Research Summary

The long-term goal of the Auerbach Laboratory is to investigate the prevalence, risk factors, and mechanisms for dual electrical disturbances of the brain (seizures) and heart (arrhythmias). We are particularly interested in improving our understanding of the multi-system cascade of events that lead to Sudden Unexpected Death in Epilepsy Patients (SUDEP), which will hopefully identify markers for SUDEP.

Bedside-to-Bench-to-Bedside Approach: We take a multi-system (brain & heart) and multi-scale (molecular, biochemical, cellular, organ, in vivo, and clinical) approach to investigating electrical diseases of the brain and heart. We perform patient database analyses to examine the co-prevalence and risk of seizures and arrhythmias. Then using cellular and animal models of the disease we perform molecular/biochemical and electrophysiological approaches to understand the underlying mechanisms for these neuro-cardiac pathologies. Ultimately, these results are validated using patient databases, and thus complete the full bedside-to-bench-to-bedside paradigm.

Bedside to Bench to Bedside Research Approach

Multi-System Approach to Understanding and Treating Genetic Ion Channel Diseases: The Auerbach Lab’s “Bedside-to-Bench-to-Bedside” approach to research involves clinical studies of humans with a history of electrical disturbances in the brain (seizures/epilepsy) and heart (arrhythmias). Additionally, we generated a genetic rabbit model of an inherited cardiac arrhythmia disease. It enables us to explore the underlying causes for these abnormalities by performing experiments at the molecular, biochemical, cellular, and whole animal levels. Each aspect of the research program feeds and motivates the others, creating a productive research cycle.

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Clinical Research Projects (Retrospective Datasets & Prospective Recordings from Wearable Sensors)

Millions of Americans have epilepsy and they are at a high risk of sudden death (e.g., SUDEP.) Unfortunately, the underlying mechanisms remain unknown.

As cardiac events are one mechanism for SUDEP, we are starting with the heart. In genetic models of epilepsy, we showed it is critical to look outside the brain, as these mutations lead to alterations in cardiac electrical function, which include altered ion channel activity, hyperexcitability, and arrhythmias.

Following a bench-to-bedside paradigm, we reported cases of cardiac ECG abnormalities and near-lethal arrhythmias in patients with severe genetic forms of epilepsy. We use analytical tools that are well accepted in the field of cardiology, but new to epilepsy and SUDEP, to identify epilepsy patient populations at risk of cardiac-related SUDEP. Additionally, we use wearable technology to acquire continuous multi-system recordings, which enables us to capture events outside the hospital. The goal is to develop a comprehensive SUDEP risk assessment tool to help identify people with epilepsy who are at risk for SUDEP, so that measures can be put in place to prevent SUDEP from occurring.

SUDEP

Clinical Database Studies: Data is collected from patients during interictal baseline periods, and surrounding seizures. The Auerbach Lab studies the patients’ ECG during these time periods in hopes of identifying cardiac biomarkers for SUDEP risk.

Basic Science Projects (Cellular and Animal Models of Long QT Syndrome)

Percent of participants with seizures graph

Starting at the patient level, we demonstrated that patients with a classically studied inherited cardiac arrhythmia disease, Long QT Syndrome (LQTS), are at an increased risk of seizures. Yet, the underlying cause for these seizures remains unknown. We developed a novel mutant rabbit model of LQTS, which reproduces the neuro-cardiac pathologies seen in LQTS patients. It enables us to conduct translational studies to investigate the mechanisms for arrhythmias and seizures in LQTS. Ongoing experimental approaches are at the molecular, biochemical, cellular electrophysiology, organ, and in vivo levels.

Long QT Syndrome: We showed that there is a higher prevalence of a history of seizures/epilepsy in patients with an inherited cardiac arrhythmias disease, Long QT syndrome, compared to their genotype negative family members. Patients with Long QT Syndrome Type 2 showed the highest prevalence of seizures.

basic science image

Rabbit Model of Long QT Syndrome Type 2: The Auerbach Lab has developed multiple mutant rabbit lines that model the neuro-cardiac electrical abnormalities seen in patients with Long QT Syndrome Type 2. Video/EEG/ECG recordings, as well as respiratory measures, are recorded from the rabbits to validate the model and examine the underlying mechanisms.

EEG/ECG Recordings of Rabbits: Using a clinical grade EEG acquisition device, the Auerbach Lab records continuous EEG/ECG recordings from up to 7 rabbits simultaneously.

Publications

Recent Publications

*Corresponding Author, ^₶Co-First Author

Ryan JM^₶, Wagner KT^₶, Yerram S, Concannon C, Lin JX, Rooney P, Hanrahan B, Titoff V, Connolly N, Cranmer R, DeMaria N, Xia X, Mykins B, Erickson S, Couderc JP, Schifitto G, Hughes I, Wang D, Erba G, Auerbach DS*. Heart rate and autonomic biomarkers distinguish convulsive epileptic vs. functional or dissociative seizures. Seizure: European Journal of Epilepsy, 2023, ISSN 1059-1311, https://doi.org/10.1016/j.seizure.2023.08.015
Singh V^₶, Ryan JM^₶, Auerbach DS*, It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade. Epilepsia, 2023. https://doi.org/10.1111/epi.17636
Sanchez-Conde FG, Jimenez-Vazquez EN, Auerbach DS*, Jones DK*. The ERG1 K⁺ Channel and Its Role in Neuronal Health and Disease. Frontiers in Molecular Neuroscience. 2022 May 3. doi: 3389/fnmol.2022.890368
Auerbach DS*, Muniz CF. [Editorial] Cardiac Safety of Lamotrigine: Still Awaiting a Verdict. Neurology. 2022 Mar 8, doi: 1212/WNL.0000000000200189
Toth J, Waickman A, Jost J, Seltzer L, Vinocur JM, Auerbach DS*. Identification and Successful Management of Near-Lethal Ventricular Tachycardia in 2q24 Deletion-Associated Developmental and Epileptic Encephalopathy. Seizure June 2021 doi: 1016/j.seizure.2021.06.003
Bosinski C, Wagner K, Zhou, X., Liu, L., Auerbach DS*. Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits. Vis. Exp.2021 Mar 27;(169), doi: 10.3791/62256 PMID: 33843929.
French JA, Perucca E, Sander J, Bergfeldt L, Baulac M, Auerbach DS, Keezer M, Thijs R, Devinsky O, Vossler D, WeltyT. FDA Safety Warning on the Cardiac Effects of Lamotrigine: An Advisory from the Ad Hoc ILAE/AES Task Force. Epilepsia Open 2021 Feb 25 doi: 1002/epi4.12475
French JA, Perucca E, Sander J, Bergfeldt L, Baulac M, Auerbach DS, Keezer M, Thijs R, Devinsky O, Vossler D, Welty T. FDA Safety Warning on the Cardiac Effects of Lamotrigine: An Advisory from the Ad Hoc ILAE/AES Task Force. Epilepsy Currents 2021 March Vol 6 (1) 45-48 doi:1177/1535759721996344 PMID: 33641454.
Kim BS^₶, Auerbach DS^₶, Sadhra H, Ling FS, Godwin M, Mohan A, Yule DI, Wagner L, Rich DQ, Tura S, Morrell C, Goldenberg I, Cameron SJ. A Sex-Specific Switch in Platelet Protease-Activated Receptor Signaling Following Myocardial Infarction. Arterioscler Thromb Vasc Biol. 2020 Nov 12 PMID: 33176447PMCID: PMC7770120.
DeMaria N, Selmi A, Kashtan S, Xia X, Wang M, Zareba W, Couderc JP, Auerbach DS^*. Autonomic and Cardiac Repolarization Lability in Long QT Syndrome. Autonomic Neuroscience: Basic & Clinical. Epub 2020 Sep 6. PMID:32942226 PMCID: PMC7704776.
Tylock K, Auerbach DS, Tang ZZ, Thornton C, Dirksen RT. Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat RNA. J. Gen. Physiol. 2020 152 (2): e201912450, PMCID: PMC7062505. PMID: 31968060
Frasier CR, Zhang H, Offord J, Dang LT, Auerbach DS, Shi H, Chen C, Goldman AM, Eckhardt LL, Bezzerides VJ, Parent JM, Isom LL. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes. Stem Cell Reports. 2018. Sep 11;11(3):626-634. doi: 10.1016/j.stemcr.2018.07.012. Epub 2018 Aug 23. PMID: 30146492; PMCID: PMC6135724. Epub 2018/08/28.
Wang M, Szepietowska B, Polonsky B, McNitt S, Moss AJ, Zareba W, Auerbach DS. Risk of Cardiac Events Associated With Antidepressant Therapy in Patients With Long QT Syndrome. Am J Cardiol. 2018 Jan 15;121(2):182-187. PubMed PMID: 29174490; PMCID: PMC5742310.
Auerbach DS*, Biton Y, Polonsky B, McNitt S, Gross RA, Dirksen RT, Moss AJ. Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications. Transl Res. 2018 Jan;191:81-92.e7. PubMed PMID: 29121487; PMCID: PMC5733703.
Bao Y, Willis BC, Frasier CR, Lopez-Santiago LF, Lin X, Ramos-Mondragón R, Auerbach DS, Chen C, Wang Z, Anumonwo J, Valdivia HH, Delmar M, Jalife J, Isom LL. Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. Circ Arrhythm Electrophysiol. 2016 Dec;9(12)PubMed PMID: 27932425; PMCID: PMC5161227
Carrell ST, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, Thornton CA. Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice. Hum Mol Genet. 2016 Aug 13;PubMed PMID: 27522499. PMCID: PMC5291200
Auerbach DS*, McNitt S, Gross RA, Zareba W, Dirksen RT, Moss AJ. Genetic biomarkers for the risk of seizures in long QT syndrome. Neurology. 2016 Oct 18;87(16):1660-1668. PubMed PMID: 27466471; PMCID: PMC5085072.

Complete List of Published Work

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