non-implantable external neurostimulators in individuals with epilepsy undergoing evaluation for surgery35,36,37. After promising preliminary results38, the device company NeuroPace was the first to launch a large, randomized, multi-center trial for their implantable responsive neurostimulation system39. The pivotal trial showed that seizure frequency decreased in study participants receiving stimulation compared to those in a control group who received a sham procedure. Based on these findings, the NeuroPace RNS® was approved by the FDA in 2013, for use along with medical treatment in adults with medically refractory focal epilepsy40. A key feature of the RNS® system is the ability for physicians to fine-tune detection and stimulation parameters for each person, possibly improving outcomes over time.
Future directions in neurostimulation and responsive therapies for epilepsy
Research continues to improve neurostimulation therapies for epilepsy. Efforts are underway to incorporate seizure forecasting and responsive stimulation into DBS for epilepsy, including a project supported through the NIH BRAIN Initiative Public-Private Partnership Program to facilitate clinical research using industry-supplied cutting-edge devices41. In addition, there is hope that future algorithms for triggering responsive epilepsy therapies will more accurately detect or even predict seizures, allowing advanced warning for patients and potentially better seizure control. In 2014, NINDS, the American Epilepsy Society, and the Epilepsy Foundation launched a crowd-sourced seizure detection and prediction challenge in which amateur computer programmers, scientists, and others from around the world competed to develop algorithms tested on long-term intracranial EEG data42. The best algorithms significantly increased seizure prediction accuracy over prior methods, a success that bolstered interest in further innovation: a second international contest was held43 in 2016, and an online portal provides access to datasets for ongoing algorithm development.
List of References
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