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:

1. 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.
2. Verdru J, Van Paesschen W. Wearable seizure detection devices in refractory epilepsy Acta Neurol Belg. 2020 Dec;120:1271-1281.
3. 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.
4. Litt B. Evaluating devices for treating epilepsy Epilepsia. 2003;44 Suppl 7:30-37.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. NIH Director’s Pioneer Award Recipients: 2020 Awardees. Available at: https://commonfund.nih.gov/pioneer/AwardRecipients20. Accessed February 7.
12. Echuaz JR WG, Litt B inventor; Active control of epileptic seizures and diagnosis based on critical systems-like behavior2012.
13. Vitale F ND, Nicholas A, Litt B, inventor; Rapid manufacturing of absorbent substates for soft, comformable sensors and conductors 2022.
14. 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.
15. 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.
16. 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.
17. Litt B. Engineering the next generation of brain scientists Neuron. 2015 Apr 8;86:16-20.