News Topics: Treatments

CURE Epilepsy Discovery: Developing Precision Medicine Treatments for Genetic Epilepsies: Present Challenges, Recent Scientific Advances, and Future Prospects

Key Points:

  • Epilepsy is a serious neurological disorder with many possible causes, and those directly linked to genetic abnormalities have undergone significant scientific breakthroughs in recent years.
  • Precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”. This concept is being applied to genetic epilepsies, but significant challenges have limited the rate at which basic science has translated into new treatments.
  • New strategies and scientific techniques may hasten the process. A recent publication in Epilepsia highlights some of them, along with the basic science that has fostered the hope for the eventual realization of precision medicine [1]. The authors suggest that greater coordination of efforts by scientists, physicians, patient advocates, and the federal government will accelerate effective, ethical, and equitable precision medicine for genetic epilepsy.
  • This publication stems from discussions at the Epilepsy Precision Medicine conference, funded in part by CURE Epilepsy and held in Washington, DC in 2019. This conference brought together the many stakeholders involved in developing precision therapies for epilepsy including researchers, physicians, funding agencies, and people with lived experience to share their experiences of epilepsy. The publication’s writing team was led by recent CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD.

 

Deep Dive:

Epilepsy is a debilitating but surprisingly common neurological disorder, with 1 in 26 people in the United States developing it over the course of their lives [2]. Despite the availability of numerous antiseizure medications (ASMs), one-third of people with epilepsy have seizures that remain treatment-resistant [3]. There are many possible causes of epilepsy, ranging from traumatic brain injuries to specific genetic mutations. Regardless of the cause, treatment remains primarily empirical or based on observation, with patients and their epileptologists often trying different and multiple ASMs in an attempt to eliminate the seizures while managing unwanted side effects. Ideally, treatments for epilepsy would precisely target the underlying biological mechanism, control seizures, and reduce the occurrence of negative side effects.

Optimism for this approach of “precision medicine” for epilepsy grew following the complete sequencing of the human genome and fueled the hope that individual genetic information could be used to develop more specific ways to treat epilepsy. Precision medicine, also known as personalized medicine, is the “tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.” Unfortunately, for most types of genetic epilepsy, the individual genetic makeup of a patient has not yet translated to clinical application of precision medicines for epilepsy. This has been due, in part, to the complexity of the underlying biological mechanisms as well as limitations in the technologies needed to advance genetic discovery to appropriate treatments.

However, the authors describe how epilepsy research is entering an exciting new phase that may enable new precision therapies for many more types of genetic epilepsy. Over the last decade, significant progress in advancing precision medicine approaches has been achieved for epilepsies caused by discrete mutation(s) in a single gene. This work has involved 1) acceleration and efficiency of gene sequencing technology and identification of epilepsy-causing, including the location and type of specific mutations in the DNA sequence of these genes, and 2) clarification of the neuronal function(s)/dysfunction of the corresponding protein and underlying biochemical pathways. In addition, the development of specific laboratory methods such as cell-based models that replicate aspects of the structure and function of the human brain and the use of zebrafish that are sensitive to ASMs have accelerated the testing of novel epilepsy treatments. Finally, new epilepsy gene-targeted technologies, for example, antisense oligonucleotides, are being tested in clinical trials, and there is active discussion about changes in clinical trial design that could enable smaller clinical trials needed for rare genetic epilepsies.

Despite these successes, multiple challenges remain for the future development and accessibility of precision therapies for epilepsy. First, genetic testing and counseling remain inaccessible to many groups, including the elderly and the poor, across the world. Second, nearly 70% of epilepsy cases involve more than one gene and thus require an improved understanding of disease risk in the context of multiple genetic mutations, overall genetic background, and environmental exposure. Third, although gene therapy is conceptually encouraging there are challenges related to large-scale development of safe, ethical, and equitable delivery of gene-based therapies to overcome. It will be critical for the research community to work together to overcome these challenges to ensure the delivery of new precision therapies for genetic epilepsies.

An important driver for the advancements that have been made toward the development of precision therapies are the many new stakeholders calling for action. Numerous patient advocacy groups, professional societies such as the American Epilepsy Society, government and non-profit funding agencies such as the National Institute of Neurological Disorders and Stroke and CURE Epilepsy, respectively, have collectively called for a coordinated and systematic approach to developing new epilepsy treatments. Progress stemming from this call to action could bring a new age of treatments for those with epilepsy, shifting from observational experience to data-driven and patient-centered precision therapy.

 

Literature Cited:

  1. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, Goldberg EM, George AL, Lerche H, Weckhuysen S, Whittemore V, Berkovic SF, Lowenstein DH. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia 2022
  2. Hesdorffer D, Logroscino G, Benn E, Katri N. Cascino G, Hauser W. Estimating risk for developing epilepsy. A population-based study in Rochester, Minnesota. Neurology 2011; 76:23–27
  3. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs. A 30-Year Longitudinal Cohort Study. JAMA Neurology 2018 75:279-286.

Precision Medicine for Genetic Epilepsy on the Horizon: Recent Advances, Present Challenges, and Suggestions for Continued Progress

Featuring the work of CURE Epilepsy Chief Scientific Officer Dr. Laura Lubbers, CURE Epilepsy Advisors Dr. Daniel Lowenstein and Dr. Vicky Whittemore, and CURE Epilepsy grantees Dr. Juliet Knowles, Dr. Lori Isom and Dr. Ethan Goldberg

Abstract found on PubMed

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

Newly Discovered Peptide Could Prevent Seizures in Epilepsy, Alzheimer’s

Article published by BioSpace

A new peptide administered through a nasal spray shows promising results as an anticonvulsant and could ultimately be further developed as a treatment to prevent seizures in both epilepsy and Alzheimer’s disease (AD).

A study published in The American Society for Clinical Investigation outlines work conducted by researchers to develop a peptide called A1R-CT that disrupts the signaling between the molecule neurabin and the adenosine 1 receptor (A1R). A1R sits on the outside of the neuron and responds to adenosine, whereas neurabin binds to the receptor and blocks it from use.

It has previously been established that A1R has neuroprotective effects and that, when activated by adenosine, it mediates an anti-convulsant response. This, however, is often blocked by neurabin.

“Neurabin is a brake, so it doesn’t do too much,” Dr. Qin Wang, neuropharmacologist and founding director of the program for Alzheimer’s therapeutics discovery at the Medical College of Georgia at Augusta University, told Science News. “But now we need to remove it to unleash A1’s power.”

Decision Making in Stereotactic Epilepsy Surgery

Abstract found on Wiley Online Library

Surgery can cure or significantly improve both the frequency and intensity of seizures in patients with medication-refractory epilepsy. The set of diagnostic and therapeutic interventions involved in the path from initial consultation to definitive surgery is complex and includes a multidisciplinary team of neurologists, neurosurgeons, neuroradiologists, and neuropsychologists, supported by a very large epilepsy-dedicated clinical architecture. In recent years, new practices and technologies have emerged that dramatically expand the scope of interventions performed: stereoelectroencephalography has become widely adopted for seizure localization; stereotactic laser ablation has enabled more focal, less-invasive, destructive interventions; and new brain stimulation devices have unlocked treatment of eloquent foci and multifocal-onset etiologies. This article articulates and illustrates the full framework for how epilepsy patients are considered for surgical intervention, with particular attention given to stereotactic approaches.

Genetic Interaction Between Scn8a and Potassium Channel Genes Kcna1 and Kcnq2

Abstract found on Wiley Online Library

Voltage-gated sodium and potassium channels regulate the initiation and termination of neuronal action potentials. Gain-of-function mutations of sodium channel Scn8a and loss-of-function mutations of potassium channels Kcna1 and Kcnq2 increase neuronal activity and lead to seizure disorders. We tested the hypothesis that reducing expression of Scn8a would compensate for loss-of-function mutations of Kcna1 or Kcnq2. Scn8aexpression was reduced by administration of an antisense oligonucleotide (ASO). This treatment lengthened survival of the Kcn1a and Kcnq2 mutants, and reduced seizure frequency in the Kcnq2 mutant mice. These observations suggest that reduction of SCN8Amay be therapeutic for genetic epilepsies resulting from potassium channel mutations.

CURE Epilepsy Discovery: Identifying a Promising Novel Treatment for Infantile Spasms

Key Points:

  •  John Swann, PhD, and his team explored an underlying cause of infantile spasms (IS), a devastating epileptic encephalopathy (an epilepsy syndrome that can lead to deterioration of the brain) that typically begins within the first year of life. This new research, funded by the National Institutes of Health (NIH), was a direct result of Dr. Swann’s findings from his work as a member of the CURE Epilepsy Infantile Spasms Initiative, conducted from 2013-2017.
  • Standard treatments for IS work in only approximately 50% of patients and can have severe side effects. The need for additional effective therapies drove Dr. Swann and his team to explore a more effective treatment with fewer or, ideally, no side effects.
  • Through extensive experimentation with an established rat model of IS and parallel studies in human tissue removed during epilepsy surgery, Dr. Swann observed very low levels of an important growth factor in the brain which has the potential to be a promising new treatment for this severe form of epilepsy.


Deep Dive:

Infantile spasms (IS) is a rare catastrophic form of epilepsy with approximately 90% of the cases beginning within the first year of life [1,2]. The condition is characterized by seizures with sudden brief jerking movements of the arms and legs or head bobs and often, though not always, an atypical, chaotic pattern of brain waves on the electroencephalogram (EEG) known as hypsarrhythmia [3]. The seizures are accompanied by significant development delays as well as cognitive and physical deterioration [2]. Standard treatments include adrenocorticotropic hormone (ACTH) or prednisone, and the antiseizure medication vigabatrin [4]. Unfortunately, only approximately 50% of children with IS respond to these treatments and there remains no reliable way of predicting who will respond favorably [4]. Even if these treatments diminish IS symptoms for a specific patient, they can have serious side effects. Therefore, scientists have been searching for other drug targets with the ultimate goal of developing alternative therapies.

One of these scientists is Dr. John Swann, Professor of Pediatrics at the Baylor College of Medicine, Director of the Gordon and Mary Cain Pediatric Neurology Research Foundation, and Principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, who leveraged findings from his work as part of the CURE Epilepsy Infantile Spasms Initiative (2013-2017). With additional funding from NIH, Dr. Swann and his team used a previously developed rat model of IS [5] that mirrors many of this disorder’s symptoms, to investigate spasms that result from pediatric brain injuries, such as those suffered during a traumatic birth.

He and the team wanted to determine if the level of a substance known as insulin-like growth factor-1 (IGF-1) was altered in the injured brains of both their rat model and in IS patients, the latter using brain tissue from IS patients who had undergone neurosurgery to stop their seizures. The rationale behind this experiment was based on two observations. The first is that the level of IGF-1 in the cerebrospinal fluid of IS patients with preexisting brain damage is low [6], and second is that IGF-1 activates a biological pathway crucial for proper brain development and neuronal function [7]. As hypothesized, data revealed that IGF-1 levels were lower in brain tissue from both the rat model and from infants with IS. Data also showed that reduced expression of IGF-1 in the rat model affected the biological pathways critical for neurodevelopmental processes [8].

These promising findings suggested that increasing the amount of IGF-1 in the brains of the rat model might alleviate at least some of the symptoms of IS. To test this idea, the researchers employed a shorter version of IGF-1 called (1-3)IGF-1 which is a natural breakdown product of IGF-1 that can cross the blood-brain barrier with much higher efficiency than the full-length IGF-1 [9].

After confirming that (1-3)IGF-1 could activate the same biological pathways responsible for regulating the processes involved in early brain development as full-length IGF-1, the researchers administered it to their rat model and successfully eliminated both the spasms as well as the hypsarrhythmia in most rodents. This exciting finding suggests that this smaller (1-3)IGF-1 or perhaps an IGF-1-like drug may one day be used to treat IS patients immediately after the condition is diagnosed. This new approach could potentially reduce or even eliminate the associated neurodevelopmental and cognitive effects of this devastating disorder without the side effects of the currently available treatments. Dr. Swann states that this research and subsequent additional funding from NIH to continue the work would not have been possible without his participation in the CURE Epilepsy Infantile Spasms Initiative.

 

Literature Cited:

  1. Pellock, JM et al. Infantile spasms: a US consensus report. Epilepsia 2010; 51: 2175-2189
  2. Cowan, L.D. & Hudson, L.S. The epidemiology and natural history of infantile spasms. Child Neurol. 1991; 6(4): 355-364.
  3. Gibbs, E.L., Fleming, N.M, & Gibbs, F.A. Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics 1954; 13(1): 66-73.
  4. Knupp, K.G. et al. Response to treatment in a prospective national infantile spasms cohort. Neurol. 2016; 79(3): 475-484.
  5. Lee, C.L. et al. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia 2008; 49(2): 298-307.
  6. Riikonen, R.S. et al. Insulin-like growth factor-1 is associated with cognitive outcome in infantile spasms. Epilepsia 2010; 51(7): 1283-1289.
  7. O’Kusky, J. & Ye, P. Neurodevelopmental effects of insulin-like growth factor signaling. Neuroendrocrincrinol. 2012; 33(3): 230-251.
  8. Ballester-Rosado, C.J. et al. A role for insulin-like growth factor 1 in the generation of epileptic spasms in a murine model. Neurol. 2022; 92(1): 45-60.
  9. Yamamoto, H. & Murphy, L.J. Enzymatic conversion of IGF-1 to des(1-3)IGF-1 in rat serum and tissues: a further potential site of growth hormone regulation of IGF-1 action. Endocrinol. 1995; 146(1): 141-148.

KETASER01 [A Trial to Test the Efficacy of Ketamine in Refractory Convulsive Status Epilepticus in Children]: What Went Right and What Went Wrong

Abstract found on Wiley Online Library

SUMMARY

Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies.

Methods: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children.

Results: During the five-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the ten participating Centers; only ten individuals (five for each study arm; five females, mean age 6.5 ±?6.3?years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s).

Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.

Emory Neuroscientists Aim to Develop Anti-Inflammatory Drugs for Epilepsy Patients

Article published by Emory News Center

The National Institute of Neurological Disorders and Stroke (NINDS) has awarded Emory neuroscientists a three-year, $2 million grant to develop new anti-inflammatory drugs for the prevention of comorbidities related to epilepsy.

Thota Ganesh, PhD, and Ray Dingledine, PhD, have been investigating the potential for EP2 antagonists, which inhibit signals from inflammatory prostaglandins, to prevent the development of comorbidities associated with epilepsy. Ganesh says EP2 antagonists act as a sort of “fire extinguisher,” interrupting the chain of events occurring in the brain in response to an initial injury by seizures.

“In animal models, we have shown EP2 receptor activation is responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficits that follow seizure-provoked induction of the enzyme cyclooxygenase 2,” Ganesh says.

The researchers will conduct further studies to identify EP2 antagonist candidate compounds for eventual study in human clinical trials. They hope to develop the first preventative treatment for cognitive deficits related to epilepsy through this research.

Xcopri Provides Long-Term Seizure Control in Patients with Focal Epilepsy

Article published by Healio

Featuring the work of CURE Epilepsy grantee Dr. Pavel Klein

Long-term use of Xcopri was safe and reduced seizures by more than 90% in adults with uncontrolled focal seizures, according to results of an open-label extension study published in Neurology.

“The findings show that the notable improvement in seizure control that was seen in patients with uncontrolled focal epilepsy is sustained over long term,” Pavel Klein, MD, lead study author and epileptologist and neurologist at Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md., told Healio. “The study shows that a significant proportion of patients with uncontrolled epilepsy continue to remain seizure-free or have at least 90% reduction for a period of time that sustained over the duration of the study — for years.”

Klein and colleagues conducted a randomized, double-blind, placebo-controlled study of Xcopri (cenobamate, SK Life Science Inc.) and assessed data from 355 adult patients with focal seizures that were uncontrolled despite being treated with up to three antiseizure medications.

According to a press release about the study findings from SK Life Science, participants, who had at least eight seizures during the 8-week baseline period, completed the 18-week, double-blind phase and continued into the open-label extension.

CURE Epilepsy Discovery: Investigating Mechanism of the Progression of Epilepsy

Key Points:

  • The development of seizures is associated with many changes in the brain; one of these changes is alterations in the white matter (the deep part of the brain) composed of axons covered in myelin. Myelin is a substance that acts as a nerve insulator and is critical for communication between neurons.
  • Dr. Juliet Knowles at Stanford University was granted both a CURE Epilepsy Taking Flight and a CURE Epilepsy Research Continuity Fund award to investigate whether changes in myelin might play a role in the development of epilepsy. Through her research, the team discovered that abnormal neuronal activity during absence seizures may lead to changes in myelination. The changes in myelin, in turn, lead to seizure progression.
  • This research paves the way for future studies that may identify ways to prevent harmful changes in myelination to treat some forms of epilepsy.


Deep Dive:

Some types of epilepsy are progressive, and the disease progression may manifest in the form of more frequent seizures, worsened control of seizures, or decline of cognition.[1] Progression of seizures has a direct correlation to the severity of epilepsy as time progresses.[2] Multiple factors may contribute to how seizures progress, but one factor that had not been investigated is a change, (known as plasticity), in the white matter or myelin of the brain. Myelin is a substance that acts as a form of insulation around the nerve cells of the brain and is essential for the conduction of electrical impulses between neurons and for the proper functioning of the brain. In fact, this white coating of myelin is what gives the collection of axons deep inside the brain the name “white matter”. Plasticity or changes in myelination can occur in response to neuronal activity and are important in the non-epileptic brain for functions such as learning, memory, and attention.[3,4] The team found that seizures in newborn infants with genetic forms of epilepsy may be associated with abnormalities in myelination.[5] These findings suggested that myelin plasticity might also occur in response to seizures. 

With her CURE Epilepsy Taking Flight Award, generously funded by the Ravichandran Foundation, Dr. Knowles and her colleagues sought to determine whether changes in myelination caused by a type of seizure called an absence seizure (formerly known as a petit mal seizure) contribute to the progression of epilepsy.[6] And when COVID-19 forced this study to be put on a temporary hold, the CURE Epilepsy Research Continuity Fund award, generously funded by the Cotton Family in memory of Vivian Cotton, helped Dr. Knowles’ team to finish these experiments when laboratories reopened. For her study, Dr. Knowles hypothesized that changes in myelin might influence seizure severity in absence seizure spreading.

Absence seizures are characterized by the abrupt stopping of behavior (“behavioral arrest”) and a specific pattern of brain activity. Even though absence seizures are typically brief, an individual can have an extremely high number of seizures in a day.[7, 8] Absence seizures originate in connections between two parts of the brain called the thalamus and cortex, after which seizure activity is transmitted through a large brain network by myelin-coated axons in white matter.[9, 10] 

The team used rodent models which had specific genetic mutations in their neurons that produce absence seizures. The pattern of seizure progression in these animals is similar to what is found in children with progressive forms of epilepsy.[2, 8] Electroencephalogram (EEG) was used to study electrical activity in the brain and the structure of neurons was examined using sophisticated microscopy techniques.[6] Additional techniques used to investigate the role of seizures in myelination included genetic interventions to block myelination (the process by which layers of myelin are produced) and drugs that decreased seizures.[6]

By using these methods, Dr. Knowles’ team first observed that there was an increase in myelination within the seizure network in seizure-prone animals, but this was seen only once seizures had started. This suggests that there is something unique and specific about the seizure activity that impacts myelination. Additionally, when Dr. Knowles’ team blocked seizures either genetically or using drugs, the increase in myelination was prevented. When the team blocked this abnormal myelination, the number of seizures decreased, and neuronal hypersynchrony decreased as well.[6] Neuronal hypersynchrony is the process by which networks of neurons fire together in an extremely organized and coordinated but abnormal way and is thought to underlie some aspects of seizure onset and spreading.[11]

The current study by Dr. Knowles’ group is the first that clearly shows that abnormal neuronal activity (in this case, due to absence seizures) can lead to harmful changes in myelination, which contribute to the continued progression of epilepsy.[6] Future work in the field will look at the exact molecules and neurotransmitters involved to better characterize this change in myelination. Although more studies are necessary, the current work suggests that developing treatments that address both abnormal neuronal activity and the associated abnormal myelination could more effectively prevent seizures and cognitive difficulties.[12] 

 

Literature Cited:

  1. Coan AC, Cendes F. Epilepsy as progressive disorders: what is the evidence that can guide our clinical decisions and how can neuroimaging help? Epilepsy Behav. 2013 Mar;26:313-321.
  2. Brigo F, Trinka E, Lattanzi S, Bragazzi NL, Nardone R, Martini M. A brief history of typical absence seizures – Petit mal revisited Epilepsy Behav. 2018 Mar;80:346-353.
  3. McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination Science. 2014 Oct 17;346:318-322.
  4. Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation Nature Neuroscience. 2020 2020/04/01;23:487-499.
  5. Sandoval Karamian AG, Wusthoff CJ, Boothroyd D, Yeom KW, Knowles JK. Neonatal genetic epilepsies display convergent white matter microstructural abnormalities Epilepsia. 2020 Dec;61:e192-e197.
  6. Knowles JK, Xu H, Soane C, Batra A, Saucedo T, Frost E, et al. Maladaptive myelination promotes generalized epilepsy progression Nature Neuroscience. 2022 2022/05/01;25:596-606.
  7. Albuja A.C. KGQ. Absence Seizure. [Updated 2021 Dec 13]. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing 2022.
  8. Guerrini R, Marini C, Barba C. Generalized epilepsies Handb Clin Neurol. 2019;161:3-15.
  9. Musgrave J, Gloor P. The role of the corpus callosum in bilateral interhemispheric synchrony of spike and wave discharge in feline generalized penicillin epilepsy Epilepsia. 1980 Aug;21:369-378.
  10. Fogerson PM, Huguenard JR. Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations Neuron. 2016 Nov 23;92:687-704.
  11. Jiruska P, de Curtis M, Jefferys JGR, Schevon CA, Schiff SJ, Schindler K. Synchronization and desynchronization in epilepsy: controversies and hypotheses J Physiol. 2013;591:787-797.
  12. Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy Epilepsia. 2018 Feb;59:273-290.