a red pencil draws the outline of a human head over a graphic of neurons

CURE Epilepsy’s Impact: Investing in Early-Stage Research Leads to Critical Advancements

Key Points:

  • Nearly 20 years ago, Peter Carlen, MD received a one-year grant from CURE Epilepsy that served as a catalyst for his research into seizure detection and electrical neurostimulation. One of the companies Dr. Carlen established continues the work in seizure detection and is currently building on his lab’s recent identification of a biomarker for sudden unexpected death in epilepsy (SUDEP).
  • For more than 20 years, through investing in paradigm-shifting ideas, CURE Epilepsy has enabled scientists to discover insights essential for advancing the understanding of epilepsy and moving us closer to a cure.

Deep Dive:

Dr. Carlen began his career as a general neurologist at the University of Toronto. He founded the Epilepsy Program at the Toronto Western Hospital 25 years ago and is now one of its staff epileptologists. With his 2002 funding from CURE Epilepsy, he collaborated with mathematician and engineer Dr. Berj Bardakjian and a student with a background in physics, Dr. Houman Khosravani, to investigate the promise of computation and engineering techniques to understand epileptic networks and to ultimately develop the ability to disrupt them.

The work facilitated by his CURE Epilepsy-funded grant has contributed substantially to prediction and treatment of epilepsy. The researchers first published a paper documenting arrest of seizure activity with brief, low frequency electrical pulses delivered to brain tissue [1] and later published two additional papers on electrical neurostimulation [2,3]. Since these initial studies, Carlen’s lab has progressed to more advanced testing paradigms with modified parameters to make the pulses more akin to what actually happens in the brain. Significantly, this newer protocol appears to result in better seizure control than the more traditional pattern of repetitive square pulses.

Perhaps some of the most frightening and challenging aspects of epilepsy are seizure unpredictability and the potential for SUDEP; thus, seizure and SUDEP forecasting remain priorities in epilepsy research. Dr. Carlen’s current research also focuses on the brainstem, a small area at the base of the brain located just above the spinal cord, that regulates functions such as breathing and heart rate. Hypothesizing that SUDEP reflects disturbances in the brainstem, Carlen’s lab measured the electrical activity from this brain region in rats and discovered that seizures originating here led to cardiorespiratory arrest and death [4,5], important findings that continue to influence the field.

Since the initial research supported by their 2002 CURE Epilepsy grant, Carlen and Bardakjian have continued to collaborate, recently making a breakthrough that could reduce overall morbidity and mortality in epilepsy: they have developed a seizure alarm and identified SUDEP biomarkers in the unique electrical patterns of the electroencephalogram (EEG) [6]. They have since founded a company called Neurometrics Technologies to develop this technology further, with the goal of combining a wireless headset with complex computer algorithms capable of analyzing a patient’s EEG patterns to predict seizures and detect SUDEP biomarkers.

Carlen finds serving as the bridge between his patients in the clinic and the basic research in his lab especially rewarding. As an epileptologist, he witnesses firsthand the intense suffering endured by people with epilepsy and, as a scientist, he is in a unique position to develop more effective treatments with little to no side effects, a true cure.

CURE Epilepsy is proud to have played a role in advancing research by Dr. Peter Carlen and his colleagues, building hope for prevention and cures, and ultimately, a world without epilepsy.


Literature Cited
[1] Khosravani, H., Carlen, P.L., & Velazquez, J.L.P. The control of seizure-like activity in the rat hippocampal slice. Biophys. J. 2003; 84: 687-695.
[2] Chiu, A.W.L., Jahromi, S.S., Khosravani, H., Carlen, P.L. & Bardakjian, B.L. The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks. J. Neural Eng. 2005; 3(1): 9-20.
[3] Khosravani, H., Pinnegar, C.R., Mitchell, J.R., Bardakjian, B.L., Federico, P., & Carlen, P.L. Increased high-frequency oscillations precede in vitro low-Mg2+ seizures. Epilepsia 2005; 46(8): 1188-1197.
[4] Salam, M.T., Montandon, G., Genov, R, Devinsky, O., Del Campo, M., & Carlen, P.L. Mortality with brainstem seizures from focal 4-aminopyridine-induced hippocampal seizures. Epilepsia 2017; 58(9): 1637-1644.
[5] Lertwittayanon, W., Devinsky, O., & Carlen, P.L. Cardiorespiratory depression from brainstem seizure activity in freely moving rats. Neurobiol. Dis. 2020; 134: 104628.
[6] Grigorovsky, V. et al. Delta-gamma phase-amplitude coupling as a biomarker of postictal generalized EEG suppression. Brain Commun. 2020; 2(2): fcaa182.

CURE Epilepsy Discovery: A Novel Molecule as a Biomarker of Epilepsy

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Gary Brennan and colleagues used three different, well-established rodent models of acquired epilepsy to identify biomarkers for both diagnosing active epilepsy and for predicting who might develop epilepsy after a brain injury.
  • The team found that a family of small molecules known as microRNAs (miRNAs)[1], which are important in regulating gene expression and brain activity, were altered in rodent models of acquired epilepsy.
  • Three of the five identified miRNAs were also present in blood samples taken from epilepsy patients, thereby validating their relevance to human epilepsy.
  • Administration of a molecule known as Ant-134, which has been previously shown to reduce seizure frequency in different animal models, affected the levels of three of the five miRNAs in rodent models of acquired epilepsy in the current study.
  • These preliminary data suggest that circulating miRNAs may represent biomarkers that can accurately diagnose epilepsy and predict who may develop it after a brain injury. Additional steps to validate these miRNAs as biomarkers of acquired epilepsy are needed.

Deep Dive:

Epilepsy is often “acquired” by injuries to the brain such as those resulting from a stroke, head trauma, or infection. There is currently no way of reliably predicting who will develop epilepsy following these types of injuries [2]. Thus, it would be valuable to have a stable, readily accessible substance (in the blood, for example) to assist with diagnosis, treatment, and epilepsy prediction following a head injury for people at risk. MicroRNAs (miRNAs), small molecules that have been implicated in the development of epilepsy [3], may make ideal biomarkers due to their relatively high concentrations in the blood. CURE Epilepsy Taking Flight Award grantee Dr. Brennan investigated whether miRNAs might be used as biomarkers of acquired epilepsy.

Dr. Brennan and his colleagues employed three different rodent models of acquired epilepsy to evaluate the feasibility of using miRNAs as biomarkers for the development of epilepsy [4]. The researchers first collected blood from all rodents to establish baseline levels of the different miRNAs. They subsequently sampled blood several times prior to the first seizure and also on the day of the first spontaneous seizure, which was indicative of the actual onset of epilepsy.

The researchers found that blood from rodents with epilepsy had several unique miRNAs, either newly-emerged or whose levels had changed during epileptogenesis –the process by which an initial “insult” or injury to the brain leads to seizures and epilepsy–and into the chronic epilepsy stage. Based on consistency among the three rodent models and previous associations with epilepsy, the researchers chose five of these miRNAs as a focus for the next steps of their work. Importantly, they found that three of the five miRNAs were also found in people with epilepsy.

Dr. Brennan also found that levels of three of the five miRNAs were affected by a potential new therapy for epilepsy called Ant-134. Anti-134 is a molecule that specifically targets a different miRNA (miRNA-134), distinct from the five miRNAs that were the focus of Dr. Brennan’s study. Anti-134 has been shown to reduce seizures in several different rodent models of epilepsy [5]. Dr. Brennan’s finding supports the idea that specific miRNAs may be useful for predicting the likelihood of developing an acquired epilepsy as well as potential indicators of treatment responsiveness.

These exciting data reveal a novel mechanism of epilepsy prediction, diagnosis, and treatment that may one day be studied in clinical trials to determine its ability to identify individuals who have suffered a brain injury that are likely to develop epilepsy.


Dr. Gary Brennan

Dr. Brennan performed his work while in the laboratory of Dr. David Henshall at the Royal College of Surgeons in Ireland. He collaborated with multiple colleagues, both in Dr. Henshall’s lab and from specialist labs across Europe.

Dr. Brennan has received additional support from the Science Foundation Ireland and is a funded investigator in the FutureNeuro Research Centre. His research group is based in the School of Biomolecular and Biomedical Science at University College Dublin.

 


Literature Cited
[1] miRNA are (a relatively newly discovered form of ribonucleic acid (RNA) and) distinct from other forms of ribonucleic acids (RNA) like mRNA or tRNA that serve different biological functions.
[2] Löscher, W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2020; 167: 107605.
[3] Henshall, D.C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 2016; 15(3): 1368-1376.
[4] Brennan, G.P. et al. Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy. Neurobiol. Dis. 2020; 144: 105048.
[5] Morris, G., Reschke, C.R., and Henshall, D.C. Targeting microRNA-134 for seizure control and disease modification in epilepsy. EbioMedicine 2019; 45: 646-654.

Understanding the Neurodevelopmental Origins of Focal Cortical Dysplasia (FCD)

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Lakshmi Subramanian is working to uncover the underlying causes of focal cortical dysplasia (FCD), a severe childhood epilepsy syndrome characterized by developmental malformations in the part of the brain known as the cortex.
  • Dr. Subramanian found that disrupting the mTOR signaling pathway caused a series of biological changes that may explain how FCD arises.
  • Understanding these changes could help researchers identify newer, more effective, and less invasive therapeutic options than those currently available.

Deep Dive:

During development in the womb, the human brain undergoes a substantial expansion in size, particularly in the outermost part known as the cortex [1]. During this time, brain cells grow and divide rapidly, normally organizing themselves into layers. As the brain develops, an orderly arrangement of cells is created, in part, by the shape, position, and movement of outer radial glia (oRG) cells. These cells give rise to newborn nerve cells in the human brain and also form the scaffold that the immature nerve cells use to navigate to their correct location, mature, and connect normally [3]. In focal cortical dysplasia (FCD), however, brain cells fail to organize properly, leading to focal lesions and usually intractable epilepsy [2]. Surgery is often the only effective treatment option.

The mTOR pathway is known to be active in human oRG cells during development [4], but the function of this pathway in these cells is unknown. Taking Flight Award grantee Dr. Lakshmi Subramanian, while working in the laboratory of Dr. Arnold Kriegstein at University of California San Francisco, sought to determine the specific role of the mTOR pathway in the development of FCD [5].

Dr. Subramanian and colleagues first successfully established simplified models of the developing human cortex in order to manipulate mTOR signals and evaluate the resulting effects on oRG cells. They activated or blocked mTOR signals in two different human tissue-based models and found that sustained mTOR signals were required to maintain oRG cell shape and structure. Specifically, when mTOR signals were disrupted, oRG cells lost their typically elongated shape, shortened significantly, and lost their ability to “move” normally in the developing brain. As a result, the scaffold along which nerve cells migrate, mature, and connect was also disrupted, providing a mechanism for how abnormal brain organization may arise in FCD.

In future research, Dr. Subramanian hopes these human brain model systems can be used to investigate how displaced, misshapen oRG cells affect long-term changes in the brain. More information about how oRG cells use mTOR signals may help identify additional components of the pathway that can be investigated as potential therapies or diagnostics. An advanced understanding of this pathway may allow for development of less invasive approaches to treating FCD and other mTOR-mediated developmental epilepsies. These proteins could conceivably be targeted to develop new diagnostics and treatments other than invasive surgery for patients with FCD and other mTOR-mediated developmental epilepsies.


Dr. Lakshmi Subramanian

Dr. Lakshmi Subramanian is a CURE Epilepsy Taking Flight Award grantee and NARSAD Young Investigator, Neuroscience/Stem Cell Biology Research at Broad Center for Regeneration Medicine, University of California San Francisco.

 


Literature Cited
[1] Hatten, M.E. Central nervous system neuronal migration. Annu. Rev. Neurosci. 1999; 22: 511-539.
[2] Iffland, P.H. and Crino, P.B. Focal cortical dysplasia: gene mutations, cell signaling, and therapeutic implications. Annu. Rev. Pathol. 2017; 12: 547-571.
[3] Ostrem, B., Di Lullo, E., and Kriegstein, A.R. oRGs and mitotic somal translocation – a role in development and disease. Curr. Opin. Neurobiol. 2017; 42: 61-67.
[4] Pollen, A.A., Bhaduri, A., Andrews, M. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 2019; 176(4): 743-756.
[5] Andrews, M.G., Subramanian, K., and Kriegstein, A.R. mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex. eLife 2020; 9: e58737.

CURE Epilepsy Discovery: Epilepsy Surgery May Be Beneficial in Reducing SUDEP

Key Points:

  • To understand how epilepsy surgery can affect the risk of SUDEP, CURE Epilepsy-grantee Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon, analyzed rates and causes of mortality in people who had epilepsy surgery versus those who hadn’t.
  • Their analysis suggests that for those who have had epilepsy surgery, there was a reduction in the occurrence of death, and significantly fewer deaths from SUDEP.
  • The reduction in the occurrence of SUDEP for those who have had surgery appeared to be most significant in the first 10 years post-surgery.

Deep Dive:

Frequent, uncontrolled seizures, particularly generalized tonic-clonic seizures (GTCS), are a risk factor for Sudden Unexpected Death in Epilepsy or SUDEP[1]. Epilepsy surgery can be an option to control or eliminate seizures in people with drug-resistant seizures. In addition to helping achieve seizure control, epilepsy surgery is also thought to reduce the risk of SUDEP, however, the evidence for this is limited. A strong understanding of how epilepsy surgery can affect SUDEP occurrence is important as it can help guide treatment decisions.

Dr. Lisa Bateman, Cedars Sinai Medical CenterCURE Epilepsy-grantee, Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon recently published results from their study comparing the number and causes of death, including SUDEP, in people who had epilepsy surgery versus those who did not undergo surgery[2].

For their study, which was generously funded by the Henry Lapham Memorial Award, the team analyzed mortality in 590 patients who had undergone epilepsy surgery between 1977 and 2014. Deaths in this surgical group were compared to those in a group of 122 people with drug-resistant epilepsy who did not have epilepsy surgery because they were either not considered suitable candidates or refused surgery.

The team found that number of deaths was significantly reduced in the surgical group versus the non-surgical group, and SUDEP was the main cause of death in both groups. Additional causes included tumors, suicide, accidental death, status epilepticus and other conditions.

Dr. Catherine Schevon, Columbia UniversityUpon further analysis, the researchers discovered that the surgical group had a statistically significant lower rate of SUDEP (1.9 per 1000 patient-years* in the surgical group versus 4.6 per 1000 patient-years in the non-surgical group), as well as a delay in the occurrence of SUDEP relative to the non-surgical group. In the surgical group, on average, SUDEP occurred 10.1 years after surgery, but in the non-surgical group it occurred an average of 5.9 years after the surgery was discussed, but not performed.

The team also found that there was a reduction in SUDEP occurrence in the first 10 years after surgery, however, this benefit appeared to lessen after this time- period. While a larger study is needed to confirm it, this finding suggests that long-term follow up of epilepsy surgery patients is important even if they are seizure-free after surgery.

This CURE Epilepsy-funded study provides evidence for the beneficial effects of epilepsy surgery in reducing overall mortality including SUDEP. A larger study will be helpful in determining how long the benefit can last and whether there are any factors that can predict who might be at greater risk for SUDEP post-surgery.

*Patient-years is a statistical term used to account for the total time all subjects spend in a study and is a more accurate measure of the rate at which an event, in this case SUDEP, occurs in the study population.

Dr. Lisa Bateman is the Director of Surgical Epilepsy Programs at Cedar Sinai Medical Center. Dr. Catherine Schevon is an Associate Professor of Neurology at Columbia University. 

Literature Cited

[1] Harden C., Tomson T., et. al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017 Apr 25;88(17):1674-1680.

[2] Casadei C.H., Carson K.W., et. al. All-cause mortality and SUDEP in a surgical epilepsy population. Epilepsy & Behavior 2020 Jul;108:107093


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

The Path to a Cure: Improving Genetic-Based Outcomes

Dr. Heather Mefford is a current CURE Grantee who is as dedicated to driving science toward cures for epilepsy as she is to treating people in her clinical practice. As Associate Professor of Pediatrics at the University of Washington and attending physician at Seattle Children’s Hospital, Dr. Mefford is making an impact both in and out of the laboratory.

Severe Pediatric Epilepsy is Often Genetic

Dr. Heather MeffordAs a physician who cares for pediatric patients living with severe epilepsy syndromes, Dr. Mefford has firsthand knowledge of the devastating impacts of seizures in children. These treatment-resistant epilepsy syndromes are usually caused by a genetic mutation and knowing what that mutation is can potentially inform the treatment plan. As such, genetic testing is a critical part of the epilepsy diagnosis and care process. Dr. Mefford describes what genetic testing involves and what kinds of tests are available in an episode of our Seizing Life® podcast. Watch or listen to learn more.

The DNA of Dr. Mefford’s Genetic Research
When not seeing patients, Dr. Mefford heads a research laboratory at the University of Washington. Over the last 10 years, Dr. Mefford’s team has identified many new epilepsy-related genes and mutations. Dr. Mefford’s lab is currently investigating a type of genetic change that does not alter the sequence of the gene itself but instead affects how the gene functions. This field of research, known as epigenetics, is relatively new and now, excitingly, is being applied to epilepsy. For her CURE-funded project, Dr. Mefford is studying a type of epigenetic change called methylation, in people with severe early-onset, treatment-resistant seizure disorders known as developmental and epileptic encephalopathies (DEE). Despite advanced genetic testing, more than 50% of people with DEE still do not have a genetic diagnosis and work like Dr. Mefford’s could ultimately improve the prognosis for children with these epilepsies.

Leading the Next Generation
To support the future of research, Dr. Mefford has helped launch the careers of the next generation of epilepsy scientists. One of her former trainees, Dr. Gemma Carvill, is also making a big impact on the field of epilepsy research. Dr. Carvill was awarded a CURE grant early in her career and now leads her own independent research program at Northwestern University in Chicago, where she also investigates the underlying genetic and epigenetic mechanisms of epilepsy.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

Female psychologist working with boy who has autism and epilepsy.

CURE Discovery: The Connection Between Stress, Autism, and Epilepsy

Key Points:

  • CURE grantee Dr. Daniel Barth and his team worked to determine if autism and epilepsy, which frequently occur together, share common causes and thus can be treated similarly.
  • The team tested if preventing brain inflammation late in pregnancy and the early days of life can treat both conditions in a rat model of epilepsy with autistic-like behaviors, which they had created in a previous study [1].
  • Unexpectedly, they found that the treatment relieved the autistic-like symptoms but had virtually no effect on the development of epilepsy. This surprising result suggests that the two disorders may have distinct underlying causes and should be treated differently.

Deep Dive:

Over 30% of people with epilepsy are also impacted by autism-spectrum disorders (ASD) [2], but the links between these two conditions are not well understood. However, we do know that the two disorders can share the same genetic causes and that they are also associated with common environmental risk factors. With the help of a CURE grant, Dr. Daniel Barth and his team at the University of Colorado worked to understand how two environmental factors might impact the chance of developing epilepsy and ASD. Specifically, they looked at stress late in pregnancy and in the early days of life and exposure to terbutaline, an asthma drug occasionally used to prevent preterm labor. Dr. Barth and his team had previously combined stress and terbutaline to develop a rat model of epilepsy with ASD-like behaviors called the “ST” model [1].

With this model, the researchers set out to tease apart the biology underlying epilepsy and ASD. While both conditions are adversely affected by chronic prenatal stress [3,4], the process by which this stress may influence the development of epilepsy and ASD may not be the same. Indeed, stress is a complex phenomenon that can induce inflammation and increase levels of stress hormones. Because stress [5] and terbutaline [6] are known to independently cause brain inflammation, Dr. Barth and his team first examined the possible benefit of a unique anti-inflammatory treatment [7] to prevent epilepsy and ASD. Notably, Dr. Barth’s study was the first to evaluate use of this treatment to prevent stress-induced inflammation early in development, when the growth of a rat’s brain is rapid but also extremely vulnerable to environmental risk factors.

The team monitored seizure activity and ASD-like behaviors, the latter of which were assessed with procedures designed to mimic the human symptoms of repetitive behavior, anxiety, and poor social interactions, in the rats during the first few months of life. Among rat pups that received the anti-inflammatory treatment, there was an increase in the density of the brain’s immune cells and in the levels of a specific protein known as IL-10, both of which reflect an anti-inflammatory response. In contrast to the strong anti-inflammatory response, however, the pups did not have a significant hormonal response, which was reflected in practically no change in the levels of two stress hormones. As predicted, blocking the inflammatory response prevented the development of ASD-like behaviors but, unexpectedly, it did nothing to prevent the onset of epilepsy [8].

Despite this unanticipated result, Dr. Barth’s work is still extremely valuable. In addition to providing a promising treatment for environmentally induced ASD, the findings show that the factors that cause ASD and epilepsy, disorders which are often thought to share the same underlying pathology, can be separated. These findings have also helped Dr. Barth and his team formulate alternative ideas about the development of epilepsy in their ST model. Indeed, as a result of critical CURE funding, they are starting to explore hormonal influences on epilepsy in their model.

Literature Cited

  1. Bercum, F.M. et al. Maternal stress combined with terbutaline leads to comorbid autistic-like behavior and epilepsy in a rat model. J. Neurosci. 2015; 35(48): 15894-15902.
  2. Spence, S. and Schneider, M. The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr. Res. 2009; 65(6): 599-606.
  3. Beversdorf, D.Q. et al. Prenatal stress, maternal immune dysregulation, and their association with autism spectrum disorders. Curr. Psychiatry Rep. 2018; 20(9): 76.
  4. Van Campen, J.S. et al. Early life stress in epilepsy: a seizure precipitant and risk factor for epileptogenesis. Epilepsy Behav. 2014; 38: 160-171.
  5. Calcia, M.A. et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology 2016; 233: 1637-1650.
  6. Zerrate, M.C. et al. Neuroinflammation and beghavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism. J. Pharmacol. Exp. Ther. 2007; 322(1): 16-22.
  7. Reber, S.O. et al. Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc. Natl. Acad. Sci USA 2016; 113(22): E3130-E3139.
  8. Smith, Z.Z. et al. Effects of immunization with heat-killed Mycobacterium vaccae on autism disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy. Brain Behav. Immun. 2020; 88: 763-780.

 


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

CURE Discovery: Temporal Lobe Epilepsy and Memory Impairment

Key Points

Picture of the researcher

  • CURE Taking Flight grantee, Dr. Tristan Shuman and his team, in collaboration with two other research groups, used a mouse model of temporal lobe epilepsy (TLE) to examine how chronic epilepsy leads to cognitive and memory deficits.
  • The team developed innovative research tools, including a wireless miniature microscope that can “see” into the brain and analyze the exact firing patterns brain cells use to communicate with each other.
  • The team found that disrupting these firing patterns plays an important role in the development of memory deficits. Restoring these firing patterns may someday provide relief from the memory deficits and cognitive delays that accompany TLE.

Deep Dive

Temporal lobe epilepsy (TLE), which occurs in the temporal lobe of the brain, is the most common type of focal epilepsy.1,2 Unfortunately, people with TLE also often experience disabling cognitive and memory impairments.1 With support from a CURE Taking Flight award, Dr. Tristan Shuman and his team may have discovered a possible cause for these debilitating symptoms. His team at the Icahn School of Medicine at Mount Sinai in New York collaborated with Dr. Peyman Golshani’s laboratory at the University of California, Los Angeles. Together, they examined how two small areas of the brain that play key roles in memory and learning share information between each other to explore possible origins of the cognitive and memory deficits that develop in people with chronic epilepsy.

HippocampusThe temporal lobe of the brain contains a region called the hippocampus which plays a vital role in regulating learning, memory, and spatial navigation.3 Dr. Shuman and his team focused on two subregions of the hippocampus important in spatial navigation: the dentate gyrus (DG) and the CA1. Spatial information from other areas in the brain enters through the DG and leaves through the CA1.3 Dr. Shuman aimed to understand if disrupting this input/output circuit contributed to the cognitive and memory deficits observed in mice with TLE.

To study the interactions between the neurons in the DG and CA1, Dr. Shuman and colleagues first developed novel tools which enabled them to make their initial findings. They determined that in mice with chronic epilepsy, electrical impulses moving between neurons in the DG and CA1 were disrupted, indicating that these two regions were not able to process spatial information.

Hippocampus

The researchers then examined how each individual neuron fired as the mice ran along a track. To accomplish this, the mice were fitted with a wireless, mouse-sized mini microscope, created by Dr. Shuman and his collaborators, that can “see” into the brain and record the activity of hundreds of neurons. They discovered that in the brains of mice with epilepsy, the number of place cells, a specific type of CA1 neuron that gathers and relays information about the position of objects in space, was reduced when compared to normal mice. In normal mice, these place cells were stable and active in the same location every day that the animals ran on the track. However, in the mice with TLE, the place cells changed their firing patterns every few minutes, indicating that the mice could not remember their location.

To further his research, Dr. Shuman collaborated with Dr. Panayiota Poirazi at the Foundation for Research and Technology Hellas in Greece to confirm his findings using a computer model. Using this approach, the team confirmed that by changing the timing of electrical inputs into the hippocampus, they could disrupt processing of spatial information.

Understanding how individual neuronal circuits are disturbed in epilepsy is a first step in creating future therapies to target disrupted firing patterns in people with epilepsy. By continuing to explore this promising avenue of research, scientists may one day be able to design therapeutic interventions that restore neuronal firing patterns, reducing seizures and improving cognitive function for people with chronic epilepsy.

Literature Cited

1Bell, B. et al. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev. Neurol. 2011; 7(3): 154-164.
2 Téllez-Zenteno, J.F. & Hernández-Ronquillo, L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res. Treat. 2012; 2012: 630853.
3 Saniya, K. et al. Neuroanatomical changes in brain structures related to cognition in epilepsy: an update. J. Nat. Sci. Biol. Med. 2017; 8(2): 139-143.

The Path to a Cure: An Update on Genetic Research

Dr. Gemma Carvill, a former CURE Grantee who is a leader in epilepsy genetic research, was awarded a Taking Flight Award in 2015, early in her career. This grant aims to encourage young investigators to conduct independent research and blossom in the field of epilepsy. Her intriguing study explored how genetic mutations can cause epilepsy to develop, particularly a group of severe, treatment-resistant childhood epilepsy syndromes called “epileptic encephalopathy”.

Since receiving her CURE grant, Dr. Carvill’s career has certainly “taken flight”. Today, she heads her own lab at Northwestern University in Chicago, IL, where her team continues to focus on understanding the underlying genetic and epigenetic mechanisms of epilepsy.

We had the chance to catch up with Dr. Carvill during a recently aired episode of our Seizing Life® podcast. Watch or Listen to learn more about epilepsy genetics and Dr. Carvill’s exciting research.

Watch Seizing Life

Taking Flight in Epilepsy Research

2018 DiscoveryIn 2018, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital in creating an international study on epilepsy genetics. Together, they identified a new cause of epilepsyde novo mutations (genetic mutations existing only in affected patients and not in their parents) in the CUX2 gene.1 CUX2 is a protein that activates (turns on) or suppresses (turns off) other genes, and specifically regulates genes involved in establishing connections between nerve cells.

Because of Drs. Carvill and Lesca’s collaboration, this genetic cause of epilepsy can now be targeted for the development of potential therapeutic interventions.

A “Crazy Idea” to Transform Clinical Care

Dr. CarvillDr. Carvill is continuing her important work with the help of a New Innovator Award from the National Institute of Health (NIH). In her own words, this award is granted to researchers with “a completely crazy idea that, if it pans out, could really transform clinical care for patients.” Her lab is examining if cell-free DNA (short fragments of DNA released when a cell dies and bursts open) found in plasma can be used as a biomarker of epilepsy.

A big challenge in diagnosing and treating epilepsy is that we only have one reliable biomarker; structural abnormalities in the brain. While widely used, EEG testing can fail to capture seizure data. Dr. Carvill’s work may lead to a new way to identify when patients have had seizures.

Hear more about this innovative work from Dr. Carvill on this episode of the Seizing Life® podcast and learn more about how discoveries in the lab are translated into improved patient care.

Literature Cited

1Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol 2018; 6

Two doctors, a man and a woman, in blue scrubs look at a brain scan.

CURE Discovery: Inhibition of an Important Brain Enzyme Attenuates the Development of Epilepsy

In his CURE-funded research, Dr. Detlev Boison and his team found that an adenosine kinase inhibitor called 5-ITU increases adenosine levels in the brain, protecting it from seizures.

Key Points

Dr. Detlev Boison

  • CURE Grantee Dr. Detlev Boison and his team discovered that short-term use of a substance called 5-ITU prevents epilepsy from developing in mouse models of acquired epilepsy.
  • 5-ITU inhibits a brain enzyme called adenosine kinase (ADK) that regulates a substance called adenosine (ADO), which, in turn, plays a critical role in preventing epilepsy following an injury to the brain.
  • Dr. Boison’s groundbreaking work supports the development of improved, more selective treatments which aim to cure underlying causes of epilepsy, rather than merely control seizures.

Deep Dive

A graphic which illustrates the relationship between adenosine and adenosine kisase.One of the most common ways of developing epilepsy is through “acquired” means, such as a severe concussion, brain infection, fever-induced seizure, or stroke. A naturally occurring substance in the brain, called adenosine (ADO), plays a protective role by decreasing excessive neuronal activity1,2 and protecting the DNA in nerve cells from changes that contribute to the development of epilepsy.3 ADO levels in the brain are regulated by an enzyme called adenosine kinase (ADK) and, unfortunately, brain injuries often trigger a series of events that elevate levels of ADK. In his CURE-funded research, Dr. Detlev Boison and his team found that an ADK inhibitor called 5-ITU increases ADO levels in the brain and protects it from seizures.

To make this discovery, the team evaluated if short-term treatment of 5-ITU following an injury to the brain could halt the development of epilepsy over the long-term.4 To do so, they used a mouse model of acquired epilepsy that reliably develops seizures two weeks after an injury. The team first had to determine the appropriate time points to administer 5-ITU following a head injury. Over a two-week period, the team monitored the progression of brain tissue damage in their mouse model, along with ADK levels and changes in EEG, analyzing samples at different days post-injury compared to controls. The team found that by the third day, ADK levels had started to increase and continued to increase over the two-week time period, accompanied by a loss of neurons in an area of the brain called the hippocampus and changes in EEG patterns by the fourteenth day post-injury.

Reasoning that 5-ITU should first be administered when ADK levels initially rise, the team gave their mouse model the substance for a limited time – for only five days starting on day 3 post-injury – and continued to monitor the mice closely. After six weeks, the team found that the 5-ITU-treated mice had little brain tissue damage, significantly decreased ADK levels, and fewer seizures compared to the control group. Importantly, these changes were sustained even after nine weeks.

Discovering that short-term inhibition of ADK leads to a long-lasting antiepileptogenic effect makes this a promising therapy, especially since it could avoid any potential toxicities and intolerable side effects from long-term use of ADK inhibitors. Such a treatment would represent a true cure for epilepsy. Dr. Boison’s groundbreaking research supports the development of improved, more selective compounds which can one day be tested in clinical trials and, hopefully, approved for clinical use.

Dr. Boison’s Research Continues

For more than 20 years CURE has been on an unrelenting mission to end epilepsy. We have funded more than 240 grants in 15 countries to better understand the causes of epilepsy, uncover new therapies, and cure epilepsy once and for all. Now it is time to take those research findings one step further.

We are thrilled to expand our current research approach with the CURE Catalyst award, and to name Dr. Boison the first grantee under this new mechanism. This grant funds translational research, where findings from basic research studies are “translated” into the next phase of research to prepare potential new treatments for clinical trials. You can learn about the continuation of Dr. Boison’s work here.

1 Fedele, D.E. et al. Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci. Lett. 2004; 370(2-3) 160-165.
2 Guttinger, M. et al. Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants. Epilepsia 2005 46(8): 1162-1169.
3 Williams-Karnesky, R.L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epilpetogenesis. J. Clin. Invest. 2013; 123(8): 3552-3563
4 Sandau, U.S. et al. Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice. Epilepsia 2019; 60: 615-625.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond, thanks to generous donors who, like us, envision a world without epilepsy.

CURE Initiative: Defending Against Post-Traumatic Epilepsy

A graphic which states, "CURE and the Department of Defense. From 2000-2019, over 400,000 US service members were diagnosed with a TBI."Post-traumatic epilepsy (PTE) is a seizure disorder resulting from injury to the brain. It is a devastating complication of traumatic brain injury (TBI), which can occur as a result of car accidents, sports-related injuries, or military combat. PTE can develop weeks, months, or even years after TBI, offering a window of opportunity for interventions to prevent seizures. Unfortunately, there is currently no way to predict who will develop epilepsy following TBI, and there are no therapies to prevent it.

CURE’s collaborative, multi-investigator PTE research program aims to develop better models to study PTE and discover methods to predict who is at risk as a way to intervene early and prevent PTE. With a $10 million grant from the US Department of Defense, this initiative brings together leading scientists in the field from around the world. This groundbreaking initiative, which launched in 2018, involves six primary investigators and their research teams for a total of over 60 scientists. To further encourage collaboration and scientific rigor, CURE has contracted with the Laboratory of Neuro Imaging (LONI) at the University of Southern California to create a database to house data from the teams and make it accessible for cross-comparison and analysis.

These teams are enhancing knowledge about PTE by researching what changes occur in the brain, as well as by developing robust animal models to study PTE. In addition, the researchers are investigating how different types of head injury can contribute to seizure onset and occurrence, and they are identifying potential EEG, MRI, or blood biomarkers to predict PTE in humans.

One exciting, ongoing PTE project is led by Dr. Jeffrey Loeb of the University of Illinois at Chicago. Dr. Loeb’s team project will focus on a type of bleeding commonly caused by TBI called subarachnoid hemorrhage. This kind of bleeding occurs when there is blood between the brain and the protective tissue surrounding the brain. By studying both rat models and in-patient instances of subarachnoid hemorrhage, Dr. Loeb’s data-driven approach will hopefully lead to methods or guidelines to help doctors take steps to prevent the development of epilepsy. Check out our recent interview with him to learn more.

We’ve also seen significant achievements over the course of the past two years. These includes a publication from Dr. Harald Sontheimer’s team at Virginia Tech University on a new mouse model for PTE,1 and a manuscript in preparation by Dr. Victoria Johnson’s team at the University of Pennsylvania on neuropathology in humans after TBI. The investigators have presented abstracts of their work at scientific meetings including the 2019 National Neurotrauma Society meeting in Pittsburgh, PA and the 2019 American Epilepsy Society Meeting in Baltimore, MD.

This collaborative, team-science approach has the potential to develop innovative ways to study PTE, build understanding of the neural mechanisms behind PTE, and ultimately help us understand who is at the greatest risk. This research can pave the way for the development of therapies to prevent and/or treat PTE, having a positive impact on the lives of all affected by TBI and PTE.

1 Shandra O., Robel S. Inducing Post-Traumatic Epilepsy in a Mouse Model of Repetitive Diffuse Traumatic Brain Injury. J Vis Exp. 2020 Feb 10;(156)

Learn More about PTE

Mike and Kim Adamle smiling as they are being interviewed for an episode of Seizing Life, a CURE podcast

Podcast: Former football star and broadcaster Mike Adamle discusses developing and managing PTE resulting from sports injuries.

Watch or Listen Now

Woman sitting at a laptop participating in a CURE webinar.

Webinar: Watch a free webinar on what triggers seizures in people who sustain traumatic brain injury.

Watch Now

Dr. Graffman being interviewed by Kelly Cervantes, CURE Board Member and Seizing Life podcast host.

Podcast: Explore the relationship between TBI and PTE, particularly in Vietnam veterans, in this Seizing Life podcast episode.

Watch or Listen Now

Woman standing in a research lab wearing a white coat with her back to the camera.

CURE Discovery: Discover the results of an innovative CURE-funded study aiming to find a way to prevent PTE.

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