World’s First Minimally Invasive Brain Pacemaker Reduces Seizures in Epileptic Patients

Article published by HospiMedica

Epilepsy is among the most prevalent neurologic disorders and affects around 1% of the global population. Despite the availability of new antiseizure medications (ASMs), over a third of epilepsy patients fail to respond to drug therapy, particularly those with focal epilepsy, and many are not candidates for epilepsy surgery. Therefore, alternative treatment strategies are necessary. Focused cortical stimulation is an innovative procedure that provides a novel approach to treating epileptic seizures and favorably influencing the course of the disease for patients with inoperable forms of focal epilepsy. Now, the world’s first minimally invasive brain pacemaker utilizes a pioneering procedure that uses subcutaneous electrodes positioned outside the cranium to suppress epileptic seizures in patients with focal epilepsy that is resistant to drug therapy.

Precisis GmbH (Heidelberg, Germany) has developed EASEE (Epicranial Application of Stimulation Electrodes for Epilepsy), a system for individualized brain stimulation, which is implanted under the scalp, specifically over the epileptic focus in the brain, without opening the cranial bone or touching the brain tissue. EASEE functions through a dual mode of action: high-frequency pulses every two minutes provide an acute, disruptive effect to prevent seizures, while a 20-minute daily application of continual current regulates hyperactive brain regions in the long term.

Monash Funded $3M for a World-First Trial of a Drug Treatment for Poorly Controlled Epilepsy

Article published by Monash University

Epilepsy affects over 150,000 Australians, and 50 million globally, with one-third struggling to control their condition with currently available anti-seizure medications. These patients with drug-resistant epilepsy have high rates of disability, mental health and thinking problems, and injury and death rates.

Now, for the first time, a new drug has been discovered that is the first potentially curative drug for people with epilepsy who are resistant to control with current anti-seizure drugs. All currently available drugs used to treat people with epilepsy are symptomatic (only reducing seizure frequency in less than 70 per cent of cases), but without a sustained effect to mitigate or cure epilepsy or its associated conditions.

In a study published in the prestigious journal, eLife, and led by Dr Pablo Casillas-Espinosa and Professor Terry O’Brien from Monash Neuroscience and the Alfred, the researchers report that sodium selenate could be the first medical disease-modifying therapy for epilepsy.

According to Dr Casillas-Espinosa, current therapies target symptoms only, “so when a patient stops or misses the medication they are as likely to have a seizure as if they had been untreated, and importantly one-third of patients don’t respond to any treatments so far,” he said.

Drug-resistant epilepsy is associated with significantly increased morbidity, mortality and cost of care.

The study, conducted in animal models revealed sodium selenate to have a long-lasting effect (after months of stopping the medication) in reducing the frequency of seizures (and in 30 per cent of cases stopping them altogether) and improving other aspects of epilepsy such as memory, learning and sensor-motor functioning.

On the strength of these findings, the researchers have been awarded a $3 million Medical Research Future Fund (MRFF) grant to start a clinical trial of sodium selenate as a curative treatment in patients with drug-resistant epilepsy. This is one of 21 Monash University medical and health research projects that received funding from the Australian Government through the MRFF announced on Tuesday 14 March 2023.

Outcomes of the Second Withdrawal of Anti-Seizure Medication in Patients with Pediatric Onset-Epilepsy

Abstract found on PubMed

Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success or recurrence rate and risk factors for seizure recurrence after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.

Highly Purified Cannabidiol Improves Stability and Postural Tone in Adult Patients with Lennox-Gastaut Syndrome: a Case Series

Abstract found on PubMed

Lennox-Gastaut Syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous antiseizure medication treatment helps reduce seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help manage patients with LGS regarding seizure control and improve other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug’s effect on the brain locomotor centers, as demonstrated in animal model studies.

CURE Epilepsy Discovery: CURE Epilepsy Grantee Discovers Specific Alterations in the Inhibitory Neurotransmitter System in Infantile Spasms (IS)

Key Points:

Infantile spasms (IS), also called West syndrome, is a rare epilepsy syndrome associated with stereotypical spasms, developmental delay, and a telltale brainwave pattern. Medications used to treat IS are not effective in everyone with IS and are associated with side effects.
CURE Epilepsy launched the Infantile Spasms Initiative (IS Initiative) in 2013 with a team science approach to bring together groups of investigators working on diverse topics related to IS; this one-of-a-kind initiative in epilepsy research contributed immensely to today’s understanding of IS and its mechanisms.
One of the Initiative’s grantees, Dr. Chris Dulla, developed a mouse model that simulates the neuronal excitation and inhibition relevant to IS. Animal models are incredibly useful to understanding the biological mechanisms underlying IS, and by better understanding the interplay between neural excitation and inhibition in IS, there is hope that we can develop targeted therapies.

Deep dive

Infantile spasms (IS) is a devastating and rare epilepsy syndrome that is typically seen in the first year of a child’s life, most commonly between four and eight months of age.[1, 2] One in 2,000 children is affected by infantile spasms, and worldwide it is estimated that one baby is diagnosed with IS every 12 minutes.[3] IS consists of the following characteristics: subtle seizures consisting of repetitive, but often subtle movements—such as jerking of the mid-section, dropping of the head, raising of the arms or wide-eyed blinks; developmental delay and cognitive and physical deterioration; and a signature disorganized, atypical brainwave pattern called “hypsarrhythmia.”[4, 5] Potential causes include brain injuries or infections, issues with brain development and malformations, gene variants, or metabolic conditions. IS can sometimes have an underlying genetic cause as well.[2, 6] Often, infants appear to develop normally until spasms start, but then show signs of regression. Some infants may have hundreds of such seizures a day.

Current treatment for IS consists of hormonal therapy such as adrenocorticotropic hormone and prednisone, and antiseizure medications such as vigabatrin. These medications are effective in approximately half of the patients with IS.[7, 8] Even infants who have been diagnosed in a timely fashion may not respond to the available treatments, or they may suffer adverse side effects. There is no reliable way to predict who will respond favorably to medications.

As there was a dire need to better understand and treat IS, because there was no advocacy group or organization dedicated to IS and no organization was focusing on finding treatments or cures, CURE Epilepsy stepped in and leveraged our expertise as well as our resources to assemble the Infantile Spasms (IS) Initiative in 2013. Committing $4 million, the Initiative brought together eight research teams working on various aspects of IS. [9] Team science” is a unique way of conducting research that leverages the strengths and expertise of scientists trained in different but related fields to solve a single, complex problem. CURE Epilepsy’s IS Initiative was the first team science approach in the epilepsy research community, and teams in the Initiative benefitted from sharing knowledge and resources to expedite understanding of IS. [9] Collectively, the Initiative studied the basic biology that may explain what causes IS, searched for biomarkers and novel drug targets, and explored ideas for improved treatments for the condition. [9]

One of the eight teams involved in the Initiative was led by Dr. Chris Dulla and his laboratory at Tufts University. Dr. Dulla’s team developed an animal model for IS by targeting a gene called Adenomatous polyposis coli (APC). For the epilepsies in general, animal models are crucial to understanding the biological mechanisms that cause seizures. Dr. Dulla’s team developed an animal model for IS by targeting a gene called Adenomatous polyposis coli (APC). Mice that were genetically altered to have a decrease in the activity of APC exhibited many of the features that were reminiscent of human IS.[10] The development of this mouse model (called “APC cKO”) was an important step in IS research as it provided a way for scientists to study IS and the mechanisms that may cause it.

Broadly speaking, there are two kinds of neurons (brain cells): “excitatory” neurons that activate other neurons, and “inhibitory” neurons that restrain other neurons. A fine balance between excitation and inhibition is critical for the brain to function, and in epilepsy, this delicate balance may be disturbed. Inhibitory neurons are modulated by a neurotransmitter called gamma amino butyric acid (GABA). In the current study, Dr. Dulla’s team wanted to study GABAergic neurotransmission in the APC cKO model. Previous studies have shown a link between GABAergic neurotransmission and IS; specifically, alterations in GABAergic transmission have been found in animal models of IS [11, 12] and in human patients with IS.[13] The ultimate goal is to better understand the interplay between excitatory and inhibitory neurotransmission in IS.[14]

In a recent study that was published in February 2023, Dr. Dulla’s team studied inhibitory neurons (also called “interneurons,” abbreviated to “INs”). They looked at a certain kind of interneuron, called a parvalbumin-positive interneuron (PV+ IN) and studied the way these interneurons looked under the microscope (i.e., their anatomy) as well as the way they functioned (i.e., their physiology). In humans, IS has a time course in terms of when seizures start. To recreate this in their mouse model, the team studied APC cKO mice at multiple time points: in infancy (postnatal days 9 and 14), and then later, as adults, and compared them to mice that did not have the genetic mutation (i.e., “wild-type” mice). The goal of the study was to understand what happens to PV+ INs in the APC cKO mouse model of IS.[14]

In normal brain development, an excess of PV+ INs are made, but then they disappear over time. The first discovery Dr. Dulla’s team made was that in APC cKO mice, there is an excess of PV+ IN death. The second important finding was that in APC cKO mice, the death of these PV+ INs occurred earlier in development as compared to wild-type mice.[14] This change in the pattern of death of PV+ INs could mean that there are subtle changes taking place in the neural circuit. Since the primary role of interneurons is to keep brain activity in check, an excess of interneurons dying very quickly may mean that the excitatory neurons run amok. In contrast, other types of interneurons did not show accelerated dying, but this change was specific to PV+ INs.[14] The change in the pattern of PV+ IN cell death in APC cKO mice was also reflected in the functioning of the brain as studied by looking at the electrical activity in the brain.14 The changes seen in the interneuron death and associated function were more pronounced at postnatal day 9 (as compared to postnatal day 14), which suggests that this is the critical period in brain development in this model, when, if GABAergic inhibition is perturbed, may lead to IS and associated symptoms.

In totality, Dr. Dulla’s findings regarding GABAergic neurotransmission and PV+ INs are complicated with respect to the sequence and timing of events. However, there is a variation in the way the inhibitory GABAergic neuronal circuitry develops and matures in APC cKO mice that suggests a critical window of events that if perturbed, may lead to spasms and behavioral impacts later on. This work positions PV + INs as a potential target to treat IS, and perhaps even offers avenues for timely diagnosis.[14] This perturbation of inhibition during a critical period in development may contribute to spasms and seizures later in life. The development of the GABAergic circuitry depends on brain activity; hence, the changes in activity of the neural circuitry seen in APC cKO mice interneurons may contribute to long-term changes in the brain. The exact link between the PV+ IN death in early development and behavioral spasms needs to be investigated in more detail, but this work lays the foundation to continue studying inhibitory transmission in IS. Future studies will reveal if stopping this excess PV+ IN death may be a therapeutic target or a cure for Infantile Spasms.

Literature Cited:

Hrachovy RA. West’s syndrome (infantile spasms). Clinical description and diagnosis Adv Exp Med Biol. 2002;497:33-50.
Shields WD. Infantile Spasms: Little Seizures, BIG Consequences. Epilepsy Curr. 2006;6:63-69
Smith MS MR, Mukherji P. Infantile Spasms. Treasure Island (FL): StatPearls [Internet]; StatPearls Publishing Updated 2022 May 29.
Eling P, Renier WO, Pomper J, Baram TZ. The mystery of the Doctor’s son, or the riddle of West syndrome Neurology. 2002 Mar 26;58:953-955.
Lux AL. West & son: the origins of West syndrome Brain Dev. 2001 Nov;23:443-446.
Osborne JP, Edwards SW, Dietrich Alber F, Hancock E, Johnson AL, Kennedy CR, et al. The underlying etiology of infantile spasms (West syndrome): Information from the International Collaborative Infantile Spasms Study (ICISS) Epilepsia. 2019 Sep;60:1861-1869.
Knupp KG, Coryell J, Nickels KC, Ryan N, Leister E, Loddenkemper T, et al. Response to treatment in a prospective national infantile spasms cohort Ann Neurol. 2016 Mar;79:475-484.
Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013 Brain Dev. 2014 Oct;36:739-751.
Lubbers L, Iyengar SS. A team science approach to discover novel targets for infantile spasms (IS). Epilepsia Open. 2021;6:49-61.
Pirone A, Alexander J, Lau LA, Hampton D, Zayachkivsky A, Yee A, et al. APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal ?-catenin levels, neonatal spasms, and chronic seizures Neurobiol Dis. 2017 Feb;98:149-157.
Marsh E, Fulp C, Gomez E, Nasrallah I, Minarcik J, Sudi J, et al. Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females Brain. 2009 Jun;132:1563-1576.
Katsarou AM, Li Q, Liu W, Moshé SL, Galanopoulou AS. Acquired parvalbumin-selective interneuronopathy in the multiple-hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs? Epilepsia Open. 2018 Dec;3:155-164.
Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings Ann Neurol. 2002 Mar;51:340-349.
Ryner RF, Derera ID, Armbruster M, Kansara A, Sommer ME, Pirone A, et al. Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome J Neurosci. 2023 Feb 22;43:1422-1440.

Epilepsy Research News: March 2023

This issue of Epilepsy Research News includes summaries of articles on:

Epilepsy-Causing Neural “Hubs” in Children

A new method of determining which brain cells lead to seizures in children has been developed. The team used noninvasive techniques and advanced computational methods to measure the electric and magnetic signals generated by neural cells to identify brain “hubs” responsible for the generation of seizures in children with epilepsy. This team retrospectively analyzed electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who had neurosurgery. They then created a virtual model of the brain and virtually implanted sensors at locations where invasive EEG contacts had been placed during neurosurgery. The researchers found that the virtual sensors could non-invasively identify highly connected hubs in patients with drug-resistant epilepsy. The authors stated that the discovery could help to identify areas of the brain that generate epileptic activity in children with drug-resistant epilepsy in a non-invasive way.

Learn More

Potential Cause of Infantile and Epileptic Spasms Syndrome

New research featuring the work of a former CURE Epilepsy grantee, Dr. Chris Dulla, and colleagues suggests that the timing of the death of a subset of neurons in the brain shortly after birth may be partly to blame for infantile and epileptic spasms syndrome (a form of which is also called infantile spasms (IS) or West syndrome), a childhood epilepsy with poor outcomes. These neurons are responsible for providing inhibitory input to the brain; the lack of these neurons may lead to too much excitation and epileptic spasms. The research suggests that it may be the timing of inhibitory neuron cell death which is important, not just the fact that it occurs. This research may suggest a potential target for the future development of treatments for infantile and epileptic spasms.

Learn More

Underreported Symptoms in Patients with Genetic Epilepsy

A new study increases our understanding of symptoms associated with changes in the STXBP1 gene, one of the most common genetic causes of childhood epilepsies and neurodevelopmental disorders. By systematically mapping symptoms and assessing their impacts on patients and their caregivers, the researchers identified previously underreported symptoms beyond just neurological symptoms. To understand these symptoms, the researchers performed more than 24 hours of interviews among 19 caregivers of 16 individuals with STXBP1-related disorders and seven healthcare professionals. In doing so, the researchers created a so-called “disease concept model,” which is meant to determine which outcomes are relevant in everyday clinical practice. These results may serve as an important foundation for future trials assessing the effectiveness of therapeutic interventions for all related symptoms.

Learn More

How Cannabidiol Counters Epileptic Seizures

A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy. The new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can also be hijacked by disease to promote seizures. The work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings suggest for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment. “Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” stated a study author. “The study also clarified, not just how CBD counters seizures, but more broadly how neural circuits are balanced in the brain.”

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How the Brain’s Immune System Response Worsens Epilepsy

In a new study using a fruit fly model of epilepsy, researchers describe a chain of events that link the brain’s immune system response to worsening seizures. The researchers used flies with a mutation in a gene known as the prickle gene, similar to the mutation in the PRICKLE gene found in humans with progressive myoclonus epilepsy with ataxia, and found that this particular mutation can lead to increases in a condition called oxidative stress. The researchers found that oxidative stress can activate the brain’s resident immune cells (called glia), which in turn triggers more severe seizures. “We have provided genetic proof that both oxidative stress and activation of the brain immune system make epilepsy worse,” stated a study author. “This is hugely significant because our data suggest that we can now repurpose exceedingly well-tolerated anti-inflammatory compounds as well as perhaps antioxidants to help control epilepsy progression.”

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CURE Epilepsy Discovery: Implantable Devices Represent a Novel Way to Detect and Treat Epilepsy

Key Points:

Approximately one-third of people with epilepsy do not respond to anti-seizure medications and there are limited treatment options for these treatment-resistant cases.
Implantable epilepsy devices offer novel avenues to detect and treat seizures by recording seizure activity from neurons (brain cells) in high-resolution and stimulating these neurons in a way that halts seizures.
Brian Litt at the University of Pennsylvania was funded by CURE Epilepsy in 2011, and his work has led to the development of electrodes and technology that offer incredible precision in recording from and stimulating neurons.
Litt’s trainees, Dr. Jonathan Viventi at Duke University and Dr. Flavia Vitale at the University of Pennsylvania, are continuing their work to develop cutting-edge implantable devices to understand and treat epilepsy at their own laboratories.

Deep dive

People with epilepsy are often prescribed anti-seizure medications (ASMs), and while they are effective in many people, about 30% of those with epilepsy continue to experience seizures. Resective surgery, where the part of the brain that generates seizures is removed, may be an option for some, but not all, people with treatment-resistant epilepsy (also called “refractory” epilepsy).[1] Devices for epilepsy represent an innovative treatment modality that has much to offer to those with treatment-resistant epilepsy.

Devices for epilepsy fall into two main categories: 1) wearable, seizure-alert devices, and 2) devices that are implanted in the body. Wearable devices can track seizures and alert a caregiver to the occurrence of a seizure. Wearable devices can have a positive impact on quality of life, and can contribute to the empowerment of the person with epilepsy by encouraging self-monitoring and self-management.[2,3] Implantable devices for epilepsy include neurostimulation devices. For example, responsive neurostimulation (RNS) devices) and deep brain stimulation (DBS) devices) reduce seizures by applying electrical stimulation to modulate brainwaves in specific areas of the brain. The RNS device can be thought of as a pacemaker for the brain; it is implanted near the seizure focus and allow for insertion of wires that send electrical pulses to interfere with seizure activity in surface areas of the brain, whereas the DBS sends electrical pulses through wires to specific areas deep within the brain that are involved with seizures.

Implantable devices hold substantial promise for those with refractory epilepsies who have inadequate therapeutic alternatives. It has been suggested that implantable devices may even become alternatives to multiple ASMs and resective epilepsy surgery.[4] The promise that devices hold for epilepsy therapy aligns with CURE Epilepsy’s goal to identify and fund cutting-edge research, challenging scientists worldwide to collaborate and innovate in pursuit of a cure for epilepsy. To this end, this CURE Epilepsy Discovery features our grantee, Dr. Brian Litt who is jointly appointed at the Perelman School of Medicine and the School of Engineering and Applied Science at the University of Pennsylvania, positioning his work is at the nexus of neuroscience and engineering.

One of the first and most impactful grants that Dr. Litt received was from CURE Epilepsy, in 2011 through “Julie’s Hope,” one of three CURE Epilepsy grants funded by Jim and Susan Schneider in honor of their daughter Julie. As a neurologist, Dr. Litt saw first-hand the impact of epilepsy on people’s lives and the lack of options that were available for refractory epilepsies. Back in 2011, the field of implantable devices used standard, rigid clinical electrodes that did not conform to the brain’s surface. Each electrode was connected to a wire, and the device was cumbersome and lent itself to surgical complications and errors. Also, given the large number of wires, it was not possible to effectively cover large areas of the brain. In his project, Dr. Litt wanted to accelerate the development of devices and demonstrate relevance in human epilepsy. Specifically, he worked to develop and refine flexible, active, implantable electrodes to monitor and stimulate the brain with a goal to cure epilepsy. Work done for this grant led to the implantation of these flexible electrodes into experimental animals to record seizures and to stimulate the brain to control seizures.[5]

Over the years, Dr. Litt’s work has led to many other discoveries. Some of the most notable ones are the use of high-resolution, active, flexible surface electrode arrays to distinguish between seizures (“ictal” events) and in-between seizures (“interictal” events). By better visualizing brainwave patterns during these specific times, we can better understand the mechanisms by which seizures begin and discover opportunities for therapeutic interventions to stop them.[6] Another notable area of work is the development of a transparent, graphene-based electrode technology that can simultaneously record brainwaves and perform optical imaging. This innovative approach allows for specificity of the brain recordings coupled with the capacity to visualize the brain regions being recorded. By studying brain activity in this way, we can better understand how the brain processes information which has implications beyond epilepsy.[7]

This work on implantable devices for epilepsy led to a large amount of data. Dr. Litt has been organizing and investigating this ‘big neuro data” by sharing it and collaborating with the international research community, using techniques such as cloud-based platforms and open data ecosystems.[8,9] On a broader level, Dr. Litt’s work with implantable electrodes has also led to the assembly of brain activity data across different epilepsy centers to be combined to create a “map” that may help guide epilepsy surgery.[10] Dr. Litt’s scientific contributions have led him to receive the NIH Director’s Pioneer Award in 2020,[11] awarded to “exceptionally creative scientists proposing pioneering approaches.” His work has also led to several patents.[12,13]

Dr. Litt is also passionate about mentoring scientists. Over the years, has trained over 50 scientists and clinician-engineers. Two of Dr. Litt’s trainees, Drs. Jonathan Viventi and Flavia Vitale are now established scientists carrying on the work to develop implantable electrodes to understand seizure dynamics and treat epilepsy. Dr. Viventi was awarded the Taking Flight Award by CURE Epilepsy in 2012 and is currently an Assistant Professor in the Department of Biomedical Engineering at Duke University. The focus of Dr. Viventi’s work is to create new technology to understand the workings of the brain at hundreds of times the resolution of current devices. By mapping the brain and its abnormal circuitry, Dr. Viventi hopes to use precision stimulation to stop seizures. His technology consists of thin-film electrode arrays that have hundreds of microelectrodes to precisely map seizure activity in the human brain. This device was tested in nine people with epilepsy, and Dr. Viventi’s team was able to precisely localize the brain areas where seizures were generated. In the future, this technology can be used to plan epilepsy surgery or target brain stimulation.[14]

Dr. Vitale is an Assistant Professor of Neurology at the University of Pennsylvania, and was awarded a Taking Flight Award by CURE Epilepsy in 2017. In this project, she wanted to focus on the concept that seizures begin in a specific region of the brain, the seizure onset zone (SOZ). Brainwaves travel or propagate to surrounding areas, ultimately resulting in seizures. The thought is that to achieve seizure freedom, the SOZ and the surrounding epileptogenic zone must be removed. However, the differentiation of these zones has been challenging using current modalities. Dr. Vitale proposed a technology to precisely map epileptic networks to understand what exact neurons were involved in seizure generation. By using tiny, flexible electrodes that can be independently controlled, she aims to understand seizures at a scale that had never been done before. Building on the work with graphene electrodes with Dr. Litt, Dr. Vitale has developed a technique to accurately map the spread of seizures by using transparent microelectrode arrays.[15] Her team is also working on the next generation of soft electrodes and techniques for safe and precise insertion of electrodes into brain structures.[16]

Thanks to Dr. Litt’s deep interest and investment in training of new scientists, he received the Landis Award for Outstanding Mentorship in 2022. Through his efforts, Dr. Litt has created a collaborative and nurturing environment in his lab, where trainees are selected not only on scientific merit but also on qualities such as thoughtfulness and real-world experience, and most importantly, the desire to use scientific knowledge for public betterment. Ever the champion of the trainees in his lab, Dr. Litt is actively equipping the next generation of brain scientists in the cross-disciplinary fields of neuroscience, surgery, engineering, computing, electronics, and device development.[17]

In conclusion, the funding that CURE Epilepsy provided to Dr. Litt in 2011 was the beginning of not only his scientific discoveries in the field of implantable devices but also an opportunity to deeply invest in the future and the next generation of scientists. While basic research can take decades to come to fruition, the rewards are great as it helps to build knowledge about how and why the brain generates seizures, and also provides insights into how the brain works in general. By funding basic research for epilepsy devices through Drs. Litt, Viventi, and Vitale, CURE Epilepsy positions the community to find a cure for epilepsy within our lifetime.

Literature Cited:

Mesraoua B, Deleu D, Kullmann DM, Shetty AK, Boon P, Perucca E, et al. Novel therapies for epilepsy in the pipeline Epilepsy Behav. 2019 Aug;97:282-290.
Verdru J, Van Paesschen W. Wearable seizure detection devices in refractory epilepsy Acta Neurol Belg. 2020 Dec;120:1271-1281.
Esmaeili B, Vieluf S, Dworetzky BA, Reinsberger C. The Potential of Wearable Devices and Mobile Health Applications in the Evaluation and Treatment of Epilepsy Neurol Clin. 2022 Nov;40:729-739.
Litt B. Evaluating devices for treating epilepsy Epilepsia. 2003;44 Suppl 7:30-37.
Viventi J, Kim DH, Vigeland L, Frechette ES, Blanco JA, Kim YS, et al. Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo Nat Neurosci. 2011 Nov 13;14:1599-1605.
Vanleer AC, Blanco JA, Wagenaar JB, Viventi J, Contreras D, Litt B. Millimeter-scale epileptiform spike propagation patterns and their relationship to seizures J Neural Eng. 2016 Apr;13:026015.
Kuzum D, Takano H, Shim E, Reed JC, Juul H, Richardson AG, et al. Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging Nat Commun. 2014 Oct 20;5:5259.
Wagenaar JB, Worrell GA, Ives Z, Dümpelmann M, Litt B, Schulze-Bonhage A. Collaborating and sharing data in epilepsy research J Clin Neurophysiol. 2015 Jun;32:235-239.
Wiener M, Sommer FT, Ives ZG, Poldrack RA, Litt B. Enabling an Open Data Ecosystem for the Neurosciences Neuron. 2016 Nov 2;92:617-621.
Bernabei JM, Sinha N, Arnold TC, Conrad E, Ong I, Pattnaik AR, et al. Normative intracranial EEG maps epileptogenic tissues in focal epilepsy Brain. 2022 Jun 30;145:1949-1961.
NIH Director’s Pioneer Award Recipients: 2020 Awardees. Available at: https://commonfund.nih.gov/pioneer/AwardRecipients20. Accessed February 7.
Echuaz JR WG, Litt B inventor; Active control of epileptic seizures and diagnosis based on critical systems-like behavior2012.
Vitale F ND, Nicholas A, Litt B, inventor; Rapid manufacturing of absorbent substates for soft, comformable sensors and conductors 2022.
Sun J, Barth K, Qiao S, Chiang CH, Wang C, Rahimpour S, et al. Intraoperative microseizure detection using a high-density micro-electrocorticography electrode array Brain Commun. 2022;4:fcac122.
Driscoll N, Rosch RE, Murphy BB, Ashourvan A, Vishnubhotla R, Dickens OO, et al. Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale Commun Biol. 2021 Jan 29;4:136.
Apollo NV, Murphy B, Prezelski K, Driscoll N, Richardson AG, Lucas TH, et al. Gels, jets, mosquitoes, and magnets: a review of implantation strategies for soft neural probes J Neural Eng. 2020 Sep 11;17:041002.
Litt B. Engineering the next generation of brain scientists Neuron. 2015 Apr 8;86:16-20.

New Method Finds Epilepsy-Causing Neural “Hubs” in Children

Article published by Inside Precision Medicine

A new, very precise, method of determining which brain cells lead to epileptic episodes in children has been developed by a team at University of Texas at Arlington and collaborators. Currently, epilepsy surgery is the safest and most effective treatment for these patients and offers a 50% chance of eliminating seizures.

The team used noninvasive techniques and advanced computational methods to measure the electric and magnetic signals generated by neural cells and identify functional networks responsible for the generation of seizures in children with epilepsy.

“This could benefit so many children who can’t control epilepsy with drugs, which represents between 20 and 30% of children suffering from epilepsy,” said Christos Papadelis, senior author, who also serves as the director of research in the Jane and John Justin Neurosciences Center at Cook Children’s Health Care System.

The paper was published in Brain, and the lead author is Ludovica Corona. It was produced in collaboration with Boston Children’s Hospital, Massachusetts General Hospital, and Harvard Medical School.

The Impact of Parent Treatment Preference and Other Factors on Recruitment: Lessons Learned from a Paediatric Epilepsy Randomised Controlled Trial

Abstract found on Trails Journal

Background: In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity.

Main body: In this paper, we critically reflect upon the factors which impacted recruitment to the pilot phase of a phase IV unblinded, randomised controlled 3×2 factorial trial examining the effectiveness of two antiseizure medications (ASMs) and a sleep behaviour intervention in children with Rolandic epilepsy. We consider the processes established to support recruitment, public and patient involvement and engagement (PPIE), site induction, our oversight of recruitment targets and figures, and the actions we took to help us understand why we failed to recruit sufficient children to continue to the substantive trial phase.

The key lessons learned were about parent preference, children’s involvement and collaboration in decision-making, potential and alternative trial designs, and elicitation of stated preferences pre-trial design.

Despite pre-funding PPIE during the trial design phase, we failed to anticipate the scale of parental treatment preference for or against antiseizure medication (ASMs) and consequent unwillingness to be randomised. Future studies should ensure more detailed and in-depth consultation to ascertain parent and/or patient preferences. More intense engagement with parents and children exploring their ideas about treatment preferences could, perhaps, have helped predict some recruitment issues. Infrequent seizures or screening children close to natural remission were possible explanations for non-consent. It is possible some clinicians were unintentionally unable to convey clinical equipoise influencing parental decision against participation. We wanted children to be involved in decisions about trial participation. However, despite having tailored written and video information to explain the trial to children we do not know whether these materials were viewed in each consent conversation or how much input children had towards parents’ decisions to participate. Novel methods such as parent/patient preference trials and/or discrete choice experiments may be the way forward.

Conclusion: The importance of diligent consultation, the consideration of novel methods such as parent/patient preference trials and/or discrete choice experiments in studies examining the effectiveness of ASMs versus no-ASMs cannot be overemphasised even in the presence of widespread clinician equipoise.

New Method Provides Important Insights into the Development of Epilepsy

Article published by News Medical Life Sciences

In epilepsy research, it has long been assumed that a leaky blood-brain barrier is a cause of inflammation in the brain. Using a novel method, researchers from Bonn University Hospital (UKB) and the University of Bonn have demonstrated that the barrier between the blood and the central nervous system remains largely intact. The approach of their study provides important insights into the development of epilepsy and could significantly optimize drug development in the pharmaceutical industry. The study results have recently been published in the renowned journal “Nature Communications”.

500 kilometers of vessels in the human brain are lined with ten square meters of thin cell layer – the blood-brain barrier (BBB). This barrier protects the brain against harmful substances as well as pathogens. It also links the brain to the other organs in the body. If this selective barrier is leaky, diseases such as Parkinson’s, multiple sclerosis, Alzheimer’s could develop. Malfunctions of the BBB also play an important role in brain tumors. Researchers at the UKB and the University of Bonn want to get to the bottom of these interactions. To study BBB transport at the cellular level, they developed micropipette-based local perfusion of capillaries, i.e. finest blood vessels, in acute brain slices and combined it with multiphoton microscopy.

Prof. Dirk Dietrich, head of the experimental neurosurgery section at the Clinic of Neurosurgery at the UKB, compares the new analysis technique of the blood-brain barrier investigated in the study to a flat bicycle tire: “If the tire loses air, you don’t know where the leak is. That’s why you hold the inflated bicycle tube under water to identify the leak. This principle also underlies our method.” The researchers use a micropipette to fill the microscopic blood vessels with a liquid from the inside. Leaks are then visible to them under the multiphoton microscope.