Despite decades of research that have led to an understanding of many causes of epilepsy and yielded over fifteen new antiseizure drugs and novel non-drug therapies, there remain no treatments that prevent epilepsy, nor are there ways to identify and prove such treatments. A major obstacle to research in this area is the fact that studies from single institutions are inadequate to answer the most important questions. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a large, international, multicenter Center without Walls (CWOW) to address this pressing need by using studies of animals and patients with traumatic brain injury (TBI) leading to post-traumatic epilepsy (PTE) to develop the techniques and patient populations necessary to carry out future cost effective full-scale clinical trials of epilepsy prevention therapies.

This is a project designed to facilitate the development of antiepileptogenic therapies by removing barriers and promoting large-scale collaborative research efforts by multidisciplinary teams of basic and clinical neuroscientists with access to extensive patient populations, well-defined and rigidly standardized animal models, and cutting-edge analytic methodology. We focus on antiepileptogenesis in PTE following TBI as this condition offers the best opportunity to determine the time of onset of the epileptogenic process in patients.

The EpiBioS4Rx Scientific Premise is: Epileptogenesis after TBI can be prevented with specific treatments; the identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. Based on the work from a P20 planning grant, our program will consist of the following: (1) identify biomarkers of epileptogenesis in our animal model and in patients, (2) Develop and utilize a standardized platform for preclinical trials of potential antiepileptogenic (AEG) drugs, (3) Identify 1 or more lead antiepileptogenic drugs for a future interventional clinical trial, (4) Establish a network of advanced TBI centers capable of carrying out future clinical trials featuring our lead antiepileptogenic drugs used in the context of a personalized, medicine-based approach utilizing our panel of biomarkers, and (5) Develop and incorporate a public engagement program involving the mutual education and collaboration of consumers, consumer organizations and professionals to design and execute future large-scale interventional clinical trials of antiepileptogenic therapies.

Study Design

We have chosen to focus on disease prevention, but results of our efforts could also inform approaches to disease modification. We plan a translational, international, multiple project, multicenter, multidisciplinary approach to: 1) identify biomarkers of epileptogenesis in our animal model and in patients, 2) develop a standardized protocol for preclinical trials of potential antiepileptogenic therapies and identify one or more potential antiepileptogenic agent, and 3) create open shared resources for the entire epilepsy research community, including an epilepsy specific bioinformatics platform and database, a robust animal model of TBI leading to PTE, a standardized preclinical protocol for the evaluation of novel antiepileptogenic therapies, a network of TBI centers capable of carrying out future clinical trials of potential antiepileptogenic interventions, and a public engagement program committed to recruitment and retention. We anticipate this work will result in one or more candidate antiepileptogenic treatments at the end of the 5-year funding period, as well as the biomarker information, resources, expertise, and patient population to carry out an economically feasible, full-scale clinical trial.

1) Identification of biomarkers and epileptogenesis in animals and patients: Even if a potential antiepileptogenic agent existed, there is no at-risk patient population in which to test its success cost effectively. We have created a collaborative multicenter, international research effort composed of multidisciplinary teams of basic and clinical neuroscientists with access to robust, well-defined animal models, extensive patient populations, standardized protocols, and cutting-edge analytic methodology. We expect that the predictive power will likely require a combination of electrophysiological, neuroimaging, and biochemical biomarkers measured at different post-injury time points, to diagnose with high sensitivity and specificity ongoing epileptogenesis independent of the severity of brain damage. We anticipate these studies will also provide insights into the fundamental neuronal mechanisms of these processes and inform basic research into novel targets for antiepileptogenic interventions.

2) Standardized preclinical trials of potential antiepileptogenic therapies and identification of one or more potential antiepileptogenic agents: Scientific evidence suggests that many compounds could have antiepileptogenic potential, but adequate evidence to justify a clinical trial is lacking, in large part due to failure to reproduce promising results in more than one laboratory and difficulty translating the preclinical to the clinical condition. This failure reflects the absence of a valid animal model of human epileptogenesis and a standardized preclinical trial protocol, which adheres to the same rigid criteria used for clinical trials. We have developed a robust standardized fluid percussion injury (FPI) rat model of TBI leading to PTE in our laboratories that replicates epileptogenesis following TBI in patients with moderate to severe TBI and have been carrying out parallel reiterative animal/human studies. We will use this model also to create a rigorous standardized protocol for testing potential antiepileptogenic therapies utilizing a double-blind randomized approach and the therapy-specific biomarkers as they become available in a manner that is reproducible in any laboratory that follows the standardized protocol. We anticipate that the identification and validation of antiepileptogenic treatments in the preclinical trials using the profile of identified biomarkers from the parallel animal/human research paradigms, together with the establishment of a network of TBI centers with appropriate facilities and expertise will enable preparation for a future, economically feasible, cost-effective, full-scale, clinical trial of safety and efficacy of antiepileptogenic therapies to prevent PTE.

3) Creation of open and shared resources for the entire epilepsy community: A key to the success of large multidisciplinary research efforts that generate “big data” is an effective shared bioinformatics approach to data storage and analysis. With the EpiBioS4Rx P20 planning grant, we have succeeded in developing a multimodality, interactive, open access bioinformatics platform specific for epilepsy and are using this resource to carry out our studies. We have achieved this short-term goal in part by leveraging programs already supported by NIH and other funding sources. We have unified the functionality between the International Electrophysiology Web Portal (iEEG.org) platform of Dr. Brian Litt, who will be providing his expertise as a consultant, and the Laboratory of Neuroimaging (LONI) platform of Dr. Arthur Toga. The latter has supported extensive studies of biomarkers and treatments for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, the genetic basis of aspects of hippocampal structure, and the exploration of computational genomics challenges. We are currently applying our bioinformatics algorithms to available animal and human electrophysiological and imaging data, and are collecting molecular, cellular, and other data to be integrated into this analytic process. Dr. Vespa from UCLA has recruited 13 TBI centers that will follow patients for two years to participate in our proposed clinical biomarker project. They will constitute a network with the facilities and expertise to perform the subsequent clinical trials once they are justified by preclinical studies and made feasible by biomarker identification. For the design of the future clinical trials, we developed an extensive public outreach program of epilepsy and TBI consumer groups committed to recruitment and retention of subjects and consumer satisfaction. We plan to make available to the greater epilepsy community all of our bioinformatics tools and resources, databank, biobank, experimental protocols for a standardized TBI/PTE animal model and preclinical evaluation of antiepileptogenic therapies, a network of TBI centers with facilities and expertise to carry out future clinical trials of antiepileptogenic interventions. To this end, collaborations have been established with a number of related programs, including Epi4K, EpGP, EPITARGET, FEBSTAT, TRACK-TBI, CENTER-TBI, ADAPT, CSR, and the VA Epilepsy Centers of Excellence to expand the patient population available for future clinical trials.

Specific Aims

Specific Aim 1: Carry out focused multicenter, collaborative, preclinical and clinical investigations to identify and validate biomarkers of Epileptogenesis following TBI and preclinical investigations to evaluate potential interventions that prevent the development of PTE as well as their effects on the identified biomarkers of epileptogenesis in a standardized animal model of TBI/PTE.

Research Project 1: Animal studies at 3 centers using a standardized lateral fluid percussion injury rat model of PTE to identify plasma, imaging, and electrophysiological biomarkers measured at different post-injury time points, alone or in combination, to diagnose with high sensitivity and specificity ongoing epileptogenesis independent of the severity of brain damage.

Research Project 2: Animal studies at 4 centers to identify targets and biomarkers for treatment implementation, which in combination with the biomarkers of epileptogenesis from Project 1, will guide rigorous randomized preclinical trials of potential AEG interventions to prevent PTE in the standardized animal model of TBI/PTE.

Research Project 3: Clinical/translational studies at 13 experienced TBI centers will identify biomarkers and validate in humans the biomarkers identified in Projects 1 and 2.

Specific Aim 2: Our multi-modal epilepsy-specific bioinformatics approaches will be applied to the results obtained in Projects 1, 2, and 3 to derive a combination of biomarkers that will reliably predict epileptogenesis following TBI in both animals and humans and identify specific AEG treatments to be used in future clinical trials. Following the completion of the aims, and in partnership with the consumer and scientific groups in the Public Engagement Core, our approach will permit the design and execution of a feasible, cost-effective, personalized medicine-focused, interventional, randomized, international clinical trial for AEG therapies in TBI.

Innovation

EpiBioS4Rx is a unique translational project. It brings together human and animal epileptogenesis research on TBI with active participation of consumer advocates to provide all the necessary information, resources, expertise, and patient population to carry out an economically feasible, full-scale clinical trial of one or more antiepileptogenic therapies at the end of the 5 year funding period.

EpiBioS4Rx has integrated existing interactive multimodality bioinformatics platforms. The unique combined platform is capable of acquiring, storing, and analyzing electrophysiological, imaging, molecular, and cellular data from animal and clinical studies that have not been used to study epileptogenesis previously, and that will constitute an open-access, epilepsy-specific database and analytics resource.

EpiBioS4Rx will develop the first validated multimodal biomarker panel for preclinical and clinical antiepileptogenesis trials.

EpiBioS4Rx will develop the first rigorous preclinical multicenter therapy-development pipeline for promising antiepileptogenic treatments to facilitate their testing in a future antiepileptogenesis clinical trial in patients with TBI. We propose to screen 5 treatment protocols for their effect on modifying PTE biomarkers in our animal model of TBI, test the leading compound for its efficacy in preventing PTE and thus prepare for a future clinical trial of the leading compound.

EpiBioS4Rx will identify at least one compound that shows an anti-epileptogenic effect in a rigorous, long-term, multicenter pre-clinical trial that is ready to proceed to be tested in a clinical trial utilizing the EpiBioS4Rx clinical TBI centers and biomarkers.

EpiBioS4Rx has enlisted the enthusiastic participation of 13 advanced clinical TBI programs. These programs have not studied epilepsy as part of their research in the past, will use the data from their extensive subject populations to identify likely biomarkers of epileptogenesis, will validate biomarkers identified in animal TBI studies, and will establish a network of advanced TBI centers with continuous EEG monitoring and other resources, expertise, and patient populations to carry out future full-scale clinical trials of antiepileptogenic agents identified in this study or others.

EpiBioS4Rx will utilize common data elements, and a rigorously designed, standardized protocol for preclinical trials of potential antiepileptogenic agents. This unique paradigm will employ therapy specific biomarkers identified in animal and human studies to identify one or more antiepileptogenic agents for full-scale clinical trials.

Our Public Engagement Core will, for the first time, bring together epilepsy and TBI advocacy and consumer groups to address common interests and concerns. This effort will not only involve patients with PTE but also patients at risk for developing PTE and will facilitate recruitment and retention of subjects for future clinical trials.

EpiBioS4Rx has developed a Charter and Publication Policy that not only establishes a code of equity among investigators but also outlines how our data, tools, and resources will be made available to the entire epilepsy community.

Infrastructure

EpiBioS4Rx has developed an extensible, portable and robust infrastructure which includes a database portal to a distributed federated architecture, a graphical framework for computational data processing via web-application clients and back-end Grid servers, and secure access control to data and services, utilizing reliable hardware resources (storage, processing and networking).

The informatics approach of this antiepileptogenetic study will involve management of heterogeneous data, data mining, exploratory data analysis, modeling, and interrogation of multimodal and multiform datasets. Specifically, the data that we will manage, process and disseminate includes proteomics data, genomics data, EEG, multichannel volumetric neuroimaging data, neurocognitive and behavioral data for patients as well as data from a diverse array of epileptogenetic animal models.

Data Federation

To enable rapid development and utilize all existing infrastructure we intend to design an efficient data federation architecture that facilitates the traversal, discovery, upload and retrieval of the imaging, genetics, clinical, demographic and behavioral data to/from all distributed and heterogeneous data sources provide by the participating institutions. This approach will utilize the available database services and leave current dataset in place avoiding data redundancy. This data federation approach will support standard data operations using an integrated virtual portal view where the real data is stored in multiple diverse sources; however it will be accessible via one centralized location. The original data sources will remain under the control of each hosting institution and data will be pulled, queried and retrieved on demand via the federated portal access.

Hardware Infrastructure

We have a significant hardware infrastructure that provides high performance, security and reliability. The fault-tolerant network infrastructure has no single points of failure having multiple switches, routers and Internet connections. A firewall appliance protects and segments the network traffic, permitting only authorized ingress and egress through. Multiple redundant database, application and web servers ensure service continuity in the event of a single system failure and also provide improved performance through load balancing of requests across the multiple machines. To augment the network-based security practices and to ensure compliance with privacy requirements, the servers utilize SSL encryption for all data transfers. Client-side de-identification of files using a signed applet integrated into the software ensures that only de-identified data is transmitted to the servers. Post-transfer redundancy checking on the files is performed to guarantee the integrity of the data. To date, we have neither suffered a system disaster, nor lost data; however as an added layer of security, sophisticated backup mechanisms are in place to protect the integrity of data.

Streamlined Data Consolidation: Users will be able to upload their raw data files directly to an extended version of the LONI infrastructure where they will automatically be classified, converted, and annotated. By automating much of this process, researchers both uploading and downloading data will be spared the time and effort currently involved in accessing and sharing epilepsy data. This streamlined data consolidation will increase the financial efficiency and scientific productivity of the CWOW and the broader epilepsy research community. In addition, physical samples will be brought together in a single biobank, further reducing coordination challenges. Much of these data have already been collected by the PIs presenting this proposal; however, the huge size of these data combined with the many different file formats makes effective navigation currently frustratingly labor-intensive and error-prone.

User-friendly data search and navigation: By converting data to consistent file formats and tagging that data with metadata, the CWOW will enable Google-style search of all available epilepsy data. However, because data will be interlinked and co-registered across data sets and modalities, the search functionality will not simply match data against individual items like Google—rather, it will find interlinked combinations of data (even across modalities and data sources) that match the desired criteria. This enables sophisticated custom searches that match the functionality of predefined query forms. Users will be able to browse data in its most appropriate visual representation and pivot from one data view or modality to another. Through our experiences with LONI, we have learned the access control and sharing mechanisms required by the community and how effectively to enable inter-project as well as community-scale data sharing. Key components include giving users explicit access control for their data and results as well as providing project groups for larger-scale permissions management. Furthermore, comparable tools that can be repurposed were developed for LONI as part of our planning grant and projects like ADNI.

Automated analysis: The LONI Pipeline contains a common framework for visual and programmatic construction of data-driven workflows for electrophysiology, imaging, and biosample data. We will customize these tools to the study of epilepsy data. With the aid of LONI’s workflow builder, complex analyses are represented visually, further supporting researchers’ investigations. Examples of Pipeline applications include developing a unified coordinate space for seizure locations across organisms, using string similarity and value overlap to predict that different contributor metadata fields are the same, and providing graphical interfaces for linking data. Co-registration algorithms will typically be invoked at upload-time but may be triggered later manually for further refinement. The IAC will provide MRI supervision and integration from different scanners and centers by supervising phantom studies, assessing quality, and fixing problems with heterogeneity. While LONI has primarily used Pipeline for human data, it has also been used to study neural networks of the mouse neocortex. The CWOW would further expand these capabilities, providing robust workflow pipelines for both humans and animal models.

Iterative improvement using novel analytical tools: The sheer quantity of data and the noise inherent in the data necessitates the development of novel analytical tools, incorporating the most recently developed mathematical and statistical tools to discover previously undetected biomarkers. Dr. Bragin et al. recently discovered a novel biomarker, repetitive high frequency oscillations and spikes (rHFOSs). Dr. Gotman, a consultant on this project, has established tools to study the relationship between spikes and HFOs and showed their links to epileptogenesis. Dr. Duncan has developed sophisticated mathematical methods to analyze both animal and human data separately and for trans-species comparisons.

We are keenly aware of multiple conceptual and technical issues regarding data analyses with biomarkers, including within subject correlation, multiplicity, multiple clinical endpoints, and selection bias. Utilization of multiple statistical approaches will allow us to address these concerns in full.

Standardized sample collection, shipping, and biobank storage protocols: The project will define methods for harvesting, freezing, and storing tissue and other biosamples (i.e. serum). Data and tissue stored for collaborating preclinical trials, such as TRACK TBI, ALLO, PPMI, TRACKHD, ICBM, AIBL, ACE, ABIDE, 4RTNI, Mapp, and the Human Connectome Project already have these protocols in place with informatics provided by LONI. Animal protocols for storing parallel samples to humans will be stored and treated in a similar fashion to compare findings from parallel human and animal studies.

A data safety monitoring board (DSMB) will advise us as we perform a rigorous multicenter preclinical antiepileptogenesis trial using a blinded, vehicle-controlled randomized study design to determine the antiepileptogenic effect of the lead compound. The results of the three projects integrated with the IAC, following the close guidance of the DSMB, will assist in planning the optimal design of a future clinical antiepileptogenesis trial for successful drugs.

People

EpiBioS4Rx is a federated consortium of international research centers. Each component of EpiBioS4Rx is multicenter with multiple autonomous investigators.

Program directed by the National Institute of Neurological Disorders and Stroke (NINDS) at NIH

Public and Community Information

Traumatic Brain Injury and epilepsy factsheet

Traumatic Brain Injury (TBI) is an injury caused by trauma to the brain from an outside force.

• TBI in the United States of America (U.S.)
  • Every 9 seconds, someone in the U.S. has a traumatic brain injury
  • Every year in the U.S. 2.5 million adults and children have a TBI.
  • There are 2.2 million people treated for TBI in emergency rooms every year
• TBI can lead to disability such as loss of strength, mood changes, changes in thinking, seizures and epilepsy
  • 1:60 people in the U.S. (approximately 5.3 million) live with TBI-related disabilities

A seizure is a surge of abnormal electrical activity in the brain. Seizures can affect how a person appears or acts for seconds to minutes. There are many types of seizures. There are a variety of symptoms that can include a brief change in movement, sensation, thinking, or awareness.

• Post-traumatic seizure: a seizure after a recent TBI, or diagnosed to be related to a prior TBI

Epilepsy is a condition where a person has repeated seizures over time.

• • In the U.S. 3 million adults and 470,000 children (≤age 17) live with active epilepsy
  • 1:26 have epilepsy at some point in their life
  • 1:3 people live with uncontrolled seizures

Post-traumatic Epilepsy (PTE) is a condition with repeated seizures that occur more than 1 week after a TBI.

• • In the U.S. seizures happen in 1 out of every 10 hospitalized persons with TBI
    • About 25% of people who have a post-traumatic seizure in the 1 week will have epilepsy
    • Up to 80% of people who have a post-traumatic seizure more than 1 week after a TBI will develop epilepsy
    • Up to 65% of people with brain injuries from bullet wounds will have epilepsy
  • Bleeding from TBI and PTE
    • 20% of people with TBI and bleeding around the brain will have epilepsy.
    • If the bleeding has to be removed with surgery, then 25% of people will have epilepsy
    • When two or more surgeries are needed after a TBI, 35% of people will have epilepsy

• Epilepsy and living with TBI
  • Along with TBI, living with epilepsy can also affect a person’s memory, changes in thinking, mood, driving and quality of life
  • Living with PTE can lead to a longer rehabilitation and worsening of other TBI comorbidities
  • Epilepsy and TBI can shorten a person’s life

• Finding, preventing and treating PTE
  • There is no current test to predict who will have PTE after TBI
  • There is no treatment to prevent PTE. We can only treat the symptom of recurrent seizures.

• More research needed for PTE
  • Current research studies will find the traces left behind by TBI that can predict epilepsy
  • If we can determine who will develop epilepsy after TBI, we will be able to develop new treatments to prevent it
  • Community participation and feedback is an important part of research to prevent PTE and improve overall health after TBI

See our terms and definitions link for more information on terms important to traumatic brain injury, epilepsy and clinical research.

Project (EpiBios4Rx) introduction:

Multiple medical centers are working together to develop ways of preventing epilepsy after . Together they are searching for what predicts epilepsy after a TBI. This will help to design treatments to prevent epilepsy after TBI. Patients and families will help doctors and scientists to plan future research for these treatments. Our goal is to develop treatments for TBI that prevent the development of post traumatic epilepsy (PTE) (i.e. antiepileptogenesis).

Together the TBI and epilepsy communities will identify the needs of people like you and help doctors and scientists to design successful treatment studies for people living with TBI. Together we will design studies with results that matter to people living with TBI. With this work we can find a treatment that will prevent PTE.

Our goals are to:

• Find the traces (biomarkers) that predict PTE.
• Develop treatments that prevent PTE.
• Partner with people living with TBI and/or epilepsy to design research to prevent PTE.
• Work with the TBI and epilepsy communities to improve the health and lifestyle for everyone living with PTE.

List of current EpiBios4Rx sites

• University of California, Los Angeles
• University of California, Davis
• University of Pittsburgh medical center
• Yale University
• University of Pennsylvania
• University of Cincinnati
• University of Miami
• Columbia University
• Phoeniz Children’s medical center
• Children’s National medical center
• The Alfred, Melbourne, Australia
• Royal Melbourne hospital center, Melbourne, Australia
• Burdenko Institute, Moscow, Russia

How can I support TBI research?

Consider enrolling in a clinical trial or a registry. This can be one of the best ways to support research toward new and better treatment options.

Clinical trials are research studies on the treatment of people. Studies involving persons with and healthy persons offer the chance to find better ways to safely detect, treat, and prevent TBI. By participating in a clinical study, healthy persons and those with TBI can benefit the lives of others living with TBI.

Government (NINDS)-funded studies on TBI, see www.clinicaltrials.gov

Information about participating in clinical trials: https://www.nih.gov/health-information/nih-clinical-research-trials-you/basics

Videos and stories from persons with epilepsy and volunteers in research studies:

• Personal stories from clinical trial volunteers – Produced by the NIH
• Video Series on Veterans with Epilepsy - VA Epilepsy Center of Excellence
• Stories from combat veterans with epilepsy – produced by CURE - Citizens United for Research In Epilepsy

Clinical trials for Parents and Children

Children are not little adults. Often treatments are only tested in adults. Children’s brains and bodies can respond to treatments differently from adults. Research designed for children is the way to get the best treatments for them. For example, clinical research for children has improved outcomes in cancer and premature birth.

Should your child participate in a clinical study?

• The safety of children is a priority for all NIH studies. Caretakers have many questions about enrolling a child in a clinical study. It’s also important that children understand what is involved. Our clinical study is committed to ensuring families get the information needed to feel comfortable and make informed decisions.

Additional information about clinical trials

• The importance of children in Clinical Trials
• Children and Clinical Studies: Videos, stories and more information.
  • Website: http://www.childrenandclinicalstudies.org/
  • Facebook group: https://www.facebook.com/Children-and-Clinical-Studies-Campaign-144563897770/?ref=ts

Can TBIs be prevented?

Adults and Children

• Wear a seatbelt or use safety seat for children when riding in a car.
• Wear a helmet when riding a bike or motorcycle, playing football, ice hockey, any contact or high velocity sport. Examples include roller skating, skateboarding; horseback riding; skiing or snowboarding.
• Storing firearms and ammunition in a locked cabinet or safe

Children or Adults disabilities

• Try to install handrails on stairways, window guards, and safety gates at the top and bottom of stairs.

Important terms and definitions

• Traumatic brain Injury (TBI)
  Traumatic Brain Injury (TBI)

  An injury caused by trauma to the brain from an outside force.

  • For example, an outside force could be a hit to a football player's helmet or an injury to the head in a car accident.
• Seizure
  Seizure

  A seizure is a surge of abnormal electrical activity in the brain. Seizures can affect how a person appears or acts for seconds to minutes. There are many types of seizures. There is a variety of symptoms that can, for example, include a brief change in movement, sensation, thinking, or awareness.

• Post-traumatic seizure
  Post-traumatic seizure

  A seizure after a recent TBI, or is diagnosed to be related to a prior TBI.

  • Differences have been seen between early and late post-traumatic seizures.
• Early post-traumatic seizure
  Early post-traumatic seizure

  A seizure that occurs less than 1 week after a TBI.

• Late post-traumatic seizure
  Late post-traumatic seizure

  A seizure that occurs more than 1 week after TBI, or is diagnosed to be related to a prior TBI.

• Epilepsy
  Epilepsy

  A condition where people have repeated seizures over time.

• Post-traumatic epilepsy (PTE)
  Post-traumatic epilepsy (PTE)

  A condition with repeated to recurrent seizures more than 1 week after a TBI.

• Epileptogenesis
  Epileptogenesis

  This happens when changes in a person’s brain leads to greater risk of having seizures.

• Preventing epileptogenesis (Anti-epileptogenesis)
  Preventing epileptogenesis (Anti-epileptogenesis)

  The goal of designing treatments to improve brain healing after TBI and lower the risk of future seizures.

• Biomarkers
  Biomarkers

  Medical conditions or injuries may leave traces (biomarkers) that could predict the extent of injury or symptoms. Biomarkers could be changes in blood, brain wave recordings (electroencephalogram), or brain imaging.

  • This project will search for traces (biomarkers) and plan treatments to prevent epilepsy after TBI.
    • For example, hemoglobin A1c in the blood can be abnormal before someone develops symptoms of diabetes. With medication, the hemoglobin A1c level can be lowered back to a normal range.
• Electroencephalogram (EEG)
  Electroencephalogram (EEG)

  A test that uses sensors on the skin to record and graph brain activity as a wave. Similar to an electrocardiogram (ECG) of the heart rate.

• Magnetic resonance imaging (MRI)
  Magnetic resonance imaging (MRI)

  of the brain is a test that uses magnetic fields to create pictures that can help detect changes in brain tissue.

• Cerebrospinal fluid (CSF):
  Cerebrospinal fluid (CSF):

  The fluid that bathes and protects the brain and spinal cord.

• Intracranial pressure
  Intracranial pressure

  The pressure on the brain inside the skull. After an injury there can be an abnormal build-up of pressure in the brain.

• Epidural hematoma
  Epidural hematoma

  Bleeding between the skull and the brain.

• Hematoma
  Hematoma

  Heavy bleeding into or around the brain caused by damage to a major blood vessel in the head.

• Subdural hematoma
  Subdural hematoma

  Bleeding between the membranes around the brain.

• Clinical trials
  Clinical trials

  Research studies on the treatment of people.

  • Diagnostic trials determine better tests to diagnose a disease.
  • Prevention trials study the best way to prevent a disease in people before it starts or prevent it from returning.

More information

Traumatic Brain Injury (TBI)

• Brain Injury Association of America: www.biausa.org
  • Information line: National Brain Injury Information Center (NBIIC): 1-800-444-6443


• Heads Up: Centers for Disease Control and Prevention (CDC): https://www.cdc.gov/headsup/index.html


• Model Systems Knowledge Translation Center: https://msktc.org/tbi


• TBI in the Military, Defense & Veterans Brain Injury Center (DVBIC): http://dvbic.dcoe.mil/tbi-military
  • Crisis Intervention (24/7)
  • Military & Veterans Crisis Line, Department of Veterans Affairs
  • 1-800-273-8255, Press 1

¿Hablas Español? Need traumatic brain injury information in Spanish?

• • https://www.biausa.org/brain-injury/about-brain-injury/nbiic/what-information-about-brain-injury-is-available-in-spanish
  • http://www.msktc.org/spanish/tbi
  • https://www.cdc.gov/headsup/pdfs/providers/spanish_fact_sheet_concussion_tbi-a.pdf

Epilepsy

• The Epilepsy Foundation of America www.efa.org
  • 24/7 Helpline
  • Our Toll-Free Helpline: 1-800-332-1000
  • (en Español 1-866-748-8008)
• Citizens United for Research in Epilepsy (CURE): https://www.cureepilepsy.org/about-epilepsy/what-is-epilepsy
• Epilepsy Awareness Day: http://www.epilepsyawarenessday.org/
• Living Well With Epilepsy: https://livingwellwithepilepsy.com/

¿Hablas Español? Need epilepsy information in Spanish?

• • • www.laepilepsia.org (EFA)

Questions about participating in clinical research?

• “Why should I participate in a clinical trial?”
  • https://www.nih.gov/health-information/nih-clinical-research-trials-you


• ¿Hablas Español? Need more information in Spanish?
  • https://www.cancer.gov/espanol/cancer/tratamiento/estudios-clinicos

Publications and Events

Publications

La Rocca M, Garner R, Amoroso N, Lutkenhoff ES, Monti MM, Vespa P, Toga AW, Duncan D. . Multiplex Networks to Characterize Seizure Development in Traumatic Brain Injury Patients. Front Neurosci. ;14:591662. doi: 10.3389/fnins.2020.591662. PMID: 33328863; PMCID: PMC7734183. . 2021 Nov 30.

Faghihpirayesh R, Ruf S, La Rocca M, Garner R, Vespa P, Erdogmus D, Duncan D.. Automatic Detection of EEG Epileptiform Abnormalities in Traumatic Brain Injury using Deep Learning. Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) 2021. . 2021 Nov 1.

Akbar MN, Ruf S, La Rocca M, Garner R, Barisano G, Cua R, Vespa P, Erdogmus D, Duncan D.. esion Normalization and Supervised Learning in Post-traumatic Seizure Classification with Diffusion MRI. International Workshop on Computational Diffusion MRI. . 2021 Oct 1. https://doi.org/10.1007/9

Lutkenhoff ES, Shrestha V, Ruiz Tejeda J, Real C, McArthur DL, Duncan D, La Rocca M, Garner R, Toga AW, Vespa PM, Monti MM. Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study. Journal of neurology, neurosurgery, and psychiatry. ;91(11):1154-1157. PubMed PMID: 32848013; PubMed Central PMCID: PMC7572. . 2020 Nov 9.

Lutkenhoff ES, Wright MJ, Shrestha V, Real C, McArthur DL, Buitrago-Blanco M, Vespa PM, Monti MM. The subcortical basis of outcome and cognitive impairment in TBI: A longitudinal cohort study. Neurology. PubMed PMID: 32907958; DOI: 10.1212/WNL.0000000000010825. . 2020 Sep 9.

Liu J, Garner R, La Rocca M, Bae EK, Duncan D. . The effects of filtering on high frequency oscillation classification. 2020 IEEE Spring Simulation Conference (SpringSim). doi: 10.22360/SpringSim.2020.MSM.008.. . 2020 May 18.

Cabeen RP, Immonen R, Harris NG, Gröhn O, Smith G, Manninen E, Garner R, Duncan D, Pitkänen A, Toga AW. . A computational diffusion mri framework for biomarker discovery in a rodent model of post-traumatic epileptogenesis. 2020 IEEE 17th International Symposium on Biomedical Imaging (ISBI). doi: 10.1109/ISBI45749.2020.9098575.. . 2020 Apr 3.

Kwon CS, Agarwal P, Subramaniam V, Dhamoon M, Mazumdar M, Yeshokumar A, Panov F, Ghatan S, Jetté N.. Readmission after neurosurgical intervention in epilepsy: A nationwide cohort analysis. Epilepsia.;61(1):61-69. PubMed PMID: 31792965; PubMed Central PMCID: PMC7227389; DOI: 10.1111/epi.16401.. . 2020 Jan 8.

Nariai H, Hussain SA, Bernardo D, Motoi H, Sonoda M, Kuroda N, Asano E, Nguyen JC, Elashoff D, Sankar R, Bragin A, Staba RJ, Wu JY. Scalp EEG interictal high frequency oscillations as an objective biomarker of infantile spasms. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology.3;131(11):2527-2536. PubMed PMID: 32927206; DOI: 10.1016/j.clinph.2020.08.013.. . 2020 Jan 6.

Garner R, La Rocca M, Vespa P, Jones N, Monti MM, Toga AW, Duncan D. Imaging biomarkers of posttraumatic epileptogenesis. Epilepsia. 2019 Oct 4.

Santana-Gomez C, Andrade P, Hudson MR, Paananen T, Ciszek R, Smith G, Ali I, Rundle BK, Ndode-Ekane XE, Casillas-Espinosa PM, Immonen R, Puhakka N, Jones N, Brady RD, Perucca P, Shultz SR, Pitkänen A, O'Brien TJ, Staba R. Harmonization of pipeline for detection of HFOs in a rat model of post-traumatic epilepsy in preclinical multicenter study on post-traumatic epileptogenesis. Epilepsy Research. 2019 Oct 2.

Engel J, Pitkanen A. Biomarkers For Epileptogenesis And Its Treatment. Neuropharmacology. 2019 Aug 1.

Li Lin, Bragin A, Staba R, Engel J. Unit firing and oscillations at seizure onset in epileptic rodents. Neurobiology of Disease. 2019 Jul 17.

Agoston DV, Vink R, Helmy A, Risling M, Nelson D, Prins M.. How to Translate Time: The Temporal Aspects of Rodent and Human Pathobiological Processes in Traumatic Brain Injury. Journal of neurotrauma;36(11):1724-1737. PubMed PMID: 30628544; DOI: 10.1089/neu.2018.6261.. . 2019 Jun 6.

Garner R, La Rocca M, Barisano G, Vespa P, Toga AW, Duncan D. A machine learning model to predict seizures susceptibility from resting-state fMRI connectivity. Proceedings: Spring Simulation Conference for the Society for Modeling and Simulation. Neurobiology of Disease. 2019 Apr 11.

Agoston DV and Kamnaksh A. Protein biomarkers of epileptogenicity after traumatic brain injury. Neurobiology of Disease. 2019 Mar 29.

Semple BD, Zamani A, Rayner G, Shultz SR, Jones NC. Affective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy. Neurobiology of Disease. 2019 Mar 28.

Dadas A, Janigro D. Breakdown of blood brain barrier as a mechanism of post-traumatic epilepsy. Neurobiology of Disease. 2019 Mar 27.

Galanopoulou AS, Engel J, Moshé SL. PREFACE: Antiepileptogenesis following traumatic brain injury. Neurobiology of Disease. 2019 Mar 26.

Brady RD, Casillas-Espinosa PM, Agoston DV, Bertram EH, Kamnaksh A, Semple BD, Shultz SR. Modelling traumatic brain injury and posttraumatic epilepsy in rodents. Neurobiology of Disease. 2019 Mar 22.

Hunter LE, Branch CA, Lipton ML. The neurobiological effects of repetitive head impacts in collision sports. Neurobiology of Disease. 2019 Mar 21.

Vespa PM, Shrestha V, Abend N, Agoston D, Au A, Bell MJ, Bleck TP, Blanco MB, Claassen J, Diaz-Arrastia R, Duncan D, Ellingson B, Foreman B, Gilmore EJ, Hirsch L, Hunn M, Kamnaksh A, McArthur D, Morokoff A, O'Brien T, O'Phelan K, Robertson CL, Rosenthal E, Staba R, Toga A, Willyerd FA, Zimmermann L, Yam E, Martinez S, Real C, Engel J Jr. The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol. Neurobiology of Disease. 2019 Mar 20.

Immonen R, Smith G, Brady. Harmonization of pipeline for preclinical multicenter MRI biomarker discovery in a rat model of post-traumatic epileptogenesis. Epilepsy Research. 2019 Feb 15.

Engel J, Bragin A, Staba R. Nonictal EEG biomarkers for diagnosis and treatment. Epilepsy Open. 2018 Dec 17.

Zhang J, Bekkers E, Chen D, Berendschot TTJM, Schouten J, Pluim JPW, Shi Y, Dashtbozorg B, Romeny BMTH.. Reconnection of Interrupted Curvilinear Structures via Cortically Inspired Completion for Ophthalmologic Images. IEEE transactions on bio-medical engineering; 65(5):1151-1165. PubMed PMID: 29683430; PubMed Central PMCID: PMC6880863; DOI: 10.1109/TBME.2017.2787025.. . 2018 May 5.

Zhan L, Jenkins LM, Wolfson OE, GadElkarim JJ, Nocito K, Thompson PM, Ajilore OA, Chung MK, Leow AD. The significance of negative correlations in brain connectivity. The Journal of comparative neurology; 525(15):3251-3265. PubMed PMID: 28675490; PubMed Central PMCID: PMC6625529; DOI: 10.1002/cne.24274.. . 2017 Oct 15.

Faghihpirayesh R, Ruf S, La Rocca M, Garner R, Vespa P, Erdogmus D, Duncan D. Automatic Detection of EEG Epileptiform Abnormalities in Traumatic Brain Injury using Deep Learning. Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) 2021. 2021 Nov 1.

Akbar MN, Ruf S, La Rocca M, Garner R, Barisano G, Cua R, Vespa P, Erdogmus D, Duncan D. Lesion Normalization and Supervised Learning in Post-traumatic Seizure Classification with Diffusion MRI. International Workshop on Computational Diffusion MRI. 2021 Oct 1. https://doi.org/10.1007/978-3-030-87615-9_12

La Rocca M, Garner R, Amoroso N, Lutkenhoff ES, Monti MM, Vespa P, Toga AW, Duncan D. Multiplex Networks to Characterize Seizure Development in Traumatic Brain Injury Patients. Front Neurosci. 2020 Nov 30;14:591662. doi: 10.3389/fnins.2020.591662. PMID: 33328863; PMCID: PMC7734183.

Liu J, Garner R, La Rocca M, Bae EK, Duncan D. The effects of filtering on high frequency oscillation classification. 2020 IEEE Spring Simulation Conference (SpringSim). 2020 May 18. doi: 10.22360/SpringSim.2020.MSM.008.

Cabeen RP, Immonen R, Harris NG, Gröhn O, Smith G, Manninen E, Garner R, Duncan D, Pitkänen A, Toga AW. A computational diffusion mri framework for biomarker discovery in a rodent model of post-traumatic epileptogenesis. 2020 IEEE 17th International Symposium on Biomedical Imaging (ISBI). 2020 Apr 3. doi: 10.1109/ISBI45749.2020.9098575.

Duncan D, Barisano G, Cabeen R, Sepehrband F, Garner R, Braimah A, Vespa P, Pitkanen A, Law M, Toga AW. Analytic Tools for Post-traumatic Epileptogenesis Biomarker Search in Multimodal Dataset of an Animal Model and Human Patients. Frontiers in Neuroinformatics. 2018;12:86.

Immonen R, Harris NG, Wright D, Johnston L, Manninen E, Smith G, Paydar A, Branch C, Grohn O. Imaging biomarkers of epileptogenecity after traumatic brain injury - Preclinical frontiers. Neurobiology of disease. 2018 Oct 12.

Correa DJ, Kwon CS, Connors S, Fureman B, Whittemore V, Jetté N, Matthern GW, Moshé SL, for the EpiBioS4Rx Public Engagement Core. Applying participatory action research in traumatic brain injury studies to prevent post-traumatic epilepsy. Neurobiology of Disease. 2018 Jul 18.

Saletti PG, Ali I, Casillas-Espinosa PM, Semple BD, Lisgaras C, Moshé SL, Galanopoulou AS. In search of antiepileptogenic treatments for post-traumatic epilepsy. Neurobiology of Disease. 2018 Jun 22.

Perucca P, Smith G, Santana-Gomez C, Bragin A, Staba R. Electrophysiological biomarkers of epileptogenicity after traumatic brain injury. Neurobiology of disease. 2018 Jun 5.

Duncan D, Vespa P, Pitkanen A, Braimah A, Lapinlampi N, Toga AW. Big data sharing and analysis to advance research in post-traumatic epilepsy. Neurobiology of disease. 2018 Jun 1.

Tubi MA, Lutkenhoff E, Blanco MB, McArthur D, Villablanca P, Ellingson B, Diaz-Arrastia R, Van Ness P, Real C, Shrestha V, Engel J. Early seizures and temporal lobe trauma predict post-traumatic epilepsy: a longitudinal study. Neurobiology of disease. 2018 Jun 1.

Pitkänen A, Ndode-Ekane X, Lapinlampi N, Puhakka N. Epilepsy biomarkers–Toward etiology and pathology specificity. Neurobiology of disease. 2018 May 18.

Engel J. Epileptogenesis, traumatic brain injury, and biomarkers. Neurobiology of disease. 2018 Apr 3.

Events

Investigators meeting at UCLA, June 2018

Investigators meeting at NIH, December 2017

Investigators meeting in Houston, TX, December 2016