Yale Researchers Receive Grant to Develop Novel Epilepsy Brain-Computer Chip Treatment

Article appeared in Yale Daily News

An interdisciplinary team of Yale researchers has designed brain-machine interface chips that, when implanted in humans, can reduce the rate of epileptic seizures.

More than three million people experience epileptic seizures in the United States, with 60 to 70 percent of patients able to successfully treat the condition with medicine. For the remaining individuals, surgically removing the parts of the brain where seizures arise, regardless of their role in everyday function, has been the only path toward mitigating the issue. A team of Yale computer scientists, engineers and surgeons have found that short-circuiting the path neurons fire during an epileptic seizure can successfully reduce the rate of seizures in patients. The Swebilius Foundation recently awarded the team a grant to continue its research.

“When the signature traits of a seizure are observed, the device stimulates that part of the brain, and it is not curative, but over time 60 percent of patients will get 50 percent fewer seizures than they had before,” said Dennis Spencer, professor emeritus of neurosurgery, who implants these brain-computer interface chips in patients.

The team is still working to increase the success rate. Currently, each chip contains two electrodes with four contacts. When attempting to short-circuit a seizure, a surgeon can only stimulate the brain on the linear path between those two electrodes.

The chips are uniquely targeted, both spatially and temporally, making them superior to medication or surgery for seizures that extend into critical regions of the brain. However, the chips’ targeted nature makes them inadequate in many cases when seizures follow a network of connections, moving quickly around the brain.

CURE Epilepsy Impact: Investing in Early-Stage Investigators Advances Careers & Leads to Groundbreaking Epilepsy Treatments

Key Points:

  • Gregory Worrell, MD, PhD (Mayo Clinic, Rochester, MN) recalls that the first grant that he received was from CURE Epilepsy and credits it with having a tremendous impact on both his career path and his groundbreaking contributions to epilepsy research.
  • According to Dr. Worrell, the initial one-year grant, awarded almost 20 years ago, was a catalyst for his research to improve devices for monitoring brain activity and forecasting seizures. 
  • The CURE Epilepsy grant, along with an NIH career developmental award, and subsequently additional ongoing NIH and foundation grants, has firmly established Dr. Worrell as an important investigator in the fields of brain neurophysiology, seizure detection, seizure forecasting, and neural modulation. 

Deep Dive:

Dr. Gregory Worrell’s path towards ultimately engaging in epilepsy research did not follow a direct road. He first trained and worked as a PhD-level physicist before entering medical school and then completed a neurology residency followed by an epilepsy fellowship. It took several additional years to reach his current role as a physician-scientist caring for epilepsy patients while simultaneously maintaining a productive research laboratory. Nevertheless, Dr. Worrell’s unique training in engineering and physics, along with the computational analyses, gave him the expertise required to understand and develop devices to monitor and modulate electrical activity of the brain.

Dr. Worrell credits his mentors, including Dr. Gregory Cascino, also at the Mayo Clinic, and Drs. Marc Dichter (a former advisor to CURE Epilepsy) and Brian Litt (a former CURE Epilepsy grantee), both at the University of Pennsylvania, with influencing his career direction. They provided the model, encouragement, and opportunity for a career as a clinician-scientist. Dr. Worrell’s first research grant was from CURE Epilepsy, and he attributes this critical funding for getting him started in epilepsy research. Even though he was also awarded an NIH training award, he feels that, in many ways, the CURE Epilepsy grant was more important because it introduced him to the community of epilepsy researchers

Dr. Worrell’s grant from CURE Epilepsy focused on high-frequency oscillations (HFO), brain waves with a frequency of greater than approximately 80 Hz that are often associated with seizure activity in specific regions of the brain [1]. This electrical activity can be detected on an electroencephalogram (EEG), but at the time (approximately 20 years ago), HFOs were rarely observed simply because the range of a typical EEG was limited to no greater than 70 Hz, biased by then-accepted practice [2]. Basic research with animal models, however, had suggested that an epileptic brain exhibits a much wider dynamic range of activity, sometimes out to frequencies greater than 1,000 Hz, and so Dr. Worrell focused his early efforts on broadening the spatial and temporal sampling of brain waves [2-4]. These so-called “wide-bandwidth” recordings have now become standard in the field. 

The early learnings achieved through the CURE Epilepsy funded research have carried over into the development of “next-generation” implantable therapeutic devices [5], done as part of an NIH Brain Initiative public-private partnership with Medtronic, a company with a long history of creating medical devices. The “public” component is funded through two NIH grants awarded to Dr. Worrell. The aims are to develop new device technology that will permit the tracking of a patient’s brain state, identify periods of increased seizure probability, and adaptively intervene to modulate the brain, moving it to a state of low seizure probability to prevent seizures from ever occurring. Importantly, it has the potential of providing something akin to a “daily weather report”, giving the patient a sense of when a seizure might occur. This is particularly crucial given that one of the most disabling aspects of epilepsy is not necessarily the seizures themselves but their unpredictability. With this type of technology, there is an opportunity to administer therapies, e.g., anti-seizure medications and/or brain stimulation, both of which have considerable side effects, in a time-limited way instead of a continual process. Creating the next generation of electrical stimulation and sensing devices for epilepsy has remained a focus of Dr. Worrell’s research. 

While Dr. Worrell is proud of his individual achievements, he notes that consequential advances in medicine are usually the outcome of team efforts, with dozens perhaps even hundreds of clinicians and scientists collaborating [5,6] To this end, he has participated in numerous clinical trials to test novel devices, including the FDA approved responsive neurostimulator (RNS®) manufactured by Neuropace Inc, to control seizures, and he derives considerable satisfaction from these collective undertakings. Dr. Worrell enthusiastically admits that he receives additional joy in life from taking care of his patients, following their progress over time, and being able to improve their quality of life through the neurophysiology/neuroengineering research performed in his own lab and through collaborations with other clinicians and scientists. In his mind, there is no greater reward than having the ability to help patients in this way

CURE Epilepsy is proud to have played a role in the illustrious career of Dr. Gregory Worrell in advancing research so that we, as a society, will one day be truly able to say that we live in a world of “no seizures and no side effects.” 

Literature Cited

  1. Chen, Z., Maturana, M.I., Burkitt, A.N., Cook, M.J., and Grayden, D.B. High-frequency oscillations in epilepsy: what have we learned and what needs to be addressed. Neurology 2021; 96(9): 439-448. 
  2. Worrell, G.A., Parish, L., Cranstoun, S.D., Jonas, R., Baltuch, G., and Litt, B. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004; 127: 1496-1506. 
  3. Worrell, G.A., Gardner, A.B., Stead, S.M., Hu, S., Goerss, S., Cascino, G.J. et al. High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings. Brain 2008; 131: 928-937.
  4. Stead, M., Bower, M., Brinkmann, B.H., Lee, K., Marsh, W.R., Meyer, F.B., Litt, B., Van Gompel, J.V., and Worrell, G.A. Microseizures and the spatiotemporal scales of human partial epilepsy. Brain 2010; 133(9): 2789-2797.  
  5. Kremen, V., Brinkman, B.H., Kin, I., Guragain, H., Nasseri, M., Magee, A.L. et al. Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J. Transl. Eng. Health Med. 2018; 6: 2500112. 
  6. Brinkmann, B. H., Wagenaar, J., Abbot, D., Adkins, P., Bosshard, S.C., Chen, M., Tieng, Q.M. et al. Crowdsourcing reproducible seizure forecasting in human and canine epilepsy. Brain 2016; 139(6): 1713-1722. 

Adult Epilepsy Treatment Reduces Seizures in Children

A surgical treatment commonly used to reduce epileptic seizures in adults also is effective and safe for children, according to a Rutgers study.

The study, published in the journal Neurosurgery, is one of the first to investigate responsive neurostimulation system (RNS)—a device similar to a pacemaker that sends electric charges to the heart, which delivers stimulation directly to the brain when needed to prevent seizures—in children.

Up to 40 percent of people who suffer from epileptic seizures do not respond to medication. RNS, which is implanted in the brain and monitors brain waves, detects seizures and unusual electrical activity that can lead to seizures, then delivers small pulses of stimulation to help the brainwaves return to normal. The system, which has not been well studied in children whose brains are still growing, is being increasingly used in pediatric centers to control seizures.

“As we expand use of RNS to children, it is critical to consider how to determine the lower age limit,” said lead author Yasunori Nagahama, an assistant professor of neurosurgery and director of pediatric epilepsy surgery at Rutgers Robert Wood Johnson Medical School. “Considering this procedure involves removing a portion of the skull to implant the device, the benefits and potential harm based on the variable skull development in individual patients should be considered. Children experience rapid skull growth within the first two years and reach about 90 percent of adult skull volume by around age 8. In this study, there were two patients under 7 years at the time RNS was implanted, including a 3-year-old, who was the youngest reported patient to undergo RNS implantation.”

Differences in Aggression as Psychiatric Side Effect of Levetiracetam (Keppra®) and Perampanel (Fycompa®) in Patients with Epilepsy

Abstract, originally published in Epilepsy & Behavior

Purpose: Aggression is the most commonly encountered antiepileptic-drug (AED)-induced psychiatric adverse effects. Levetiracetam (LEV) is well known to be associated with increased rates of aggression, while perampanel (PER) is also recognized as a potentially aggression-promoting agent, though opinions vary. However, few studies have addressed questions regarding whether the nature of irritability-aggression differs between those drugs. The present study used a standardized rating scale to examine aggression among patient with epilepsy who received LEV or PER using specific measures to confirm the effects of the drugs.

Methods: We enrolled 144 consecutive outpatients receiving treatment for epilepsy with LEV (n = 103) or PER (n = 41), and determined their effects regarding aggression using the Buss-Perry Aggression Questionnaire (BAQ). For analysis, total BAQ scores for the LEV and PER subjects were compared to determine whether the aggression-promoting effects of the agents differed, and which BAQ subdomains (physical aggression, verbal aggression, anger, hostility) were related to production of aggression in patients taking either LEV or PER. As a subsidiary analysis, clinical variables inclusive of administered AED type that showed a significant impact on BAQ scores were determined.

Results: The LEV group had a significantly higher hostility score (19.4 ± 5.8) as compared to the PER group (17.2 ± 6.3) in subscale analysis (p < 0.05). In multiple regression analysis, LEV had a significant association with higher hostility score (P = 0.006).

Conclusion: Our results indicate that while easily visible outward-directed aggression tends to be dominant in patients given perampanel, aggression provoked by levetiracetam may be felt more subjectively or in an inward-directed manner, which can lead to more diverse expression and misrecognition.

CURE Epilepsy Discovery: Targeting Infantile Spasms After Disease Onset

Key Points:

  • CURE Epilepsy awardee, Dr. Aristea Galanopoulou and colleagues at Albert Einstein College of Medicine in New York sought a way to prevent the devastating consequences of already-established infantile spasms (IS). 
  • They used a novel, more clinically relevant IS rat model [1] to test the effect of a specific substance known as rapamycin on motor seizures, spasms, and sleep wave patterns, both immediately and over time.  
  • Data show that rapamycin appears to be an effective treatment for IS and that short-term administration early in life and during the peak of spasms can prevent future seizures in adulthood and even improve cognitive outcomes.  

Deep Dive:

Infantile spasms (IS) is a rare (~0.03% of all live births) and catastrophic type of epilepsy that usually first manifests between 3 to 7 months of age [2,3], and infants with poor response to first-line treatment are at an increased risk for a more serious form of epilepsy known as Lennox-Gastaut syndrome (LGS) [4]. Because one of the symptoms includes stereotypical jerks resembling colic, IS is difficult for parents and sometimes even pediatricians to recognize. Conclusive diagnosis is made by the spasms themselves, developmental delay, and often an abnormal, disorganized electroencephalographic (EEG) pattern known as hypsarrhythmia. This chaotic EEG pattern is observed between seizures and characterized by irregular, nonrhythmic waves and spikes of electrical activity [2,3].

IS is commonly treated with a combination of one or two specific steroids (adrenocorticotropic hormone [ACTH] and/or prednisone) and/or the antiseizure medication (ASM) vigabatrin [3,5,6]. These treatments are only effective in approximately 50% of patients [7] and, for those who do respond, diagnosis must be made early enough to minimize significant cognitive deterioration. However, these therapies do not reduce the incidence of future epilepsy and almost two-thirds of these infants continue to have seizures that do not respond to existing therapies [6]. Unfortunately, at present there is no consistent way of predicting who will respond to these treatments. Moreover, the optimal therapy would not only acutely arrest seizure activity but would also possess a “permanent” disease-modifying effect and perhaps even reverse any cognitive decline that had already taken place.

More severe and most frequent causes of IS stem from structural abnormalities in specific regions of the brain [2]. To understand the underlying biology of this form of IS and identify effective treatments, Dr. Aristea Galanopoulou, a member of CURE Epilepsy’s Infantile Spasms Initiative [8], at the Albert Einstein College of Medicine, and colleagues Drs. Solomon Moshé and Morris Scantlebury, developed a rat model known as the “multiple-hit model.” This model has brain lesions that closely mirror those observed in the brains of infants with IS, along with more visible traits such as developmental delay, behavior problems, poor social skills, drug resistance, EEG abnormalities, and potential emergence of other seizure types [1].

Using this model, Dr. Galanopoulou’s team created a platform for screening the potential for various drugs to treat IS. The investigators first used the model to test the ability of the drug rapamycin, an inhibitor of a neuronal signaling pathway linked to epilepsy, to affect IS symptoms [9]. Importantly, rapamycin was given in a 3-day pulse (as opposed to continuous administration) and only after the onset of spasms. This strategy of drug delivery is meaningful since it mimics what happens in clinical practice. A previous study from this group [9] had shown that the rapamycin stopped the spasms and was able to partially restore learning and memory deficiencies, which suggests that the rapamycin was able to modify the progression of IS. However, rapamycin did not diminish any of the other seizure types or reduce the size of the structural lesions.

To better understand the long-term effects of the pulse rapamycin treatment, the researchers then examined [10] whether it reduced the rate of epilepsy in adult rats with IS. The same 3-day pulse of rapamycin was given to the “multiple-hit” rats and investigated in greater detail. In the absence of rapamycin, and similar to the clinical picture of some severe cases of IS in humans, rats eventually exhibited LGS-like features such as motor seizures during sleep and a distinct EEG pattern termed “slow spike-wave discharges”. Importantly, the pulse rapamycin treatment that had been used to stop spasms early in life significantly reduced the rate of epilepsy with motor seizures in adult rats with IS. Furthermore, rapamycin also reversed the sleep disorder seen in these rats, suggesting an interesting relationship between sleep and epilepsy. These preclinical findings raise hope that drugs like rapamycin may be developed for treatment of IS, to both stop spasms and prevent lifelong epilepsy and associated comorbidities, filling a current gap in the clinical management of IS.

Literature Cited

  1. Scantlebury, M.H. et al. A model of symptomatic infantile spasms syndrome. Neurobiol. Dis. 2010; 37(3): 604-612. 
  2. Pellock, J.M et alInfantile spasms: a U.S. consensus report. Epilepsia 2010; 51: 2175-2189. 
  3. D’Alonzo et al. West syndrome: a review and guide for paediatricians. Clin. Drug. Investig. 2018; 38: 113-124. 
  4. Nelson, J.A. et al. Evolution of infantile spasms to Lennox-Gastaut Syndrome: what is there to know J. Child Neurol. 2021; 36(9): 752-759. 
  5. Riikonen, R. Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs 2014; 28(4): 279-290. 
  6. Riikonen, R. Infantile spasms: outcome in clinical studies. Pediatr. Neurol. 2020; 108: 54-64. 
  7. Knupp, K.G. et alResponse to treatment in a prospective national infantile spasms cohort. Ann. Neurol. 2016; 79(3): 475-484 
  8. CURE Infantile Spasms Consortium, Lubbers, L., & Iyengar, S.S. A team science approach to discover novel targets for infantile spasms. Epilepsia Open 2020; 6(1): 49-61. 
  9. Raffo, E. et al. A pulse rapamycin therapy for infantile spasms and associated decline.Neurobiol. Dis. 2011;43: 322-329. 
  10. Akman, O. et al. Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions. Epilepsia 2021; 62(8): 1985-1999. 

Focused Ultrasound May Benefit Some Patients With Epilepsy

Article originally published in Epilepsia

Results from a study published in Epilepsia suggest that focused ultrasound, which can be used to non-invasively target circuits in the brain, may benefit some patients with epilepsy who experience seizures that do not respond to standard anti-seizure medications.

In the study of six patients with drug-resistant seizures, two patients had fewer seizures within three days of receiving focused ultrasound; however, one patient showed signs of more frequent subclinical seizures (which are not felt by the individual).

Imaging tests after the treatment revealed no negative effects on the brain. One patient reported feeling heat on the scalp during the treatment, and one patient experienced temporary memory impairment that resolved within three weeks.

Neuromodulation is an alternative treatment for drug-resistant epilepsy. Compared with the present modalities used in neuromodulation for epilepsy, focused ultrasound can access deeper brain regions and focus on the main target of the epileptic network in a relatively less invasive approach. It gives new hope and sheds new light for patients with drug-resistant epilepsy.”

Hsiang-Yu Yu, MD, senior author, Taipei Veterans General Hospital, Taiwan

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MicroRNAs in the Development of Resistance to Antiseizure Drugs and Their Potential as Biomarkers in Pharmacoresistant Epilepsy

Summary, article originally published in Epilepsia

Although many new antiseizure drugs have been developed in the past decade, approximately 30%–40% of patients remain pharmacoresistant. There are no clinical tools or guidelines for predicting therapeutic response in individual patients, leaving them no choice other than to try all antiseizure drugs available as they suffer debilitating seizures with no relief. The discovery of predictive biomarkers and early identification of pharmacoresistant patients is of the highest priority in this group. MicroRNAs (miRNAs), a class of short non-coding RNAs negatively regulating gene expression, have emerged in recent years in epilepsy, following a broader trend of their exploitation as biomarkers of various complex human diseases. We performed a systematic search of the PubMed database for original research articles focused on miRNA expression level profiling in patients with drug-resistant epilepsy or drug-resistant preclinical models and cell cultures. In this review, we summarize 17 publications concerning miRNAs as potential new biomarkers of resistance to antiseizure drugs and their potential role in the development of drug resistance or epilepsy. Although numerous knowledge gaps need to be filled and reviewed, and articles share some study design pitfalls, several miRNAs dysregulated in brain tissue and blood serum were identified independently by more than one paper. These results suggest a unique opportunity for disease monitoring and personalized therapeutic management in the future.

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CURE Epilepsy Discovery: Identification of Environmental Contributors to SUDEP

Key Points:

  • CURE Epilepsy awardee Dr. Franck Kalume and colleagues at the Seattle Children’s Research Institute and New York University sought to identify simple environmental factors that may increase the risk of SUDEP. 
  • The team examined the effects of increased temperature and moderate exercise on several basal involuntary bodily functions of an established mouse model of Dravet syndrome (DS), a severe form of epilepsy with an increased incidence of SUDEP. 
  • When compared to normal mice, DS mice showed diminished regulation of core body temperature as well as cardiac and respiratory function.
  • Understanding the mechanisms behind these impairments might help develop effective approaches to reduce the risk of and perhaps even prevent SUDEP.

Deep Dive:

Sudden unexpected death in epilepsy (SUDEP) is devasting event that occurs in approximately 1 in 1,000 people with epilepsy [1,2]. It appears to be related to seizure-induced dysfunction of the autonomic nervous system (ANS) [3] The ANS controls body functions essential for survival and is responsive to environmental changesSome of these functions include maintenance of core body temperature as well as tight regulation of heart and breathing rates. Previous research has revealed that disruptions in ANS function related to a seizure event are marked by diminished control of these three body processes, but the precise nature and mechanisms of these weakened responses are not clear.

Dr. Franck Kalume, a recipient of CURE Epilepsy’s Sleep and Epilepsy Award, generously funded by the BAND Foundation, explored this important area of research by utilizing his mouse model of Dravet syndrome (DS). [4] DS is a treatment-resistant form of epilepsy with a high risk of SUDEP, and an increased prevalence of ANS dysfunction. This particular mouse model was developed by deleting the gene linked to most cases of DS in humans (known as SCN1A), which is also one of the many genes responsible for propagating electrical signals in the brain.

The first set of experiments involved assessing the ability of DS mice to regulate 1) core body temperature, 2) heart rate, and 3) breathing rate in response to an increase in surrounding temperature, i.e., to 86-90°F. Responses from the DS mice and control mice were subsequently compared [5].  

Before elevating the external temperature, the internal body temperatures of both DS and control mice were similar. In the first 15 min after heat exposure, the core body temperature in both groups increased, although the absolute temperature and rate of this increase was much smaller in DS versus control mice. As exposure to heat was reduced, the core body temperature returned to baseline in control animals, but in DS mice, body temperature remained elevated. These observations suggest that DS mice have deficits in thermoregulation (an ability to control core body temperature).  

Dr. Kalume and his team developed another set of DS mice in which the SCN1A gene had been deleted only in neurons responsible for transmitting inhibitory electrical signals in the brain [5]. The same responses were observed in this second group of DS mice, indicating that thermoregulation is most likely mediated by these inhibitory neurons. 

Along with deficits in controlling core body temperature, the DS mice also had problems regulating cardiac and respiratory function in response to elevated temperature. Specifically, although the heart rate of DS mice increased to only half that of control mice, the rate of recovery was much slower after the heat source had been removed. Likewise, even though the breathing rates decreased in both DS and control mice in response to higher temperatures, it recovered partially in control mice but not at all in DS mice.  

The effect of moderate exercise (running on a treadmill) on heart rate as well as heart rate variability was also assessed [5]. During this exercise challenge, the highest heart rate level reached was much lower in DS than in control mice, and it took much longer for DS mice to reach their peak values. Similar responses were observed for heart rate variability, all of which suggest impaired cardiac function in DS. 

Together, these findings imply that there are clear abnormalities within the ANS of DS mice and, by extension, in people with DS and possibly other intractable epilepsies. Understanding the biological bases of these irregularities and how environmental changes may adversely affect them will likely assist in the development of novel methods to reduce seizure-related health consequences as well as the high risk of SUDEP.   

This work was conducted in collaboration with Dr. Orrin Devinsky of New York University. 

Read more about Dr. Kalume’s research in sleep and epilepsy here



Literature Cited

  1. Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088. 
  2. Devinsky, O. & Sisodiya, S.M. SUDEP: Advances and challenges. Epilepsy Curr. 2020; 20(6 Suppl): 29S-31S. 
  3. Kalume, F. Sudden unexpected death in Dravet syndrome: respiratory & other physiological dysfunctions. Respir. Physiol. Neurobiol. 2013; 189: 324-328. 
  4. Kalume, F. et al. Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 2013; 123: 1798-1808. 
  5. Sahai, N. et al. Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome. Neurobiol. Dis. 2021; 147: 105154. 

CURE Epilepsy Discovery: Optimizing Brain Stimulation for People with Drug-Resistant Epilepsy

Key Points:

• Taking Flight grantee Dr. Ankit Khambhati and colleagues at the University of California – San Francisco sought to understand why some people with drug-resistant epilepsy respond better than others to responsive neurostimulation (RNS) therapy.

• After examining the pattern of brain waves of approximately 50 patients, the investigators identified a new biomarker that could predict which people would most benefit from RNS therapy.

• This important finding has the potential to help neurologists decide which patients would benefit the most from an RNS device before it is actually implanted in the brain.

Deep Dive:

Of the millions of people who are impacted by epilepsy, approximately one-third do not respond to currently available antiseizure medications [1], adversely affecting their quality of life. Among those with drug-resistant focal epilepsy (seizures that start from a single area in the brain, formerly known as partial seizures), one of the more effective treatment options involves brain stimulation [2], including the Neuropace Responsive Neurostimulation System® (RNS) [3]. The RNS is a ‘smart’ device implanted on the surface of the brain, with two thin wires placed where the seizures begin. It monitors brain waves recorded from the wires to produce what is called an intracranial electroencephalogram (iEEG). When the RNS device senses abnormal neural activity, it responds with subtle electrical pulses to either terminate or suppress an emerging seizure. The iEEG data can also be mined for research purposes to identify changing patterns in the brain waves as a patient’s condition improves.

The RNS is effective at reducing seizures in many patients with focal epilepsy, but it does not work for every patient, and it is not clear why. Dr. Khambhati and his colleagues, Drs. Edward Chang and Vikram Rao, thought that the lack of response in some people may be related to some seemingly inconsistent observations from numerous clinical trials of the RNS System. As mentioned above, the RNS device was designed to send electrical pulses to terminate a developing seizure only when abnormal electrical activity was detected, but the researchers found actual stimulation often occurred more than 1,000 times a day. This did not correlate with the actual number of seizures reported suggesting a significant amount of abnormal activity between seizures. In addition, clinically significant improvements, i.e., reduction in seizure frequency, occurred gradually over time, often years rather than just immediately after electrical stimulation by RNS [4]. Together, these observations suggested that there is abnormal electrical activity that occurs between seizures, possibly exacerbating them, and that the RNS device both terminates seizures and may also slowly modify how they are generated.

To explore this possibility, Dr. Khambhati and colleagues capitalized on the availability of many years’ worth of iEEG data from approximately 50 patients with an implanted RNS device [5]. Upon close examination of the data, they found a wide range of RNS response effectiveness among these patients and categorized them in three separate groups: super, intermediate, and poor responders based on the percent reduction in seizures.

Comparing the iEEG patterns from each of these groups allowed the researchers to conclude that RNS therapy, in addition to suppressing an emerging seizure, was also inducing a rewiring of the epileptic network, essentially disrupting it. This, in turn, dramatically decreased the brain’s tendency to generate excessive excitatory electrical activity sufficient to trigger a seizure. More importantly, the researchers found that much of this rewiring was a result of stimulation that occurred between seizures rather than just before the “buildup” of electrical activity indicative of seizure onset. Furthermore, since each of the three responder groups exhibited different iEEG “fingerprints”, the researchers were also able to consolidate these data to generate a powerful algorithm that could examine iEEG patterns and pinpoint unique biomarkers reflecting a prospective patient’s likely response to an implanted RNS device.

With this critical advancement, clinical care of patients with focal epilepsy being treated with RNS therapy may be improved beyond the typical adjustment of stimulation parameters. Neurologists may now be able to predict how a patient will respond to RNS, better counsel patients on their prognosis, and adjust stimulation parameters accordingly. Ideally, this discovery will help determine if a patient will even benefit from RNS therapy before the device is even implanted in the brain, thereby reducing unnecessary treatment risks for patients with focal epilepsy.

Literature Cited
1. Chen, Z. et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018; 75: 279-286.
2. Foutz, T. & Wong, M. Brain stimulation treatments in epilepsy: basic mechanisms and clinical advances. Biomed. J 2021; in press
3. Morrell, M.J. RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011; 77: 1295-1304.
4. Nair, D.R. et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology 2020; 95: e1244-e1256.
5. Khambhati, A.N. et al. Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy. Sci. Transl. Med. 2021; 13(608): eabf6588.

A Possible New Pathway for Treating Epileptic Seizures in Patients with Autism

Autism affects about 2% of children in the United States, and about 30% of these children have seizures. Recent large-scale genetic studies revealed that genetic variants in a sodium channel, called voltage-gated sodium channel Nav1.2, is a leading cause of autism. Overactive sodium channels in the neuron cause seizures. Doctors often treat seizures by giving the patient a medication meant to close the sodium channels, reducing the flow of sodium through axons. For many patients such treatment works, but in some cases — up to 20 or 30% — the treatment doesn’t work. These children have “loss-of-function” variants in Nav1.2, which is expected to reduce the sodium channel activity as “anti-seizures.” Thus, how the deficiency in sodium channel Nav1.2 leads to seizures is a major mystery in the field that puzzles physicians and scientists.

Yang Yang, an assistant professor of medicinal chemistry and molecular pharmacology at Purdue University, and his team, including first-author of the paper post-doctoral researcher Jingliang Zhang, tackled the issue. They discovered that in Nav1.2 deficient neurons, the expressions of many potassium channels are surprisingly reduced. The Nav1.2 deficiency itself doesn’t cause seizures; the issue arises when the potassium channels over-compensate for the sodium channels’ deficiency by shutting down too many potassium channels, making the neuron hyperexcitable, which causes seizures. In such cases, treating the sodium channel clearly does not work. Yang and his team suggest that developing medicines to open the potassium channels would help control seizures in these patients. Notably, researchers from the University of California, San Francisco led by Kevin Bender’s research group made a similar observation independently. Yang and Bender’s papers were published back-to-back in the same issue of Cell Reports.

“We’re looking at genetic makeup, so doctors can proscribe a drug and gene therapy based on genes identified — personalized medicines,” Yang said. “Our research points toward a direction for future research, maybe future treatments. We are peacetime warriors, fighting humanity’s biggest enemy: disease. There are kids dying because of these conditions. Our goal is to help them, to help their parents and their families. This kind of basic research is a vital part of finding new drugs.”